Trial Outcomes & Findings for Safety and Tolerability Study of PCI-32765 in B Cell Lymphoma and Chronic Lymphocytic Leukemia (NCT NCT01109069)

Last Updated: 2020-05-27

Results Overview

Subjects were to receive ibrutinib once daily at the dose level the subject was receiving in the parent study until disease progression or unacceptable toxicity. The study included Screening, Treatment (from the first dose until study drug discontinuation), and Follow-up Phases.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

199 participants

Primary outcome timeframe

30 days after last dose of study drug, continue up to 6 months

Results posted on

2020-05-27

Participant Flow

27 July 2010 (the first Patient enrolled) to 31 March 2016 (the Last patient enrolled), Study was approved on June 2010.

This study was open to subjects from prior ibrutinib studies who met eligibility criteria for rollover from their parent study and wanted to continue receiving study drug.

Participant milestones

Participant milestones
Measure	A LONG-TERM SAFETY STUDY OF BRUTON'S TYROSINE KINASE (BTK) INH A Long-term Safety Study of Bruton's Tyrosine Kinase (Btk) Inhibitor PCI-32765 in B Cell Lymphoma and Chronic Lymphocytic Leukemia. This is a multicenter(16 sites in the USA), open-label, monotherapy, long-term extension study designed to evaluate the long-term (\> 6 months) safety and tolerability of a fixed daily dosing regimen of ibrutinib. Ibrutinib was supplied as 140 mg or 40 mg capsules for oral administration. Subjects were to receive daily administration of a fixed dose of ibrutinib at the same dose level as in the parent study (up to 840 mg).
Overall Study STARTED	199
Overall Study COMPLETED	106
Overall Study NOT COMPLETED	93

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Safety and Tolerability Study of PCI-32765 in B Cell Lymphoma and Chronic Lymphocytic Leukemia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	A Long-term Safety Study of Bruton's Tyrosine Kinase (Btk) Inh n=199 Participants A Long-term Safety Study of Bruton's Tyrosine Kinase (Btk) Inhibitor PCI-32765 in B Cell Lymphoma and Chronic Lymphocytic Leukemia. This is a multicenter(16 sites in the USA), open-label, monotherapy, long-term extension study designed to evaluate the long-term (\> 6 months) safety and tolerability of a fixed daily dosing regimen of ibrutinib. Ibrutinib was supplied as 140 mg or 40 mg capsules for oral administration. Subjects were to receive daily administration of a fixed dose of ibrutinib at the same dose level as in the parent study (up to 840 mg).
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	83 Participants n=5 Participants
Age, Categorical >=65 years	116 Participants n=5 Participants
Age, Continuous	65.6 Years STANDARD_DEVIATION 8.98 • n=5 Participants
Sex: Female, Male Female	56 Participants n=5 Participants
Sex: Female, Male Male	143 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	6 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	192 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	8 Participants n=5 Participants
Race (NIH/OMB) White	185 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants n=5 Participants
Region of Enrollment United States	199 participants n=5 Participants
Estimated creatinine clearance rate (mL/min)	85.55 ML/min STANDARD_DEVIATION 34.150 • n=5 Participants

PRIMARY outcome

Timeframe: 30 days after last dose of study drug, continue up to 6 months

Outcome measures

Outcome measures
Measure	A LONG-TERM SAFETY STUDY OF BRUTON'S TYROSINE KINASE (BTK) INH n=199 Participants A Long-term Safety Study of Bruton's Tyrosine Kinase (Btk) Inhibitor PCI-32765 in B Cell Lymphoma and Chronic Lymphocytic Leukemia. This is a multicenter(16 sites in the USA), open-label, monotherapy, long-term extension study designed to evaluate the long-term (\> 6 months) safety and tolerability of a fixed daily dosing regimen of ibrutinib. Ibrutinib was supplied as 140 mg or 40 mg capsules for oral administration. Subjects were to receive daily administration of a fixed dose of ibrutinib at the same dose level as in the parent study (up to 840 mg).
Number of Subjects With Adverse Events	199 Participants

SECONDARY outcome

Timeframe: 30 days after last dose of study drug, continue up to 6 months

A progressive disease confirmed by a CT scan.

