Macular Degeneration
Conditions
Keywords
Eye diseases, Vision Impairment and Blindness, Eyes and Vision, Seniors, Neovascular Age-Related Macular Degeneration (AMD), Retinal Disease
Brief summary
This study is a phase III, double-masked, randomized, study of the efficacy and safety of VEGF Trap-Eye in patients with neovascular age-related macular degeneration. Approximately 1200 patients will be randomized in Europe, Asia, Japan, Australia and South America.
Detailed description
Data of this trial (VIEW 2) was pooled with data of a sister trial (VIEW 1, NCT00509795), and an integrated analyses of the combined data was performed.
Interventions
DRUGRanibizumab
Participants received a 0.5 mg dose of Ranibizumab via intravitreal (IVT) injection administered every 4 weeks for the first year. Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks.
Participants received a 2.0 mg dose of Aflibercept Injection administered every 4 weeks for the first year. Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks.
Sponsors
Regeneron Pharmaceuticals
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed informed consent. * Men and women \>/=50 years of age. * Active primary or recurrent subfoveal CNV lesions secondary to AMD, including juxtafoveal lesions that affect the fovea as evidenced by Fluorescein angiography (FA) in the study eye. * ETDRS Best-Corrected Visual Acuity letter score of 73 to 25 (= Acuity of 20/40 to 20/320) in the study eye at 4 meters. * Willing, committed, and able to return for ALL clinic visits and complete all study-related procedures. * Able to read, (or, if unable to read due to visual impairment, be read to verbatim by the person administering the informed consent or a family member) understand and willing to sign the informed consent form.
Exclusion criteria
* Any prior ocular (in the study eye) or systemic treatment or surgery for neovascular AMD, except dietary supplements or vitamins. * Any prior or concomitant therapy with another investigational agent to treat neovascular AMD in the study eye. * Any prior treatment with anti-VEGF agents in the study eye. * Total lesion size \>12 disc areas (30.5 mm, including blood, scars and neovascularization) as assessed by FA in the study eye. * Subretinal hemorrhages that is either 50% or more of the total lesion area, or if the blood is under the fovea and is 1 or more disc areas in size in the study eye (if the blood is under the fovea, then the fovea must be surrounded by 270 degrees by visible CNV). * Scar or fibrosis making up \>50% of the total lesion in the study eye. * Scar, fibrosis, or atrophy involving the center of the fovea in the study eye. * Presence of retinal pigment epithelial tears or rips involving the macula in the study eye. * History of any vitreous hemorrhage within 4 weeks prior to Visit 1 in the study eye. * Presence of other causes of CNV in the study eye. * Prior vitrectomy in the study eye. * History of retinal detachment or treatment or surgery for retinal detachment in the study eye. * Any history of macular hole of stage 2 and above in the study eye. * Any intraocular or periocular surgery within 3 months of Day 1 on the study eye, except lid surgery, which may not have taken place within 1 month of Day 1, as long as it is unlikely to interfere with the injection. * History or clinical evidence of diabetic retinopathy, diabetic macular edema or any retinal vascular disease other than AMD in either eye.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Maintained Vision at Week 52 - Last Observation Carried Forward (LOCF) | At week 52 | Maintenance of vision was defined as a loss of \< 15 letters in the ETDRS (Early Treatment Diabetic Retinopathy Study) letter score (defined study baseline range of ETDRS Best Corrected Visual Acuity letter score of 73 to 25 (= Acuity of 20/40 to 20/320) in the study eye; a higher score represents better functioning. Nominator = (Number of participants who maintained vision \* 100); Denominator = Number of participants analyzed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by ETDRS Letter Score at Week 52 - LOCF | Baseline and at week 52 | Defined study baseline range of ETDRS Best Corrected Visual Acuity letter score of 73 to 25 (= Acuity of 20/40 to 20/320) in the study eye; a higher score represents better functioning. |
| Percentage of Participants Who Gained at Least 15 Letters of Vision in the ETDRS Letter Score in the Study Eye at Week 52 - LOCF | At week 52 | Defined study baseline range of ETDRS Best Corrected Visual Acuity letter score of 73 to 25 (= Acuity of 20/40 to 20/320) in the study eye; a higher score represents better functioning. Nominator = (Number of participants who maintained vision \* 100); Denominator = Number of participants analyzed. |
| Mean Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Total Score at Week 52 - LOCF | Baseline and at week 52 | The possible range of the NEI VFQ-25 total score is between 0 (worst possible) and 100 (best possible). |
| Mean Change From Baseline in Choroidal Neovascularization (CNV) Area at Week 52 - LOCF | Baseline and at week 52 | CNV area values measured in square millimeters; lower values represent better outcomes. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Colombia, Czechia, France, Germany, Hungary, India, Israel, Italy, Japan, Latvia, Mexico, Netherlands, Poland, Portugal, Singapore, Slovakia, South Korea, Spain, Sweden, Switzerland, United Kingdom
Participant flow
Recruitment details
The study was conducted at 186 study centers in 26 countries. Recruitment period: 21 Apr 2008 - 4 Sep 2009.
