Trial Outcomes & Findings for Ibrutinib With Rituximab in Adults With Waldenström's Macroglobulinemia (NCT NCT02165397)

NCT ID: NCT02165397

Last Updated: 2021-03-03

Results Overview

PFS was defined as the time from date randomization to date of first IRC-confirmed disease progression (PD) assessed according to the modified VIth International Workshop on Waldenström's Macroglobulinemia (IWWM) criteria (National Comprehensive Cancer Network \[NCCN\] 2014) or death due to any cause, whichever occurs first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. As the median PFS was not reached in the Ibrutinib + Rituximab arm at the time of the analysis, Kaplan Meier landmark estimate of the PFS rate at 54 months (that is, the estimated percentage of participants with PFS at Month 54) is presented.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 181 participants
• Primary outcome timeframe: Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr])
• Results posted on: 2021-03-03

Participant Flow

This study was conducted in 48 sites (10 in the United States, 30 in Europe, 4 in Canada and 4 in Australia).

Participants were randomized in a 1:1 ratio to receive ibrutinib + rituximab (Ibr+R) or placebo + rituximab (Pbo+R). Separately, participants refractory to treatment with rituximab were enrolled in an open-label ibrutinib monotherapy substudy to further investigate the safety and efficacy of ibrutinib.

Participant milestones

Measure	Ibrutinib + Rituximab Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m\^2 intravenous (IV) per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Placebo + Rituximab Placebo: 3 capsules of placebo orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m\^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Open-Label Substudy: Ibrutinib Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Participants (rituximab refractory) were treated in an open-label substudy independently of the 2 randomized main treatment arms.
Overall Study STARTED	75	75	31
Overall Study COMPLETED	61	56	21
Overall Study NOT COMPLETED	14	19	10

Reasons for withdrawal

Measure	Ibrutinib + Rituximab Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m\^2 intravenous (IV) per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Placebo + Rituximab Placebo: 3 capsules of placebo orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m\^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Open-Label Substudy: Ibrutinib Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Participants (rituximab refractory) were treated in an open-label substudy independently of the 2 randomized main treatment arms.
Overall Study Death	7	10	8
Overall Study Lost to Follow-up	1	3	0
Overall Study Withdrawal by Subject	6	6	1
Overall Study Other, Not Specified	0	0	1

Baseline Characteristics

Ibrutinib With Rituximab in Adults With Waldenström's Macroglobulinemia

Baseline characteristics by cohort

Measure	Ibrutinib + Rituximab n=75 Participants Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m\^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Placebo + Rituximab n=75 Participants Placebo: 3 capsules of placebo orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m\^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Open-Label Substudy: Ibrutinib n=31 Participants Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Participants (rituximab refractory) were treated in an open-label substudy independently of the 2 randomized main treatment arms.	Total n=181 Participants Total of all reporting groups
Age, Customized < 65 years old	28 Participants n=5 Participants	30 Participants n=7 Participants	14 Participants n=5 Participants	72 Participants n=4 Participants
Age, Customized >= 65 years old	47 Participants n=5 Participants	45 Participants n=7 Participants	17 Participants n=5 Participants	109 Participants n=4 Participants
Sex: Female, Male Female	30 Participants n=5 Participants	21 Participants n=7 Participants	11 Participants n=5 Participants	62 Participants n=4 Participants
Sex: Female, Male Male	45 Participants n=5 Participants	54 Participants n=7 Participants	20 Participants n=5 Participants	119 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	5 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	72 Participants n=5 Participants	74 Participants n=7 Participants	30 Participants n=5 Participants	176 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	3 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	5 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) White	58 Participants n=5 Participants	60 Participants n=7 Participants	26 Participants n=5 Participants	144 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	13 Participants n=5 Participants	14 Participants n=7 Participants	3 Participants n=5 Participants	30 Participants n=4 Participants

PRIMARY outcome

Timeframe: Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr])

Population: Intent to Treat population: all randomized/enrolled participants

PFS was defined as the time from date randomization to date of first IRC-confirmed disease progression (PD) assessed according to the modified VIth International Workshop on Waldenström's Macroglobulinemia (IWWM) criteria (National Comprehensive Cancer Network [NCCN] 2014) or death due to any cause, whichever occurs first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death.

As the median PFS was not reached in the Ibrutinib + Rituximab arm at the time of the analysis, Kaplan Meier landmark estimate of the PFS rate at 54 months (that is, the estimated percentage of participants with PFS at Month 54) is presented.