Outcome measures

Outcome measures
Measure	A LONG-TERM SAFETY STUDY OF BRUTON'S TYROSINE KINASE (BTK) INH n=199 Participants A Long-term Safety Study of Bruton's Tyrosine Kinase (Btk) Inhibitor PCI-32765 in B Cell Lymphoma and Chronic Lymphocytic Leukemia. This is a multicenter(16 sites in the USA), open-label, monotherapy, long-term extension study designed to evaluate the long-term (\> 6 months) safety and tolerability of a fixed daily dosing regimen of ibrutinib. Ibrutinib was supplied as 140 mg or 40 mg capsules for oral administration. Subjects were to receive daily administration of a fixed dose of ibrutinib at the same dose level as in the parent study (up to 840 mg).
Progressive Disease (PD)	70 Participants

SECONDARY outcome

Timeframe: 30 days after last dose of study drug

All death events are due to AE, progressive disease, and other reasons.

Outcome measures

Outcome measures
Measure	A LONG-TERM SAFETY STUDY OF BRUTON'S TYROSINE KINASE (BTK) INH n=199 Participants A Long-term Safety Study of Bruton's Tyrosine Kinase (Btk) Inhibitor PCI-32765 in B Cell Lymphoma and Chronic Lymphocytic Leukemia. This is a multicenter(16 sites in the USA), open-label, monotherapy, long-term extension study designed to evaluate the long-term (\> 6 months) safety and tolerability of a fixed daily dosing regimen of ibrutinib. Ibrutinib was supplied as 140 mg or 40 mg capsules for oral administration. Subjects were to receive daily administration of a fixed dose of ibrutinib at the same dose level as in the parent study (up to 840 mg).
Death Event	42 Participants

SECONDARY outcome

Timeframe: 30 days after last dose of study drug, continue up to 6 months

Investigator-assessed responses were summarized descriptively for subjects with CLL/SLL and listed for subjects with other NHLs based on the efficacy population.

Outcome measures

Outcome measures
Measure	A LONG-TERM SAFETY STUDY OF BRUTON'S TYROSINE KINASE (BTK) INH n=199 Participants A Long-term Safety Study of Bruton's Tyrosine Kinase (Btk) Inhibitor PCI-32765 in B Cell Lymphoma and Chronic Lymphocytic Leukemia. This is a multicenter(16 sites in the USA), open-label, monotherapy, long-term extension study designed to evaluate the long-term (\> 6 months) safety and tolerability of a fixed daily dosing regimen of ibrutinib. Ibrutinib was supplied as 140 mg or 40 mg capsules for oral administration. Subjects were to receive daily administration of a fixed dose of ibrutinib at the same dose level as in the parent study (up to 840 mg).
Documented Responses CLL/SLL	180 Participants
Documented Responses Other NHL	16 Participants
Documented Responses Treatment discontinuation	3 Participants

