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Study Title and Description

Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration.



Key Questions Addressed
1 What is the effect of Aflibercept for treating neovascular age-related macular degeneration?
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Primary Publication Information
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TitleData
Title Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration.
Author Heier JS., Brown DM., Chong V., Korobelnik JF., Kaiser PK., Nguyen QD., Kirchhof B., Ho A., Ogura Y., Yancopoulos GD., Stahl N., Vitti R., Berliner AJ., Soo Y., Anderesi M., Groetzbach G., Sommerauer B., Sandbrink R., Simader C., Schmidt-Erfurth U.
Country Ophthalmic Consultants of Boston and Tufts University School of Medicine, Boston, Massachusetts, USA.
Year 2012
Numbers Pubmed ID: 23084240

Secondary Publication Information
There are currently no secondary publications defined for this study.


Extraction Form: Aflibercept for neovascular age-related macular degeneration
Arms
Number Title Description Comments
1 Intravitreal aflibercept 0.5 mg every 4 weeks
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2 Intravitreal aflibercept 2.0 mg every 4 weeks
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3 Intravitreal aflibercept 2.0 mg every 8 weeks intravitreal aflibercept 2.0 mg every 8 weeks after 3 initial doses at weeks 0, 4, and 8 (to maintain masking, sham injections were given at the interim 4-week visits after week 8)
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4 Intravitreal ranibizumab 0.5 mg every 4 weeks
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Design Details
Question... Follow Up Answer Follow-up Answer
Page 2537-48
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Study design parallel-group randomized controlled trial
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Number randomly assigned 1217 total participants (1217 eyes)· 304 in the aflibercept 0.5 mg every 4 weeks group· 304 in the aflibercept 2.0 mg every 4 weeks group· 303 in the aflibercept 2.0 mg every 8 weeks group· 306 in the ranibizumab group
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Exclusions after randomization Full analysis: 7 total participants· 3 in the aflibercept 0.5 mg every 4 wee ks group, 0 in the aflibercept 2.0 mg every 4weeks group, 2 in the aflibercept 2.0 mg every 8 weeks group, and 2 in the ranibizumabgroup Safety analysis: 2 total participants (both in the ranibizumab group)
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Losses to follow-up 103 participants discontinued treatment at 1-year follow-up· 30 in the aflibercept 0.5 mg every 4 weeks group· 16 in the aflibercept 2.0 mg every 4 weeks group· 30 in the aflibercept 2.0 mg every 8 weeks group· 27 in the ranibizumab group
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Number analyzed Full analysis - 1210 total participants at 1-year follow-up· 301 in the aflibercept 0.5 mg every 4 weeks group· 304 in the aflibercept 2.0 mg every 4 weeks group,· 301 in the aflibercept 2.0 mg every 8 weeks group· 304 in the ranibizumab groupSafety analysis - 1215 total participants at 1-year follow-up· 304 in the aflibercept 0.5 mg every 4 weeks group· 304 in the aflibercept 2.0 mg every 4 weeks group· 303 in the aflibercept 2.0 mg every 8 weeks group· 304 in the ranibizumab group
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Unit of analysis individual (1 study eye per participant)How were missing data handled? missing values imputed using last observation carried forward approach
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Power calculation none reported
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Country United States and Canada (154 study sites)
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Mean age (range not reported) 78 years in the aflibercept 0.5 mg every 4 weeks group, 78 years in the aflibercept 2.0 mg every 4 weeks group, 78 years in the aflibercept 2.0 mg every 8 weeks group, and 78 years in the ranibizumab group
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Gender 134 men (44.5%) and 167 women (55.5%) in the aflibercept 0.5 mg every 4 weeks group, 110 men (36.2%) and 194 women (63.8%) in the aflibercept 2.0 mg every 4 weeks group, 123 men (40.9%) and 178 women (59.1%) in the aflibercept 2.0 mg every 8 weeks group, and 132 men (43.4%) and 172 women (56.6%) in the ranibizumab group
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Inclusion criteria 50 years of age or older; diagnosed with neovascular AMD in the study eye; active subfoveal CNV lesions of any subtype (12 optic disc areas or smaller) constituting greater than or equal to 50% of total lesion size; BCVA between 73 and 25 Early Treatment Diabetic Retinopathy Study (ETDRS) chart letters (20/40 to 20/320 Snellen equivalent); willingness and ability to return for clinic visits and complete study-related procedures; ability to provide informed consent
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Exclusion criteria prior or concomitant treatment for AMD in the study eye; prior treatment with anti-VEGF therapy; subretinal hemorrhage or scar or fibrosis constituting > 50% of total lesion size or involving the center of the fovea in the study eye; retinal pigment epithelial tears or rips involving the macula in the study eye; history of other ocular conditions such as vitreous hemorrhage, retinal detachment, macular hole, corneal transplant, corneal dystrophy, diabetic retinopathy, diabetic macular edema, uveitis, scleromalacia; presence of other ocular conditions such as uncontrolled glaucoma, significant media opacities, phakia or pseudophakia with absence of posterior capsule, intraocular inflammation or infection; prior vitrectomy, trabeculectomy, or other filtration surgery or therapy in the study eye
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Equivalence of baseline characteristics yes; "Baseline demographics and disease characteristics were evenly balanced among all treatment groups"
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Intervention 1 intravitreal aflibercept 0.5 mg every 4 weeks
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Intervention 2 intravitreal aflibercept 2.0 mg every 4 weeks
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Intervention 3 intravitreal aflibercept 2.0 mg every 8 weeks after 3 initial doses at weeks 0, 4, and 8 (to maintain masking, sham injections were given at the interim 4-week visits after week 8)
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Intervention 4 intravitreal ranibizumab 0.5 mg every 4 weeks
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Length of follow-up 1 year for primary end point; dosing for all groups changed to as needed (PRN) after 1 year and follow-up at 2 years from baseline
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Primary outcome, as defined in study reports "proportion of patients maintaining vision at week 52 (losing < 15 letters on Early Treatment Diabetic Retinopathy Study [ETDRS] chart)"