Outcome measures

Measure	Ibrutinib + Rituximab n=75 Participants Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m\^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Placebo + Rituximab n=75 Participants Placebo: 3 capsules of placebo orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m\^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Open-Label Substudy: Ibrutinib n=31 Participants Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Participants (rituximab refractory) were treated in an open-label substudy independently of the 2 randomized main treatment arms.
Progression Free Survival (PFS) Based on Independent Review Committee (IRC) Assessment - Kaplan Meier Landmark Estimates at Month 54	68.0 percentage of participants Interval 54.8 to 78.1	25.3 percentage of participants Interval 15.3 to 36.6	39.7 percentage of participants Interval 22.3 to 56.7

SECONDARY outcome

Timeframe: Median time on study: 49.7 months (Ibr+R and Pbo+R) and 57.9 months (Open-Label Ibr)

Population: Intent to Treat population: all randomized/enrolled participants

ORR, defined as the percentage of participants achieving a best overall response of protocol-specified complete response (CR), very good partial response (VGPR), or partial response (PR) per the IRC assessment at or prior to initiation of subsequent antineoplastic therapy and confirmed by 2 consecutive assessments. IRC assessment of response was conducted according to the modified VIth IWWM (NCCN 2014) criteria and incorporated assessments from the central radiology review. CR required complete resolution of lymphadenopathy/splenomegaly if present at baseline. VGPR and PR required reduction in lymphadenopathy/splenomegaly if present at baseline.. Kaplan-Meier estimate.

Outcome measures

Measure	Ibrutinib + Rituximab n=75 Participants Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m\^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Placebo + Rituximab n=75 Participants Placebo: 3 capsules of placebo orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m\^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Open-Label Substudy: Ibrutinib n=31 Participants Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Participants (rituximab refractory) were treated in an open-label substudy independently of the 2 randomized main treatment arms.
Overall Response Rate (ORR) Based on IRC Assessment Up to 3 Years After Last Participant Randomized	76.0 percentage of participants	30.7 percentage of participants	77.4 percentage of participants

SECONDARY outcome

Timeframe: Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr])

Population: Intent to Treat population: all randomized/enrolled participants

TTnT was measured from the date of randomization to the start date of any subsequent WM treatment. Participants without subsequent treatment were censored at the date of the last study visit.

As the median TTnT was not reached in the Ibrutinib + Rituximab arm and the Open-Label Substudy arm at the time of the analysis, Kaplan Meier landmark estimate of the TTnT rate at 54 months (that is, the estimated percentage of participants not receiving subsequent WM treatment at Month 54) are presented.

Outcome measures

Measure	Ibrutinib + Rituximab n=75 Participants Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m\^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Placebo + Rituximab n=75 Participants Placebo: 3 capsules of placebo orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m\^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Open-Label Substudy: Ibrutinib n=31 Participants Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Participants (rituximab refractory) were treated in an open-label substudy independently of the 2 randomized main treatment arms.
Time to Next Treatment (TnT) Time From the Date of Randomization to the Start Date of Any Subsequent WM Treatment.	87.4 percentage of participants Interval 77.2 to 93.3	29.4 percentage of participants Interval 18.2 to 41.6	64.6 percentage of participants Interval 44.1 to 79.2

SECONDARY outcome

Timeframe: Median time on study: 49.7 months (Ibr+R and Pbo+R) and 57.9 months (Open-Label Ibr)

Population: Intent to Treat population: all randomized/enrolled participants

Percentage of participants achieving a sustained improvement in Hgb at or prior to initiation of subsequent antineoplastic therapy. Hgb improvement is defined as an increase of ≥ 2 g/dL over baseline regardless of baseline value, or an increase to >11 g/dL with a ≥0.5 g/dL improvement if baseline is ≤ 11 g/dL. Sustained Hgb improvement is defined as improvement that is sustained continuously for ≥ 56 days (8 weeks) without blood transfusion or growth factors, which includes hemoglobin > 110 g/L with at least a 5 g/L improvement if baseline ≤110 g/L or increase ≥20 g/L over baseline.