Adverse Events

IBRUTINIB/PCI-32765

Serious events: 111 serious events

Other events: 114 other events

Deaths: 111 deaths

Serious adverse events

Serious adverse events
Measure	IBRUTINIB/PCI-32765 n=199 participants at risk This was a multicenter, open-label, monotherapy, long-term extension study designed to evaluate the long-term (\> 6 months) safety and tolerability of a fixed daily dosing regimen of ibrutinib. PCI-32765: Dose based on parent protocol CLL: chronic lymphocytic leukemia/ SLL: small lymphocytic lymphoma.
Infections and infestations Clostridium difficile colitis	1.0% 2/199 • Number of events 2 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Diverticulitis	1.0% 2/199 • Number of events 3 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Blood and lymphatic system disorders Febrile neutropenia	2.0% 4/199 • Number of events 5 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Blood and lymphatic system disorders Anaemia	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Blood and lymphatic system disorders Neutropenia	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Cardiac disorders Atrial fibrillation	10.6% 21/199 • Number of events 25 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Cardiac disorders Angina pectoris	1.0% 2/199 • Number of events 2 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Cardiac disorders Atrial flutter	1.0% 2/199 • Number of events 2 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Cardiac disorders Sinus bradycardia	1.0% 2/199 • Number of events 2 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Cardiac disorders Arteriosclerosis coronary artery	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Cardiac disorders Atrioventricular block complete	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Cardiac disorders Bundle branch block left	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Cardiac disorders Bundle branch block right	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Cardiac disorders Cardiac failure congestive	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Cardiac disorders Cardio-respiratory arrest	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Cardiac disorders Coronary artery disease	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Cardiac disorders Ischaemic cardiomyopathy	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Cardiac disorders Myocardial infarction	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Cardiac disorders Palpitations	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Cardiac disorders Pericarditis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Cardiac disorders Subendocardial ischaemia	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Cardiac disorders Ventricular tachycardia	0.50% 1/199 • Number of events 2 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Ear and labyrinth disorders Haematotympanum	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Eye disorders Uveitis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Gastrointestinal disorders Diarrhoea	1.5% 3/199 • Number of events 3 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Gastrointestinal disorders Abdominal pain upper	1.0% 2/199 • Number of events 2 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Gastrointestinal disorders Gastrointestinal haemorrhage	1.0% 2/199 • Number of events 2 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	1.0% 2/199 • Number of events 2 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Gastrointestinal disorders Dysphagia	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Gastrointestinal disorders Enteritis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Gastrointestinal disorders Nausea	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Gastrointestinal disorders Oesophageal ulcer	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Gastrointestinal disorders Pancreatitis necrotising	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Gastrointestinal disorders Small intestinal obstruction	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Gastrointestinal disorders Umbilical hernia	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Gastrointestinal disorders Vomiting	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
General disorders Pyrexia	4.0% 8/199 • Number of events 9 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
General disorders Asthenia	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
General disorders Chest pain	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
General disorders Fatigue	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
General disorders Multiple organ dysfunction syndrome	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Hepatobiliary disorders Cholecystitis	1.0% 2/199 • Number of events 2 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Hepatobiliary disorders Cholecystitis acute	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Pneumonia	16.1% 32/199 • Number of events 61 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Cellulitis	6.5% 13/199 • Number of events 16 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Sepsis	5.5% 11/199 • Number of events 12 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Urinary tract infection	3.0% 6/199 • Number of events 7 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Gastroenteritis	1.5% 3/199 • Number of events 4 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Gastroenteritis viral	1.5% 3/199 • Number of events 4 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Herpes zoster	1.5% 3/199 • Number of events 3 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Septic shock	1.5% 3/199 • Number of events 3 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Bacteraemia	1.0% 2/199 • Number of events 2 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Gastroenteritis clostridial	1.0% 2/199 • Number of events 2 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Influenza	1.0% 2/199 • Number of events 3 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Localised infection	1.0% 2/199 • Number of events 2 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Lung infection	1.0% 2/199 • Number of events 3 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Urosepsis	1.0% 2/199 • Number of events 2 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Viral infection	1.0% 2/199 • Number of events 2 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Acute sinusitis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Appendicitis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Bronchitis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Bronchopulmonary aspergillosis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Cellulitis orbital	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Cellulitis staphylococcal	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Clostridial sepsis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Clostridium difficile infection	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Dengue fever	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Ear infection	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Fusarium infection	0.50% 1/199 • Number of events 3 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Gangrene	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Gastrointestinal infection	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Klebsiella infection	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Klebsiella sepsis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Lymphangitis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Osteomyelitis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Parainfluenzae virus infection	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Pelvic abscess	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Pharyngitis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Pilonidal cyst	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Pneumonia bacterial	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Pneumonia fungal	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Pneumonia legionella	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Pneumonia pseudomonal	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Pneumonia respiratory syncytial viral	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Pseudomonal bacteraemia	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Pseudomonas infection	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Pyelonephritis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Sinusitis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Staphylococcal infection	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Vestibular neuronitis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Wound infection	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Wound infection staphylococcal	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Injury, poisoning and procedural complications Subdural haematoma	1.5% 3/199 • Number of events 4 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Injury, poisoning and procedural complications Fall	1.0% 2/199 • Number of events 2 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Injury, poisoning and procedural complications Femoral neck fracture	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Injury, poisoning and procedural complications Hip fracture	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Injury, poisoning and procedural complications Perirenal haematoma	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Injury, poisoning and procedural complications Splenic rupture	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Injury, poisoning and procedural complications Subarachnoid haemorrhage	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Injury, poisoning and procedural complications Thermal burn	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Investigations Transaminases increased	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Metabolism and nutrition disorders Hypercalcaemia	1.0% 2/199 • Number of events 2 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Metabolism and nutrition disorders Decreased appetite	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Metabolism and nutrition disorders Dehydration	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Metabolism and nutrition disorders Diabetic ketosis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Metabolism and nutrition disorders Failure to thrive	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Musculoskeletal and connective tissue disorders Osteoarthritis	1.0% 2/199 • Number of events 2 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Musculoskeletal and connective tissue disorders Lumbar spinal stenosis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Musculoskeletal and connective tissue disorders Pain in extremity	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Musculoskeletal and connective tissue disorders Spinal column stenosis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Musculoskeletal and connective tissue disorders Spondylolisthesis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Chronic lymphocytic leukaemia	1.5% 3/199 • Number of events 4 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung adenocarcinoma	1.5% 3/199 • Number of events 3 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Richter's syndrome	1.5% 3/199 • Number of events 4 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder neoplasm	1.0% 2/199 • Number of events 2 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenocarcinoma	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Appendix cancer	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder transitional cell carcinoma	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Chronic lymphocytic leukaemia transformation	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Invasive ductal breast carcinoma	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung adenocarcinoma recurrent	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant melanoma	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Mantle cell lymphoma	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to central nervous system	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to lung	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Myelodysplastic syndrome	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Nasopharyngeal cancer	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neuroendocrine carcinoma of the skin	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Ovarian cancer	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Ovarian cancer metastatic	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Renal cell carcinoma	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Nervous system disorders Syncope	1.5% 3/199 • Number of events 3 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Nervous system disorders Headache	1.0% 2/199 • Number of events 2 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Nervous system disorders Transient ischaemic attack	1.0% 2/199 • Number of events 2 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Nervous system disorders Autoimmune neuropathy	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Nervous system disorders Cauda equina syndrome	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Nervous system disorders Dizziness	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Nervous system disorders Embolic stroke	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Nervous system disorders Encephalopathy	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Nervous system disorders Hypoaesthesia	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Nervous system disorders Ischaemic stroke	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Nervous system disorders Myelitis transverse	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Nervous system disorders Optic neuritis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Psychiatric disorders Mental status changes	1.5% 3/199 • Number of events 3 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Psychiatric disorders Confusional state	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Renal and urinary disorders Acute kidney injury	2.0% 4/199 • Number of events 4 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Renal and urinary disorders Haematuria	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Renal and urinary disorders Ureterolithiasis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Renal and urinary disorders Urinary retention	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Reproductive system and breast disorders Prostatic obstruction	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Reproductive system and breast disorders Prostatitis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Respiratory, thoracic and mediastinal disorders Dyspnoea	2.0% 4/199 • Number of events 5 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Respiratory, thoracic and mediastinal disorders Pleural effusion	2.0% 4/199 • Number of events 5 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Respiratory, thoracic and mediastinal disorders Atelectasis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Respiratory, thoracic and mediastinal disorders Pulmonary alveolar haemorrhage	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.50% 1/199 • Number of events 2 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Respiratory, thoracic and mediastinal disorders Tachypnoea	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Respiratory, thoracic and mediastinal disorders Tracheal stenosis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Skin and subcutaneous tissue disorders Eosinophilic pustular folliculitis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Vascular disorders Hypotension	1.5% 3/199 • Number of events 4 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Vascular disorders Aortic aneurysm	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Vascular disorders Aortic stenosis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Vascular disorders Deep vein thrombosis	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Vascular disorders Hypertension	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Vascular disorders Orthostatic hypotension	0.50% 1/199 • Number of events 1 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.