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Secondary outcomes, as defined in study reports change in BCVA, proportion gaining greater than or equal to 15 letters, change in total National Eye Institute 25-Item Visual Function Questionnaire (NEI-VFQ-25) score, change in CNV area on fluorescein angiography, retinal thickness and persistent fluid as assessed by OCT, mean number of intravitreal injections, adverse events
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Intervals at which outcomes assessed every 4 weeks through 96 weeks; week 1 after first treatment for safety assessment; weeks 12, 24, 36, and 52 for the NEI-VFQ-25 assessment
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Type of study reports published journal articles; clinical trial registration
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Funding sources "Sponsored by Regeneron Pharmaceuticals, Inc, Tarrytown, New York, and Bayer HealthCare, Berlin Germany. The sponsors participated in the design and conduct of the study, analysis of the data, and preparation of the manuscript"
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Disclosures of interest "J.S.H. is a consultant to and has received research funding from Alimera, Allergan, Fovea, Genentech, Genzyme, GlaxoSmithKline, Neovista, and Regeneron Pharmaceuticals. He has also received travel support from Regeneron Pharmaceuticals. D.M.B. is a consultant to Alimera, Allergan, Bayer, Genentech/Roche, Novartis, Regeneron Pharmaceuticals, and Thrombogenics and has received research funding from Alcon, Alimera, Allergan, Eli Lilly, Genentech, GlaxoSmithKline, Novartis, Regeneron Pharmaceuticals, and Thrombogenics. He has also received travel support from Regeneron Pharmaceuticals and lecture fees from Genentech. V.C. is a consultant to Alimera and Bayer and has received research funding from Alcon, Allergan, Bayer, Novartis, and Pfizer. He is an advisory board member for Allergan and Novartis and has also received travel support from Bayer. J.-F.K. is a consultant to Alcon, Bayer, and Thea and an advisory board member for Allergan, Bayer, and Novartis. He has received travel support from Regeneron Pharmaceuticals. P.K.K. is a consultant to Bayer, Genentech, Novartis, and Regeneron Pharmaceuticals. He has received research funding from Regeneron Pharmaceuticals. Q.D.N. is a consultant to Bausch & Lomb and Santen and has received research funding from Genentech, Novartis, and Pfizer. B.K. has received travel support from Bayer. A.H. is a consultant to Alcon, Allergan, Centocor, Johnson & Johnson, Neovista, Merck, Ophthotech, Oraya, Paloma, P.R.N., Q.L.T., Regeneron Pharmaceuticals, and Thrombogenics. He has received research funding and lecture fees from Alcon, Allergan, Genentech, Neovista, Ophthotech, Oraya, P.R.N., Q.L.T., Regeneron Pharmaceuticals, and Second Sight. Y.O. is a consultant to Alcon and Bayer and has received travel support from Bayer. G.D.Y., N.S., R.V., A.J.B., and Y.S. are employees of Regeneron Pharmaceuticals. M.A., G.G., B.S., and R.S. are employees of Bayer HealthCare. C.S.'s institution has received payments from the Medical University of Vienna for data monitoring/reviewing and statistical analysis. U.S.-E. is a consultant to Alcon, Allergan, Bayer HealthCare, and Novartis, and an advisory board member for Alcon and Novartis. She has received travel support from Bayer HealthCare and lecture fees from Bayer HealthCare and Novartis"
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Study period July 2007 to September 2010
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Subgroup analyses none reported
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Full analysis - 38 total participants
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Safety analysis - 36 total participants
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Random sequence generation (selection bias):Authors' judgement Unclear risk
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Random sequence generation (selection bias):Support for judgement The method of random sequence generation was unclear. &";Consecutively enrolled patients were assigned to treatment groups on the basis of a predetermined central randomization scheme with balanced allocation, managed by an interactive voice response system&";
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Allocation concealment (selection bias):Authors' judgement Low risk
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Allocation concealment (selection bias):Support for judgement Central randomization: &";Consecutively enrolled patients were assigned to treatment groups on the basis of a predetermined central randomization scheme with balanced allocation, managed by an interactive voice response system&";
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Masking of participants and personnel (performance bias):Authors' judgement Low risk
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Masking of participants and personnel (performance bias):Support for judgement &";Patients were masked as to treatments. An unmasked investigator also was responsible for the receipt, tracking, preparation, destruction, and administration of study drug, as well as safety assessments both pre- and post-dose...All other study site personnel were masked to treatment assignment by separating study records or masked packaging&";
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Masking of outcome assessment (detection bias):Authors' judgement Low risk
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Masking of outcome assessment (detection bias):Support for judgement &";A separate masked physician assessed adverse events and supervised the masked assessment of efficacy. All other study site personnel were masked to treatment assignment by separating study records or masked packaging. Optical coherence tomography technicians and visual acuity examiners remained masked relative to treatment assignment&";
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Incomplete outcome data (attrition bias):Authors' judgement Low risk
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Incomplete outcome data (attrition bias):Support for judgement A full analysis set and a per protocol set were reported. Last observation carried forward (LOCF) approach was used to impute missing values; 91.1% to 96.4% of participants per treatment group completed 52 weeks of follow-up
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Selective reporting (reporting bias):Authors' judgement Low risk
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Selective reporting (reporting bias):Support for judgement The study was registered at clinicaltrials.gov; intended outcomes were reported
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Other bias:Authors' judgement High risk
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Other bias:Support for judgement Many authors are employees of, consultants to, or have received research funding from Regeneron Pharmaceuticals, which manufactures aflibercept and participated in the design of the trial, collected and analyzed data, and prepared the study reports
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Results & Comparisons