Outcome measures

Measure	Ibrutinib + Rituximab n=75 Participants Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m\^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Placebo + Rituximab n=75 Participants Placebo: 3 capsules of placebo orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m\^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Open-Label Substudy: Ibrutinib n=31 Participants Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Participants (rituximab refractory) were treated in an open-label substudy independently of the 2 randomized main treatment arms.
Percentage of Participants With Sustained Hemoglobin (Hgb) Improvement Up to 3 Years After Last Participant Randomized	77.3 percentage of participants	42.7 percentage of participants	71.0 percentage of participants

SECONDARY outcome

Timeframe: Baseline, 25 weeks

Population: Intent to Treat population: all randomized/enrolled participants

Percentage of participants with ≥ 3 points increase from baseline by Week 25 in the FACIT-Fatigue subscale score.The FACIT-Fatigue is a 13-item questionnaire that assesses participant reported fatigue and its impact upon daily activities and function over the past 7 days. Each of the 13 items of the FACIT-Fatigue Scale ranges from 0-4, with a range of possible total scores from 0 (extreme fatigue) to 52 (no fatigue). Scores below 30 indicate severe fatigue.

Outcome measures

Measure	Ibrutinib + Rituximab n=75 Participants Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m\^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Placebo + Rituximab n=75 Participants Placebo: 3 capsules of placebo orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m\^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Open-Label Substudy: Ibrutinib n=31 Participants Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Participants (rituximab refractory) were treated in an open-label substudy independently of the 2 randomized main treatment arms.
Percentage of Participants With ≥ 3 Points Increase From Baseline by Week 25 in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Subscale Score	68.0 percentage of participants	54.7 percentage of participants	87.1 percentage of participants

SECONDARY outcome

Timeframe: Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr])

Population: Intent to Treat population: all randomized/enrolled participants

OS, defined as the time from the date of randomization to the date of death from any cause. All deaths observed as the time of the analysis were considered as events. For participants who were not known to have died at the time of the analysis, OS data were censored at the date last known alive.

As the median OS was not reached in any treatment arm at the time of the analysis, Kaplan Meier point estimates of the OS rate (that is, the estimated percentage of participants still surviving at Month 54) are presented.

Outcome measures

Measure	Ibrutinib + Rituximab n=75 Participants Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m\^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Placebo + Rituximab n=75 Participants Placebo: 3 capsules of placebo orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m\^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Open-Label Substudy: Ibrutinib n=31 Participants Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Participants (rituximab refractory) were treated in an open-label substudy independently of the 2 randomized main treatment arms.
Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 54	86.4 percentage of participants Interval 73.7 to 93.3	84.2 percentage of participants Interval 71.3 to 91.6	73.4 percentage of participants Interval 53.7 to 85.7

