Trial Outcomes & Findings for Treat & Extend Treatment With 0.5mg Ranibizumab vs Monthly Treatment With 0.5mg Ranibizumab (NCT NCT01748292)

Last Updated: 2019-06-04

Results Overview

Mean change in Best-Corrected Visual Acuity (BCVA) by Early Treatment Diabetic Retinopathy Study (ETDRS) letter score from baseline through weeks 24-28, baseline through weeks 48-56, baseline through weeks 72-82, baseline to week 104, baseline through weeks 128-132 and baseline to week 156. The ETDRS protocol is a widely accepted international standard for macular laser photocoagulation treatment. A higher score represents better functioning. The scale ranges from 0 to 100 letters

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

60 participants

Primary outcome timeframe

6, 12, 18, 24, 30, and 36 months

Results posted on

2019-06-04

Participant Flow

Sixty patients were enrolled between February 2013 and January 2014.

Participant milestones

Participant milestones
Measure	Monthly IVT Ranibizumab Monthly intravitreal injections (IVT) ranibizumab for 24 months, not less than 21 days apart to not more than 35 days apart 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.	Treat and Extend IVT Ranibizumab 0.5 mg intravitreal injections (IVT) ranibizumab for 3 consecutive months followed by a treat and extend protocol in which follow-up intervals are increased when there is no clinical and SD-OCT evidence of disease activity by 2-week intervals and patients are treated at every visit. (Comparator arm) 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.
Overall Study STARTED	20	40
Overall Study COMPLETED	18	28
Overall Study NOT COMPLETED	2	12

Reasons for withdrawal

Reasons for withdrawal
Measure	Monthly IVT Ranibizumab Monthly intravitreal injections (IVT) ranibizumab for 24 months, not less than 21 days apart to not more than 35 days apart 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.	Treat and Extend IVT Ranibizumab 0.5 mg intravitreal injections (IVT) ranibizumab for 3 consecutive months followed by a treat and extend protocol in which follow-up intervals are increased when there is no clinical and SD-OCT evidence of disease activity by 2-week intervals and patients are treated at every visit. (Comparator arm) 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.
Overall Study Adverse Event	2	4
Overall Study Lost to Follow-up	0	3
Overall Study Death	0	3
Overall Study Withdrawal by Subject	0	2

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Monthly IVT Ranibizumab n=20 Participants Monthly intravitreal injections (IVT) ranibizumab for 24 months, not less than 21 days apart to not more than 35 days apart 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.	Treat and Extend IVT Ranibizumab n=40 Participants 0.5 mg intravitreal injections (IVT) ranibizumab for 3 consecutive months followed by a treat and extend protocol in which follow-up intervals are increased when there is no clinical and SD-OCT evidence of disease activity by 2-week intervals and patients are treated at every visit. (Comparator arm) 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.	Total n=60 Participants Total of all reporting groups
Age, Continuous	79 years n=20 Participants	76 years n=40 Participants	77 years n=60 Participants
Sex: Female, Male Female	12 Participants n=20 Participants	26 Participants n=40 Participants	38 Participants n=60 Participants
Sex: Female, Male Male	8 Participants n=20 Participants	14 Participants n=40 Participants	22 Participants n=60 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Number of Right Eyes Enrolled	10 Participants n=20 Participants	16 Participants n=40 Participants	26 Participants n=60 Participants
Number of Participants with Posterior Chamber Intraocular Lenses	10 Participants n=20 Participants	22 Participants n=40 Participants	32 Participants n=60 Participants
Diabetes Mellitus	2 Participants n=20 Participants	9 Participants n=40 Participants	11 Participants n=60 Participants
Hypertension	16 Participants n=20 Participants	31 Participants n=40 Participants	47 Participants n=60 Participants
Early Treatment Diabetic Retinopathy Study Best-Corrected Visual Acuity	60.3 letters n=20 Participants	59.9 letters n=40 Participants	60.0 letters n=60 Participants
Central Retinal Thickness	533 microns n=20 Participants	489 microns n=40 Participants	511 microns n=60 Participants

PRIMARY outcome

Timeframe: 6, 12, 18, 24, 30, and 36 months

Population: All participants were included in analysis. Due to participant attrition, missed visits, and variable follow-up intervals in the Treat and Extend arm, the population analyzed at each time point is equal to or smaller than the population still enrolled at that time point.