Pre-assignment details
2031 participants were screened, 1240 were randomized and 1204 received at least 1 dose of study drug. 1204 participants were included in the Safety-Analysis Set (SAS). 1202 participants with at least 1 post-baseline measurement were included in the Full-Analysis Set (FAS).
Participants by arm
| Arm | Count |
|---|---|
| Ranibizumab 0.5mg Q4 Participants received a dose of 0.5 mg Ranibizumab every 4 weeks for the first year (intravitreal \[IVT\] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks. | 291 |
| Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q4 Participants received a dose of 2.0 mg Aflibercept Injection every 4 weeks for the first year (intravitreal \[IVT\] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks. | 309 |
| Aflibercept Injection (EYLEA, VEGF Trap-Eye) 0.5mg Q4 Participants received a dose of 0.5 mg Aflibercept Injection every 4 weeks for the first year (intravitreal \[IVT\] injection). Thereafter a dose may be administered as frequently as every 4 weeks, but no less frequently than every 12 weeks. | 296 |
| Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q8 Participants received a dose of 2.0 mg Aflibercept Injection every 8 weeks (including one additional 2.0 mg dose at Week 4) for the first year (IVT injection) and were to receive sham injections at interim monthly visits. During the second year, participants received 2.0 mg aflibercept as frequently as every 4 weeks, but no less frequently than every 12 weeks. | 306 |
| Total | 1,202 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 6 | 8 | 9 |
| Overall Study | Death | 1 | 3 | 2 | 1 |
| Overall Study | Lack of Efficacy | 0 | 0 | 1 | 1 |
| Overall Study | Lost to Follow-up | 4 | 1 | 2 | 2 |
| Overall Study | Other (no further information available) | 7 | 6 | 10 | 5 |
| Overall Study | Protocol Violation | 2 | 1 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 11 | 15 | 13 | 11 |
Baseline characteristics
| Characteristic | Total | Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q8 | Aflibercept Injection (EYLEA, VEGF Trap-Eye) 0.5mg Q4 | Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q4 | Ranibizumab 0.5mg Q4 |
|---|---|---|---|---|---|
| Age, Continuous | 73.9 years STANDARD_DEVIATION 8.7 | 73.8 years STANDARD_DEVIATION 8.6 | 74.7 years STANDARD_DEVIATION 8.6 | 74.1 years STANDARD_DEVIATION 8.5 | 73.0 years STANDARD_DEVIATION 9 |
| Area of Choroidal Neovascularization (CNV) | 7.83 mm^2 STANDARD_DEVIATION 5.48 | 7.75 mm^2 STANDARD_DEVIATION 5.52 | 7.70 mm^2 STANDARD_DEVIATION 5.26 | 8.25 mm^2 STANDARD_DEVIATION 5.77 | 7.59 mm^2 STANDARD_DEVIATION 5.34 |
| Baseline lesion type Minimally classic | 425 participants | 106 participants | 103 participants | 112 participants | 104 participants |
| Baseline lesion type Missing | 5 participants | 2 participants | 0 participants | 2 participants | 1 participants |
| Baseline lesion type Occult | 462 participants | 110 participants | 113 participants | 123 participants | 116 participants |
| Baseline lesion type Predominantly classic | 310 participants | 88 participants | 80 participants | 72 participants | 70 participants |
| Baseline total lesion size | 8.28 mm^2 STANDARD_DEVIATION 5.82 | 8.22 mm^2 STANDARD_DEVIATION 5.87 | 8.17 mm^2 STANDARD_DEVIATION 5.51 | 8.72 mm^2 STANDARD_DEVIATION 6.14 | 8.01 mm^2 STANDARD_DEVIATION 5.74 |
| Best Corrected Visual Acuity (BCVA), assessed by ETDRS chart | 52.4 Letters correctly read STANDARD_DEVIATION 13.9 | 51.6 Letters correctly read STANDARD_DEVIATION 13.9 | 51.6 Letters correctly read STANDARD_DEVIATION 14.2 | 52.8 Letters correctly read STANDARD_DEVIATION 13.9 | 53.8 Letters correctly read STANDARD_DEVIATION 13.5 |
| Ethnicity Hispanic or Latino | 212 participants | 55 participants | 55 participants | 50 participants | 52 participants |
| Ethnicity Not Hispanic or Latino | 990 participants | 251 participants | 241 participants | 259 participants | 239 participants |
| National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) total score | 72.10 scores on a scale STANDARD_DEVIATION 18.99 | 71.30 scores on a scale STANDARD_DEVIATION 19.06 | 74.04 scores on a scale STANDARD_DEVIATION 18.22 | 70.27 scores on a scale STANDARD_DEVIATION 19.41 | 72.90 scores on a scale STANDARD_DEVIATION 19.09 |