Adverse Events

Ibrutinib + Rituximab

Serious events: 40 serious events

Other events: 75 other events

Deaths: 9 deaths

Placebo + Rituximab

Serious events: 25 serious events

Other events: 75 other events

Deaths: 10 deaths

Open-Label Substudy: Ibrutinib

Serious events: 16 serious events

Other events: 30 other events

Deaths: 8 deaths

Serious adverse events

Measure	Ibrutinib + Rituximab n=75 participants at risk Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m\^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Placebo + Rituximab n=75 participants at risk Placebo: 3 capsules of placebo orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m\^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Open-Label Substudy: Ibrutinib n=31 participants at risk Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment.
Blood and lymphatic system disorders Anaemia	2.7% 2/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	3.2% 1/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Blood and lymphatic system disorders Immune thrombocytopenic purpura	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Blood and lymphatic system disorders Leukopenia	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Blood and lymphatic system disorders Neutropenia	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	3.2% 1/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	3.2% 1/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Cardiac disorders Angina pectoris	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Cardiac disorders Angina unstable	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Cardiac disorders Atrial fibrillation	10.7% 8/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Cardiac disorders Cardiac failure	2.7% 2/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Cardiac disorders Cardiac tamponade	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Cardiac disorders Coronary artery disease	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Cardiac disorders Left ventricular failure	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Cardiac disorders Myocardial infarction	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Cardiac disorders Myocardial ischaemia	2.7% 2/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Cardiac disorders Pericarditis	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Cardiac disorders Prinzmetal angina	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Congenital, familial and genetic disorders Hypertrophic cardiomyopathy	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Eye disorders Ulcerative keratitis	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Gastrointestinal disorders Abdominal pain	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	3.2% 1/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Gastrointestinal disorders Constipation	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	3.2% 1/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Gastrointestinal disorders Diarrhoea	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	3.2% 1/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Gastrointestinal disorders Faecalith	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	3.2% 1/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Gastrointestinal disorders Ileus	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	3.2% 1/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Gastrointestinal disorders Melaena	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
General disorders Asthenia	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	3.2% 1/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
General disorders Death	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
General disorders Fatigue	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
General disorders Gait disturbance	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
General disorders General physical health deterioration	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
General disorders Oedema peripheral	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
General disorders Pyrexia	2.7% 2/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Hepatobiliary disorders Cholecystitis	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Hepatobiliary disorders Cholecystitis acute	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	3.2% 1/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Arthritis bacterial	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Atypical pneumonia	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Cellulitis	2.7% 2/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	3.2% 1/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Clostridium difficile colitis	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Enterococcal sepsis	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Erysipelas	2.7% 2/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Escherichia sepsis	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	3.2% 1/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Gastroenteritis	2.7% 2/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Hemianopia	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	3.2% 1/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Orchitis	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	3.2% 1/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Osteomyelitis	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Pneumonia	10.7% 8/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	2.7% 2/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	3.2% 1/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Pneumonia bacterial	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Pneumonia pneumococcal	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Pneumonia viral	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Prostatic abscess	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	3.2% 1/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Pulmonary sepsis	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Respiratory syncytial virus infection	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Respiratory tract infection	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	3.2% 1/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Sepsis	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Septic shock	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Staphylococcal bacteraemia	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Staphylococcal sepsis	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Streptococcal bacteraemia	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Subcutaneous abscess	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Upper respiratory tract infection	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Urosepsis	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Injury, poisoning and procedural complications Fall	4.0% 3/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Injury, poisoning and procedural complications Femur fracture	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	3.2% 1/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Injury, poisoning and procedural complications Infusion related reaction	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.7% 5/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Injury, poisoning and procedural complications Lower limb fracture	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Injury, poisoning and procedural complications Pelvic fracture	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Injury, poisoning and procedural complications Spinal compression fracture	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Injury, poisoning and procedural complications Spinal fracture	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Injury, poisoning and procedural complications Subdural haematoma	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Injury, poisoning and procedural complications Tendon injury	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Investigations Neutrophil count decreased	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Metabolism and nutrition disorders Dehydration	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	3.2% 1/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Metabolism and nutrition disorders Fluid overload	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Metabolism and nutrition disorders Hyponatraemia	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Metabolism and nutrition disorders Lactic acidosis	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Musculoskeletal and connective tissue disorders Arthralgia	4.0% 3/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Musculoskeletal and connective tissue disorders Breast cancer metastatic	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Musculoskeletal and connective tissue disorders Fracture pain	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Musculoskeletal and connective tissue disorders Joint swelling	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Musculoskeletal and connective tissue disorders Mobility decreased	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	3.2% 1/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Musculoskeletal and connective tissue disorders Psoriatic arthropathy	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Musculoskeletal and connective tissue disorders Soft tissue necrosis	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Musculoskeletal and connective tissue disorders Synovial cyst	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Musculoskeletal and connective tissue disorders Tendonitis	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Benign pancreatic neoplasm	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bing-Neel syndrome	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Diffuse large B-cell lymphoma	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	3.2% 1/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Invasive lobular breast carcinoma	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Renal cell carcinoma	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	3.2% 1/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Small cell lung cancer	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Nervous system disorders Aphasia	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	3.2% 1/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Nervous system disorders Haemorrhage intracranial	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Nervous system disorders Lumbar radiculopathy	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Nervous system disorders Syncope	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Nervous system disorders Transient ischaemic attack	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	3.2% 1/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Renal and urinary disorders Acute kidney injury	2.7% 2/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Renal and urinary disorders Dysuria	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Renal and urinary disorders Haematuria	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Renal and urinary disorders Urinary retention	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Reproductive system and breast disorders Prostatitis	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Respiratory, thoracic and mediastinal disorders Bronchopneumopathy	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Respiratory, thoracic and mediastinal disorders Dyspnoea	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Respiratory, thoracic and mediastinal disorders Epistaxis	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Respiratory, thoracic and mediastinal disorders Lung disorder	2.7% 2/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	3.2% 1/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Skin and subcutaneous tissue disorders Eczema	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Skin and subcutaneous tissue disorders Purpura	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Vascular disorders Circulatory collapse	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Vascular disorders Hypertension	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Vascular disorders Hypotension	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.