Outcome measures

Outcome measures
Measure	Monthly IVT Ranibizumab n=20 Participants Monthly intravitreal injections (IVT) ranibizumab for 24 months, not less than 21 days apart to not more than 35 days apart 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.	Treat and Extend IVT Ranibizumab n=40 Participants 0.5 mg intravitreal injections (IVT) ranibizumab for 3 consecutive months followed by a treat and extend protocol in which follow-up intervals are increased when there is no clinical and SD-OCT evidence of disease activity by 2-week intervals and patients are treated at every visit. (Comparator arm) 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.
Mean Change in BCVA by ETDRS Letter Score From Baseline Month 6	10.5 ETDRS BCVA Letters Standard Error 1.3	7.3 ETDRS BCVA Letters Standard Error 1.9
Mean Change in BCVA by ETDRS Letter Score From Baseline Month 12	9.2 ETDRS BCVA Letters Standard Error 1.4	10.5 ETDRS BCVA Letters Standard Error 2.0
Mean Change in BCVA by ETDRS Letter Score From Baseline Month 18	10.4 ETDRS BCVA Letters Standard Error 1.9	9.0 ETDRS BCVA Letters Standard Error 3.2
Mean Change in BCVA by ETDRS Letter Score From Baseline Month 24	10.5 ETDRS BCVA Letters Standard Error 1.9	8.7 ETDRS BCVA Letters Standard Error 3.6
Mean Change in BCVA by ETDRS Letter Score From Baseline Month 30	9.7 ETDRS BCVA Letters Standard Error 2.3	.95 ETDRS BCVA Letters Standard Error 4.4
Mean Change in BCVA by ETDRS Letter Score From Baseline Month 36	8.6 ETDRS BCVA Letters Standard Error 2.8	4.1 ETDRS BCVA Letters Standard Error 4.0

SECONDARY outcome

Timeframe: 36 months

Incidence and severity of adverse events both ocular and non-ocular

Outcome measures

Outcome measures
Measure	Monthly IVT Ranibizumab n=20 Participants Monthly intravitreal injections (IVT) ranibizumab for 24 months, not less than 21 days apart to not more than 35 days apart 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.	Treat and Extend IVT Ranibizumab n=40 Participants 0.5 mg intravitreal injections (IVT) ranibizumab for 3 consecutive months followed by a treat and extend protocol in which follow-up intervals are increased when there is no clinical and SD-OCT evidence of disease activity by 2-week intervals and patients are treated at every visit. (Comparator arm) 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.
Incidence and Severity of Adverse Events (Ocular and Non-ocular) Participants Experiencing Serious Ocular AE	2 Participants	6 Participants
Incidence and Severity of Adverse Events (Ocular and Non-ocular) Participants Experiencing Serious Systemic AE	7 Participants	20 Participants

SECONDARY outcome

Timeframe: 12, 24, and 36 months

Total number of intravitreal injections required from baseline through weeks 48-57 (week closest to week 52), baseline through week 104 and baseline through week 156.

Outcome measures

Outcome measures
Measure	Monthly IVT Ranibizumab n=20 Participants Monthly intravitreal injections (IVT) ranibizumab for 24 months, not less than 21 days apart to not more than 35 days apart 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.	Treat and Extend IVT Ranibizumab n=40 Participants 0.5 mg intravitreal injections (IVT) ranibizumab for 3 consecutive months followed by a treat and extend protocol in which follow-up intervals are increased when there is no clinical and SD-OCT evidence of disease activity by 2-week intervals and patients are treated at every visit. (Comparator arm) 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.
Total Number of Intravitreal Injections Required Month 12	13.0 injections Interval 13.0 to 13.0	10.1 injections Interval 7.0 to 13.0
Total Number of Intravitreal Injections Required Month 24	25.5 injections Interval 22.0 to 27.0	18.6 injections Interval 10.0 to 25.0
Total Number of Intravitreal Injections Required Month 36	31.5 injections Interval 25.0 to 39.0	25 injections Interval 10.0 to 37.0

SECONDARY outcome

Timeframe: 6, 12, 18, 24, 30, and 36 months

Population: Per protocol, imaging was conducted at each study visit and is assumed to be perfectly correlated with the number of visits. Therefore, only visits were specifically analyzed. Additionally, given the high correlation between number of visits and injections administered (reported previously), this analysis was performed only at M12, M24, and M36.