| Race Asian | 257 participants | 69 participants | 61 participants | 67 participants | 60 participants |
| Race Black or African American | 4 participants | 2 participants | 1 participants | 0 participants | 1 participants |
| Race Missing | 66 participants | 18 participants | 15 participants | 16 participants | 17 participants |
| Race White | 875 participants | 217 participants | 219 participants | 226 participants | 213 participants |
| Sex: Female, Male Female | 667 Participants | 175 Participants | 147 Participants | 176 Participants | 169 Participants |
| Sex: Female, Male Male | 535 Participants | 131 Participants | 149 Participants | 133 Participants | 122 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 254 / 291 | 259 / 309 | 251 / 297 | 260 / 307 |
| serious Total, serious adverse events | 65 / 291 | 81 / 309 | 72 / 297 | 81 / 307 |
Outcome results
Primary
Percentage of Participants Who Maintained Vision at Week 52 - Last Observation Carried Forward (LOCF)
Maintenance of vision was defined as a loss of \< 15 letters in the ETDRS (Early Treatment Diabetic Retinopathy Study) letter score (defined study baseline range of ETDRS Best Corrected Visual Acuity letter score of 73 to 25 (= Acuity of 20/40 to 20/320) in the study eye; a higher score represents better functioning. Nominator = (Number of participants who maintained vision \* 100); Denominator = Number of participants analyzed.
Time frame: At week 52
Population: Per-Protocol Set (PPS); imputation technique: LOCF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ranibizumab 0.5mg Q4 | Percentage of Participants Who Maintained Vision at Week 52 - Last Observation Carried Forward (LOCF) | 94.42 Percentage of participants |
| Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q4 | Percentage of Participants Who Maintained Vision at Week 52 - Last Observation Carried Forward (LOCF) | 95.62 Percentage of participants |
| Aflibercept Injection (EYLEA, VEGF Trap-Eye) 0.5mg Q4 | Percentage of Participants Who Maintained Vision at Week 52 - Last Observation Carried Forward (LOCF) | 96.27 Percentage of participants |
| Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q8 | Percentage of Participants Who Maintained Vision at Week 52 - Last Observation Carried Forward (LOCF) | 95.56 Percentage of participants |
Comparison: null hypothesis: pi ≤ pc-delta where pi is the probability that a participant maintained vision at week 52 under Aflibercept 2mg Q4, pc is the probability that a participant maintained vision at week 52 under Ranibizumab 0.5mg Q4 and delta is the non-inferiority margin. The null hypothesis is tested calculating a two-sided 95 % confidence using normal approximation of the difference of percentages of participants maintaining vision at week 52 (Ranibizumab 0.5mg Q4 minus Aflibercept 2mg Q4).95% CI: [-4.86, 2.46]
Comparison: null hypothesis: pi ≤ pc-delta where pi is the probability that a participant maintained vision at week 52 under Aflibercept 0.5mg Q4, pc is the probability that a participant maintained vision at week 52 under Ranibizumab 0.5mg Q4 and delta is the non-inferiority margin. The null hypothesis is tested calculating a two-sided 95 % confidence using normal approximation of the difference of percentages of participants maintaining vision at week 52 (Ranibizumab 0.5mg Q4 minus Aflibercept 0.5mg Q4).95% CI: [-5.4, 1.71]
Comparison: null hypothesis: pi ≤ pc-delta where pi is the probability that a participant maintained vision at week 52 under Aflibercept 2mg Q8, pc is the probability that a participant maintained vision at week 52 under Ranibizumab 0.5mg Q4 and delta is the non-inferiority margin. The null hypothesis is tested calculating a two-sided 95 % confidence using normal approximation of the difference of percentages of participants maintaining vision at week 52 (Ranibizumab 0.5mg Q4 minus Aflibercept 2mg Q8).95% CI: [-4.81, 2.55]
Secondary
Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by ETDRS Letter Score at Week 52 - LOCF
Defined study baseline range of ETDRS Best Corrected Visual Acuity letter score of 73 to 25 (= Acuity of 20/40 to 20/320) in the study eye; a higher score represents better functioning.