Other adverse events

Measure	Ibrutinib + Rituximab n=75 participants at risk Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m\^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Placebo + Rituximab n=75 participants at risk Placebo: 3 capsules of placebo orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Rituximab: 375 mg/m\^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab.	Open-Label Substudy: Ibrutinib n=31 participants at risk Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment.
Blood and lymphatic system disorders Anaemia	22.7% 17/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	28.0% 21/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	16.1% 5/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Blood and lymphatic system disorders Increased tendency to bruise	12.0% 9/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	2.7% 2/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	25.8% 8/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Blood and lymphatic system disorders Lymphadenopathy	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Blood and lymphatic system disorders Neutropenia	16.0% 12/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	9.3% 7/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	29.0% 9/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Blood and lymphatic system disorders Spontaneous haematoma	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Blood and lymphatic system disorders Thrombocytopenia	6.7% 5/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	10.7% 8/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	19.4% 6/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Cardiac disorders Atrial fibrillation	14.7% 11/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Cardiac disorders Palpitations	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Ear and labyrinth disorders Tinnitus	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	12.9% 4/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Eye disorders Cataract	9.3% 7/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	12.9% 4/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Eye disorders Diplopia	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Eye disorders Dry eye	6.7% 5/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.7% 5/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	9.7% 3/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Eye disorders Eye irritation	8.0% 6/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Eye disorders Lacrimation increased	12.0% 9/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	4.0% 3/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Eye disorders Photophobia	8.0% 6/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	2.7% 2/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Eye disorders Vision blurred	9.3% 7/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	2.7% 2/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	12.9% 4/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Eye disorders Visual acuity reduced	12.0% 9/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	4.0% 3/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Eye disorders Vitreous detachment	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Eye disorders Vitreous floaters	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	2.7% 2/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Gastrointestinal disorders Abdominal discomfort	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	9.7% 3/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Gastrointestinal disorders Abdominal distension	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Gastrointestinal disorders Abdominal pain	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	2.7% 2/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	12.9% 4/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Gastrointestinal disorders Abdominal pain upper	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	2.7% 2/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Gastrointestinal disorders Constipation	12.0% 9/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	12.0% 9/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	16.1% 5/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Gastrointestinal disorders Diarrhoea	30.7% 23/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	14.7% 11/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	45.2% 14/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Gastrointestinal disorders Dry mouth	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Gastrointestinal disorders Dyspepsia	17.3% 13/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Gastrointestinal disorders Gastritis	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Gastrointestinal disorders Gastrooesophageal reflux disease	9.3% 7/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	9.7% 3/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Gastrointestinal disorders Gingival bleeding	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Gastrointestinal disorders Nausea	22.7% 17/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	12.0% 9/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	22.6% 7/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Gastrointestinal disorders Stomatitis	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Gastrointestinal disorders Vomiting	6.7% 5/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	10.7% 8/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
General disorders Asthenia	16.0% 12/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	25.3% 19/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	12.9% 4/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
General disorders Chest pain	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
General disorders Chills	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
General disorders Fatigue	17.3% 13/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	24.0% 18/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	16.1% 5/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
General disorders Influenza like illness	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
General disorders Oedema peripheral	22.7% 17/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	12.0% 9/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	16.1% 5/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
General disorders Pyrexia	16.0% 12/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	16.0% 12/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	35.5% 11/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Bronchitis	14.7% 11/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.7% 5/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	9.7% 3/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Cellulitis	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	9.7% 3/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Conjunctivitis	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	4.0% 3/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	12.9% 4/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Folliculitis	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Herpes zoster	8.0% 6/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Influenza	13.3% 10/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.7% 5/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Localised infection	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Nasopharyngitis	16.0% 12/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	9.3% 7/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	9.7% 3/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Oral herpes	8.0% 6/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Paronychia	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Pneumonia	6.7% 5/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	2.7% 2/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Respiratory tract infection	8.0% 6/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	2.7% 2/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	16.1% 5/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Respiratory tract infection viral	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Rhinitis	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Sinusitis	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	2.7% 2/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	12.9% 4/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Upper respiratory tract infection	13.3% 10/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	4.0% 3/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	19.4% 6/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Infections