Results Data
Outcome: Proportion of patients who lost >15 letters of BCVA at 1 year and 2 years      Population: All Participants
Time Point Measure Intravitreal aflibercept 0.5 mg every 4 weeks Intravitreal aflibercept 2.0 mg every 4 weeks Intravitreal aflibercept 2.0 mg every 8 weeks Intravitreal ranibizumab 0.5 mg every 4 weeks


1 years

N Analyzed 301 304 301 304
Unit 15 (5%) 15 (4.9%) 17 (5.6%) 19 (6.3%)
Outcome: Mean change in BCVA at 1 year      Population: All Participants
Time Point Measure Intravitreal aflibercept 0.5 mg every 4 weeks Intravitreal aflibercept 2.0 mg every 4 weeks Intravitreal aflibercept 2.0 mg every 8 weeks Intravitreal ranibizumab 0.5 mg every 4 weeks


1 years

N Analyzed 301 304 301 304
Mean 6.9 10.9 7.9 8.1
SD 13.4 13.8 15.0 15.3
Outcome: Proportion gaining greater than or equal to 15 letters      Population: All Participants
Time Point Measure Intravitreal aflibercept 0.5 mg every 4 weeks Intravitreal aflibercept 2.0 mg every 4 weeks Intravitreal aflibercept 2.0 mg every 8 weeks Intravitreal ranibizumab 0.5 mg every 4 weeks