Time frame: Baseline and at week 52
Population: Full-Analysis Set (FAS); imputation technique: LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranibizumab 0.5mg Q4 | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by ETDRS Letter Score at Week 52 - LOCF | 9.4 Letters correctly read | Standard Deviation 13.5 |
| Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q4 | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by ETDRS Letter Score at Week 52 - LOCF | 7.6 Letters correctly read | Standard Deviation 12.6 |
| Aflibercept Injection (EYLEA, VEGF Trap-Eye) 0.5mg Q4 | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by ETDRS Letter Score at Week 52 - LOCF | 9.7 Letters correctly read | Standard Deviation 14.1 |
| Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q8 | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by ETDRS Letter Score at Week 52 - LOCF | 8.9 Letters correctly read | Standard Deviation 14.4 |
Comparison: The pairwise comparison is performed as contrast statement in the analysis of covariance model with treatment group as fixed factor (all 4 treatment groups) and the baseline ETDRS letter score as covariate. The null hypothesis is that both mean changes are equal.p-value: 0.07695% CI: [-4.1009, 0.204]ANCOVA
Comparison: The pairwise comparison is performed as contrast statement in the analysis of covariance model with treatment group as fixed factor (all 4 treatment groups) and the baseline ETDRS letter score as covariate. The null hypothesis is that both mean changes are equal.p-value: 0.955595% CI: [-2.2398, 2.1158]ANCOVA
Comparison: The pairwise comparison is performed as contrast statement in the analysis of covariance model with treatment group as fixed factor (all 4 treatment groups) and the baseline ETDRS letter score as covariate. The null hypothesis is that both mean changes are equal.p-value: 0.413195% CI: [-3.0615, 1.2587]ANCOVA
Secondary
Mean Change From Baseline in Choroidal Neovascularization (CNV) Area at Week 52 - LOCF
CNV area values measured in square millimeters; lower values represent better outcomes.
Time frame: Baseline and at week 52
Population: Full-Analysis Set with assessment for this outcome measure; imputation technique: LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranibizumab 0.5mg Q4 | Mean Change From Baseline in Choroidal Neovascularization (CNV) Area at Week 52 - LOCF | -4.16 mm^2 | Standard Deviation 5.9 |
| Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q4 | Mean Change From Baseline in Choroidal Neovascularization (CNV) Area at Week 52 - LOCF | -5.95 mm^2 | Standard Deviation 6.12 |
| Aflibercept Injection (EYLEA, VEGF Trap-Eye) 0.5mg Q4 | Mean Change From Baseline in Choroidal Neovascularization (CNV) Area at Week 52 - LOCF | -4.24 mm^2 | Standard Deviation 6.13 |
| Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q8 | Mean Change From Baseline in Choroidal Neovascularization (CNV) Area at Week 52 - LOCF | -5.16 mm^2 | Standard Deviation 5.87 |
Comparison: The pairwise comparison is performed as contrast statement in the analysis of covariance model with treatment group as fixed factor (all 4 treatment groups) and the baseline CNV area as covariate. The null hypothesis is that both mean changes are equal.p-value: 0.003895% CI: [-1.979, -0.382]ANCOVA
Comparison: The pairwise comparison is performed as contrast statement in the analysis of covariance model with treatment group as fixed factor (all 4 treatment groups) and the baseline CNV area as covariate. The null hypothesis is that both mean changes are equal.p-value: 0.678495% CI: [-0.632, 0.972]ANCOVA
Comparison: The pairwise comparison is performed as contrast statement in the analysis of covariance model with treatment group as fixed factor (all 4 treatment groups) and the baseline CNV area as covariate. The null hypothesis is that both mean changes are equal.p-value: 0.072795% CI: [-1.534, 0.068]ANCOVA
Secondary
Mean Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Total Score at Week 52 - LOCF
The possible range of the NEI VFQ-25 total score is between 0 (worst possible) and 100 (best possible).