Other adverse events

Other adverse events
Measure	IBRUTINIB/PCI-32765 n=199 participants at risk This was a multicenter, open-label, monotherapy, long-term extension study designed to evaluate the long-term (\> 6 months) safety and tolerability of a fixed daily dosing regimen of ibrutinib. PCI-32765: Dose based on parent protocol CLL: chronic lymphocytic leukemia/ SLL: small lymphocytic lymphoma.
Blood and lymphatic system disorders Neutropenia	10.6% 21/199 • Number of events 24 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Blood and lymphatic system disorders Thrombocytopenia	5.0% 10/199 • Number of events 23 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Ear and labyrinth disorders Cataract	7.0% 14/199 • Number of events 20 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Gastrointestinal disorders Diarrohea	4.5% 9/199 • Number of events 10 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Infections and infestations Upper Respiratory Track Infection	4.5% 9/199 • Number of events 10 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Investigations Lymphocyte count decreased	12.1% 24/199 • Number of events 59 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Investigations Neutrophil Count decreased	8.5% 17/199 • Number of events 32 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Investigations White Blood cell count decreased	4.0% 8/199 • Number of events 12 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Metabolism and nutrition disorders Hyperglycemia	5.0% 10/199 • Number of events 15 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.
Vascular disorders Hypertension	33.7% 67/199 • Number of events 197 • 8 Years, 5 months. This is a safety longterm follow-up study, it doesn't have any common milestones. Adverse event data collection included Grade 3 or 4 AEs and major hemorrhage AEs, and the following: Grade 2 or higher eye-related AEs, and AEs of any grade that were serious, an +other malignancy, or led to dose reduction or treatment discontinuation.

Additional Information

James Dean

Pharmacyclics

Phone: 669-224-1880

Email: [email protected]

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 the study are submitted for publication (ii) notification that submission of the multicenter results is no longer planned (iii) 18 months after study termination.
Publication restrictions are in place

Restriction type: OTHER