1 years

N Analyzed 301 304 301 304
Unit 75 (24.9%) 114 (37.5%) 92 (30.6%) 94 (30.9%)


2 years

N Analyzed
Mean
SD
Outcome: Quality-of-life improvement      Population: All Participants
Time Point Measure Intravitreal aflibercept 0.5 mg every 4 weeks Intravitreal aflibercept 2.0 mg every 4 weeks Intravitreal aflibercept 2.0 mg every 8 weeks Intravitreal ranibizumab 0.5 mg every 4 weeks


1 years

N Analyzed 301 304 301 304
Mean 4.5 6.7 5.1 4.9
SD 11.9 13.5 14.7 14.0
Outcome: Change in CNV area on fluorescein angiography      Population: All Participants
Time Point Measure Intravitreal aflibercept 0.5 mg every 4 weeks Intravitreal aflibercept 2.0 mg every 4 weeks Intravitreal aflibercept 2.0 mg every 8 weeks Intravitreal ranibizumab 0.5 mg every 4 weeks


1 years

N Analyzed 301 304 301 304
Mean -3.5 -4.6 -3.4 -4.2
SD 5.3 5.5 6.0 5.6
Outcome: Retinal thickness      Population: All Participants
Time Point Measure Intravitreal aflibercept 0.5 mg every 4 weeks Intravitreal aflibercept 2.0 mg every 4 weeks Intravitreal aflibercept 2.0 mg every 8 weeks Intravitreal ranibizumab 0.5 mg every 4 weeks


1 years

N Analyzed 301 304 301 304
Mean -115.6 -116.5 -128.5 -116.8
SD 104.1 98.4 108.5 109.0
Outcome: Absence of fluid events      Population: All Participants
Time Point Measure Intravitreal aflibercept 0.5 mg every 4 weeks Intravitreal aflibercept 2.0 mg every 4 weeks Intravitreal aflibercept 2.0 mg every 8 weeks Intravitreal ranibizumab 0.5 mg every 4 weeks


2 years

N Analyzed 270 285 265 269
Unit 148 (54.8%) 184 (64.6%) 168 (63.4%) 171 (63.6%)
Outcome: Mean number of intravitreal injections      Population: All Participants
Time Point Measure Intravitreal aflibercept 0.5 mg every 4 weeks Intravitreal aflibercept 2.0 mg every 4 weeks Intravitreal aflibercept 2.0 mg every 8 weeks Intravitreal ranibizumab 0.5 mg every 4 weeks


2 years

N Analyzed
Unit
Outcome: Mean change in BCVA at 2 years      Population: All Participants
Time Point Measure Intravitreal aflibercept 0.5 mg every 4 weeks Intravitreal aflibercept 2.0 mg every 4 weeks Intravitreal aflibercept 2.0 mg every 8 weeks Intravitreal ranibizumab 0.5 mg every 4 weeks


2 years

N Analyzed
Mean
SD

Adverse Events
Arm or Total Title Description Proportion of participants/eyes Comments
Intravitreal aflibercept 0.5 mg every 4 weeks Arterial thrombotic events 7 (2.3%)
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Intravitreal aflibercept 2.0 mg every 4 weeks 2 (0.7%)
Intravitreal aflibercept 2.0 mg every 8 weeks 6 (2.0%)
Intravitreal ranibizumab 0.5 mg every 4 weeks 5 (1.6%)
Total 20 (1.6%)
Intravitreal aflibercept 0.5 mg every 4 weeks Serious systemic adverse events 50 (16.4%)
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Intravitreal aflibercept 2.0 mg every 4 weeks 40 (13.2%)
Intravitreal aflibercept 2.0 mg every 8 weeks 51 (16.8%)
Intravitreal ranibizumab 0.5 mg every 4 weeks 57 (18.8%)
Total 198 (16.3%)
Intravitreal aflibercept 0.5 mg every 4 weeks Serious ocular adverse events 2 (0.7%)
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Intravitreal aflibercept 2.0 mg every 4 weeks 4 (1.3%)
Intravitreal aflibercept 2.0 mg every 8 weeks 2 (0.7%)
Intravitreal ranibizumab 0.5 mg every 4 weeks 7 (2.3%)
Total 15 (1.2%)