Time frame: Baseline and at week 52
Population: Full-Analysis Set with assessment for this outcome measure; imputation technique: LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranibizumab 0.5mg Q4 | Mean Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Total Score at Week 52 - LOCF | 6.3 Scores on a scale | Standard Deviation 14.8 |
| Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q4 | Mean Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Total Score at Week 52 - LOCF | 4.5 Scores on a scale | Standard Deviation 15 |
| Aflibercept Injection (EYLEA, VEGF Trap-Eye) 0.5mg Q4 | Mean Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Total Score at Week 52 - LOCF | 5.1 Scores on a scale | Standard Deviation 13.7 |
| Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q8 | Mean Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Total Score at Week 52 - LOCF | 4.9 Scores on a scale | Standard Deviation 14.7 |
Comparison: The pairwise comparison is performed as contrast statement in the analysis of covariance model with treatment group as fixed factor (all 4 treatment groups) and the baseline NEI VFQ-25 total score as covariate. The null hypothesis is that both mean changes are equal.p-value: 0.009795% CI: [-4.9012, -0.6757]ANCOVA
Comparison: The pairwise comparison is performed as contrast statement in the analysis of covariance model with treatment group as fixed factor (all 4 treatment groups) and the baseline NEI VFQ-25 total score as covariate. The null hypothesis is that both mean changes are equal.p-value: 0.391795% CI: [-3.0658, 1.2019]ANCOVA
Comparison: The pairwise comparison is performed as contrast statement in the analysis of covariance model with treatment group as fixed factor (all 4 treatment groups) and the baseline NEI VFQ-25 total score as covariate. The null hypothesis is that both mean changes are equal.p-value: 0.071795% CI: [-4.0659, 0.1718]ANCOVA
Secondary
Percentage of Participants Who Gained at Least 15 Letters of Vision in the ETDRS Letter Score in the Study Eye at Week 52 - LOCF
Defined study baseline range of ETDRS Best Corrected Visual Acuity letter score of 73 to 25 (= Acuity of 20/40 to 20/320) in the study eye; a higher score represents better functioning. Nominator = (Number of participants who maintained vision \* 100); Denominator = Number of participants analyzed.
Time frame: At week 52
Population: Full-Analysis Set; imputation technique: LOCF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ranibizumab 0.5mg Q4 | Percentage of Participants Who Gained at Least 15 Letters of Vision in the ETDRS Letter Score in the Study Eye at Week 52 - LOCF | 34.02 Percentage of participants |
| Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q4 | Percentage of Participants Who Gained at Least 15 Letters of Vision in the ETDRS Letter Score in the Study Eye at Week 52 - LOCF | 29.45 Percentage of participants |
| Aflibercept Injection (EYLEA, VEGF Trap-Eye) 0.5mg Q4 | Percentage of Participants Who Gained at Least 15 Letters of Vision in the ETDRS Letter Score in the Study Eye at Week 52 - LOCF | 34.80 Percentage of participants |
| Aflibercept Injection (EYLEA, VEGF Trap-Eye) 2mg Q8 | Percentage of Participants Who Gained at Least 15 Letters of Vision in the ETDRS Letter Score in the Study Eye at Week 52 - LOCF | 31.37 Percentage of participants |
Comparison: The null hypothesis is that the two proportions are equal.p-value: 0.22995% CI: [-12.02, 2.88]Chi-squared
Comparison: The null hypothesis is that the two proportions are equal.p-value: 0.84395% CI: [-6.91, 8.46]Chi-squared
Comparison: The null hypothesis is that the two proportions are equal.p-value: 0.4995% CI: [-10.18, 4.88]Chi-squared