Total number of office visits and imaging studies performed from baseline through weeks 24-28 (week closest to week 26), baseline through weeks 48-56 (week closest to week 52), baseline through weeks 72-82 (week closest to week 78), baseline through week 104, baseline through weeks 128-132 (week closest to week 132) and baseline through week 156

Outcome measures

Outcome measures
Measure	Monthly IVT Ranibizumab n=20 Participants Monthly intravitreal injections (IVT) ranibizumab for 24 months, not less than 21 days apart to not more than 35 days apart 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.	Treat and Extend IVT Ranibizumab n=40 Participants 0.5 mg intravitreal injections (IVT) ranibizumab for 3 consecutive months followed by a treat and extend protocol in which follow-up intervals are increased when there is no clinical and SD-OCT evidence of disease activity by 2-week intervals and patients are treated at every visit. (Comparator arm) 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.
Total Number of Office Visits and Imaging Studies Performed During Study Period Number of Visits through Month 12	262 scheduled visits completed	364 scheduled visits completed
Total Number of Office Visits and Imaging Studies Performed During Study Period Number of Visits through Month 24	560 scheduled visits completed	838 scheduled visits completed
Total Number of Office Visits and Imaging Studies Performed During Study Period Number of Visits through Month 36	801 scheduled visits completed	1143 scheduled visits completed

SECONDARY outcome

Timeframe: 12, 24, and 36 months

Percentage of subjects with persistent active exudation on SD-OCT from baseline through weeks 48-57 (week closest to week 52), baseline through week 104 and baseline through week 156.

Outcome measures

Outcome measures
Measure	Monthly IVT Ranibizumab n=20 Participants Monthly intravitreal injections (IVT) ranibizumab for 24 months, not less than 21 days apart to not more than 35 days apart 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.	Treat and Extend IVT Ranibizumab n=40 Participants 0.5 mg intravitreal injections (IVT) ranibizumab for 3 consecutive months followed by a treat and extend protocol in which follow-up intervals are increased when there is no clinical and SD-OCT evidence of disease activity by 2-week intervals and patients are treated at every visit. (Comparator arm) 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.
Percentage of Subjects With Persistent Active Exudation on SD-OCT Month 12	3 Participants	9 Participants
Percentage of Subjects With Persistent Active Exudation on SD-OCT Month 24	5 Participants	9 Participants
Percentage of Subjects With Persistent Active Exudation on SD-OCT Month 36	9 Participants	8 Participants

SECONDARY outcome

Timeframe: 12, 24, and 36 months

Mean change in central foveal thickness by SD-OCT from baseline to weeks 48-57, baseline to week 104 and baseline to week 156.

Outcome measures

Outcome measures
Measure	Monthly IVT Ranibizumab n=20 Participants Monthly intravitreal injections (IVT) ranibizumab for 24 months, not less than 21 days apart to not more than 35 days apart 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.	Treat and Extend IVT Ranibizumab n=40 Participants 0.5 mg intravitreal injections (IVT) ranibizumab for 3 consecutive months followed by a treat and extend protocol in which follow-up intervals are increased when there is no clinical and SD-OCT evidence of disease activity by 2-week intervals and patients are treated at every visit. (Comparator arm) 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.
Mean Change in Central Foveal Thickness Month 12	-246 microns Standard Error 43	-173 microns Standard Error 31
Mean Change in Central Foveal Thickness Month 24	-170 microns Standard Error 37	-170 microns Standard Error 37
Mean Change in Central Foveal Thickness Month 36	-188 microns Standard Error 42	-183 microns Standard Error 32

SECONDARY outcome

Timeframe: 6, 12, 18, 24, 30, and 36 months

Population: This analysis was never performed because we were logistically unable to collect the data.

Percentage of subjects with persistent leakage on fluorescein angiography from baseline through weeks 24-28, baseline to weeks 48-56, baseline to weeks 72-82, baseline to week 104, baseline to weeks 128- 132 and baseline to week 156.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 6, 12, 18, 24, 30, and 36 months

Population: This analysis was never performed because we were logistically unable to collect the data.

CNVM lesion size at baseline, compared to baseline to weeks 24-28, baseline to weeks 48-56, baseline to weeks 72-82, baseline to week 104, baseline to weeks 128-132 and baseline to week 156, as determined by fluorescein angiography.

Outcome measures

Outcome data not reported

Adverse Events

Monthly IVT Ranibizumab

Serious events: 7 serious events

Other events: 2 other events

Deaths: 0 deaths

Treat and Extend IVT Ranibizumab

Serious events: 23 serious events

Other events: 4 other events

Deaths: 3 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Monthly IVT Ranibizumab n=20 participants at risk Monthly intravitreal injections (IVT) ranibizumab for 24 months, not less than 21 days apart to not more than 35 days apart 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.	Treat and Extend IVT Ranibizumab n=40 participants at risk 0.5 mg intravitreal injections (IVT) ranibizumab for 3 consecutive months followed by a treat and extend protocol in which follow-up intervals are increased when there is no clinical and SD-OCT evidence of disease activity by 2-week intervals and patients are treated at every visit. (Comparator arm) 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.
Eye disorders Subretinal hemorrhage	5.0% 1/20 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	2.5% 1/40 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Eye disorders Progressive macular atrophy	0.00% 0/20 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	7.5% 3/40 • Number of events 3 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Eye disorders Hollenhorst plaque	5.0% 1/20 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	0.00% 0/40 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study