and infestations Urinary tract infection	14.7% 11/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	9.7% 3/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Injury, poisoning and procedural complications Contusion	9.3% 7/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Injury, poisoning and procedural complications Fall	9.3% 7/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	4.0% 3/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	9.7% 3/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Injury, poisoning and procedural complications Infusion related reaction	42.7% 32/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	57.3% 43/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Injury, poisoning and procedural complications Traumatic haematoma	6.7% 5/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Metabolism and nutrition disorders Decreased appetite	4.0% 3/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	9.3% 7/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	9.7% 3/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Metabolism and nutrition disorders Gout	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Metabolism and nutrition disorders Hyperuricaemia	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Metabolism and nutrition disorders Hypokalaemia	12.0% 9/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Metabolism and nutrition disorders Hyponatraemia	6.7% 5/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	2.7% 2/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Metabolism and nutrition disorders Iron deficiency	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Musculoskeletal and connective tissue disorders Arthralgia	25.3% 19/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	12.0% 9/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	22.6% 7/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Musculoskeletal and connective tissue disorders Back pain	17.3% 13/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	9.3% 7/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	29.0% 9/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Musculoskeletal and connective tissue disorders Muscle spasms	21.3% 16/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	12.0% 9/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	16.1% 5/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Musculoskeletal and connective tissue disorders Muscular weakness	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Musculoskeletal and connective tissue disorders Myalgia	6.7% 5/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	4.0% 3/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Musculoskeletal and connective tissue disorders Osteoarthritis	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	1.3% 1/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Musculoskeletal and connective tissue disorders Pain in extremity	13.3% 10/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	8.0% 6/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	16.1% 5/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour flare	8.0% 6/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	46.7% 35/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Nervous system disorders Dizziness	13.3% 10/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	8.0% 6/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	12.9% 4/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Nervous system disorders Headache	17.3% 13/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	22.7% 17/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	22.6% 7/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Nervous system disorders Paraesthesia	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Nervous system disorders Peripheral sensory neuropathy	6.7% 5/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Nervous system disorders Sciatica	8.0% 6/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	9.7% 3/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Psychiatric disorders Depression	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	9.7% 3/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Psychiatric disorders Insomnia	16.0% 12/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	4.0% 3/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Renal and urinary disorders Haematuria	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Respiratory, thoracic and mediastinal disorders Cough	21.3% 16/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	10.7% 8/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	29.0% 9/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Respiratory, thoracic and mediastinal disorders Dyspnoea	10.7% 8/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	13.3% 10/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	9.7% 3/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Respiratory, thoracic and mediastinal disorders Epistaxis	10.7% 8/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	9.3% 7/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	12.9% 4/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	2.7% 2/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	9.7% 3/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Respiratory, thoracic and mediastinal disorders Productive cough	4.0% 3/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	6.7% 5/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.7% 5/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Skin and subcutaneous tissue disorders Actinic keratosis	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Skin and subcutaneous tissue disorders Dermatitis contact	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Skin and subcutaneous tissue disorders Dry skin	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	19.4% 6/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Skin and subcutaneous tissue disorders Ecchymosis	12.0% 9/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Skin and subcutaneous tissue disorders Onychoclasis	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	12.9% 4/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Skin and subcutaneous tissue disorders Onycholysis	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Skin and subcutaneous tissue disorders Petechiae	9.3% 7/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	12.9% 4/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Skin and subcutaneous tissue disorders Pruritus	8.0% 6/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Skin and subcutaneous tissue disorders Psoriasis	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	6.5% 2/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Skin and subcutaneous tissue disorders Rash erythematous	9.3% 7/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	2.7% 2/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Skin and subcutaneous tissue disorders Rash maculo-papular	6.7% 5/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	4.0% 3/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	9.7% 3/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Skin and subcutaneous tissue disorders Skin lesion	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Vascular disorders Hypertension	24.0% 18/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	4.0% 3/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	25.8% 8/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Vascular disorders Hypotension	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	9.7% 3/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Investigations Blood Creatinine Increased	6.7% 5/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.
Investigations Blood Uric Acid Increased	5.3% 4/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/75 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.	0.00% 0/31 • From first dose of study drug up to 30 days after the last dose of study drug. Median duration of treatment was 47.7 months for the Ibr+R arm, 15.5 months for the Pbo+R arm, and 40.7 months for the Open-Label Ibr arm.

Additional Information

Lori Styles

Pharmacyclics LLC, An AbbVie Company

Phone: (408) 215-3770

Email: lstyles@pcyc.com

Results disclosure agreements

• Principal investigator is a sponsor employee 1. Institution/Investigator will not publish without Sponsor prior review and approval 2. Institution/Investigator will not publish until the earlier of (i) results of study are submitted for publication (ii) notification that submission of the multicenter results are no longer planned (iii) 18 months after study termination.
• Publication restrictions are in place

Restriction type: OTHER