Additional Information

Charles C. Wykoff, MD, PhD

Retina Consultants of Houston

Phone: 713-524-3434

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Monthly IVT Ranibizumab n=20 participants at risk Monthly intravitreal injections (IVT) ranibizumab for 24 months, not less than 21 days apart to not more than 35 days apart 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.	Treat and Extend IVT Ranibizumab n=40 participants at risk 0.5 mg intravitreal injections (IVT) ranibizumab for 3 consecutive months followed by a treat and extend protocol in which follow-up intervals are increased when there is no clinical and SD-OCT evidence of disease activity by 2-week intervals and patients are treated at every visit. (Comparator arm) 0.5 mg ranibizumab: Subject will receive drug (ranibizumab) via intravitreal injections (IVT) at every visit.
Eye disorders Unexplained vision loss, left eye	0.00% 0/20 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	2.5% 1/40 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Vascular disorders Temporal arteritis	0.00% 0/20 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	2.5% 1/40 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Musculoskeletal and connective tissue disorders Worsening of gout, cellulitis	5.0% 1/20 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	0.00% 0/40 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Eye disorders Retinal pigment epithelium tear	0.00% 0/20 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	2.5% 1/40 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Respiratory, thoracic and mediastinal disorders Severe pneumonia, dehydration, anemia, COPD, emphysema, lung cancer	0.00% 0/20 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	2.5% 1/40 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Respiratory, thoracic and mediastinal disorders Bronchitis and Pleural Effusion	5.0% 1/20 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	0.00% 0/40 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Injury, poisoning and procedural complications Fall	5.0% 1/20 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	10.0% 4/40 • Number of events 4 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
General disorders Leukocytosis	5.0% 1/20 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	0.00% 0/40 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Injury, poisoning and procedural complications Broken ribs	5.0% 1/20 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	0.00% 0/40 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.00% 0/20 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	2.5% 1/40 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Cardiac disorders Myocardial infarction	0.00% 0/20 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	2.5% 1/40 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Musculoskeletal and connective tissue disorders Osteoarthritis	0.00% 0/20 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	2.5% 1/40 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	5.0% 1/20 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	2.5% 1/40 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Musculoskeletal and connective tissue disorders Worsening of arthritis	5.0% 1/20 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	0.00% 0/40 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Nervous system disorders Cerebrovascular accident	10.0% 2/20 • Number of events 2 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	2.5% 1/40 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
General disorders Abdominal pain	0.00% 0/20 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	2.5% 1/40 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Vascular disorders Hypotension	0.00% 0/20 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	2.5% 1/40 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Small cell lung cancer	0.00% 0/20 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	2.5% 1/40 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Hepatobiliary disorders Acute cholecystitis with abnormal liver function tests	0.00% 0/20 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	2.5% 1/40 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Infections and infestations Acute varicella zoster encephalitis	0.00% 0/20 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	2.5% 1/40 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Respiratory, thoracic and mediastinal disorders Worsening of COPD	0.00% 0/20 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	2.5% 1/40 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	5.0% 1/20 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	0.00% 0/40 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Infections and infestations Meningitis, urinary tract infection, and congestive heart failure	0.00% 0/20 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	2.5% 1/40 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Cardiac disorders Atrial fibrillation	0.00% 0/20 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	2.5% 1/40 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Injury, poisoning and procedural complications (Death) High cervical vertebral fracture w/ severed spinal cord tear in descending aorta	0.00% 0/20 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	2.5% 1/40 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Nervous system disorders (Death) Hemorrhagic stroke	0.00% 0/20 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	2.5% 1/40 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Eye disorders Subretinal hemorrhage	0.00% 0/20 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	2.5% 1/40 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Gastrointestinal disorders (Death) hypoxemia; gastrointestinal bleed; duodenal ulcer	0.00% 0/20 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	2.5% 1/40 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Injury, poisoning and procedural complications Motor vehicle accident	0.00% 0/20 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	2.5% 1/40 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Infections and infestations Influenza B	0.00% 0/20 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	2.5% 1/40 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study
Cardiac disorders Coronary artery disease	0.00% 0/20 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study	2.5% 1/40 • Number of events 1 • 3 years (entire study period) Adverse events were assessed at every study visit during the 3-year study