Retinal Vein Occlusion
Conditions
Keywords
Macular Edema, Central Retinal Vein Occlusion, CRVO, VEGF Trap-Eye, best-corrected visual acuity
Brief summary
To determine the efficacy of vascular endothelial growth factor (VEGF) Trap-Eye injected into the eye on vision function in subjects with macular edema as a consequence of central retinal vein occlusion
Interventions
Intravitreal injection. Weeks 0 to 20 of Aflibercept Injection every 4 weeks; Weeks 24 to 52 every 4 weeks PRN (pro re nata, on demand); plus additional on Week 60 and 68.
OTHERSham treatment
Sham treatment. Weeks 0 to 52 sham treatment every 4 weeks; plus additional on Week 60 and 68.
Sponsors
Regeneron Pharmaceuticals
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Center-involved macular edema secondary to central retinal vein occlusion (CRVO) for no longer than 9 months with mean central subfield thickness ≥ 250 μm on optical coherence tomography (OCT) * Adults ≥ 18 years * Early treatment diabetic retinopathy study (ETDRS) best corrected visual acuity (BCVA) of 20/40 to 20/320 (73 to 24 letters) in the study eye
Exclusion criteria
* Any prior treatment with anti-VEGF agents in the study eye (Pegaptanib sodium, anecortave acetate, bevacizumab, ranibizumab, etc.) or previous administration of systemic anti-angiogenic medications * Prior panretinal laser photocoagulation or macular laser photocoagulation in the study eye * CRVO disease duration \> 9 months from date of diagnosis * Previous use of intraocular corticosteroids in the study eye or use of periocular corticosteroids in the study eye within the 3 months prior to Day 1 * Iris neovascularization, vitreous hemorrhage, traction retinal detachment, or preretinal fibrosis involving the macula in either the study eye or fellow eye
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Gained at Least 15 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 24 With Discontinued Participants Before Week 24 Evaluated as Failures | Baseline and Week 24 | Defined study baseline range of Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score of 73 to 24 (= 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 |
|---|---|---|
| Percentage of Participants Who Developed Neovascularization During the First 24 Weeks | From baseline until Week 24 | Formation of blood vessels in the anterior segment, optic disc, or elsewhere in the fundus up to Week 24 |
| Change From Baseline in BCVA as Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Week 24 - Last Observation Carried Forward (LOCF) | Baseline and Week 24 | Defined study baseline range of ETDRS Best Corrected Visual Acuity letter score of 73 to 24 (= Acuity of 20/40 to 20/320) in the study eye; a higher score represents better functioning. However, because this was assessed at the screening visit, subjects may have had a higher BCVA recorded at the baseline visit and would not have been excluded from the study. |
| Change From Baseline in Central Retinal Thickness (CRT) at Week 24 - LOCF | Baseline and Week 24 | — |
| Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Total Score at Week 24 - LOCF | Baseline and Week 24 | The NEI VFQ-25 total score ranges from 0-100 with a score of 0 being the worst outcome and 100 being the best outcome. The NEI VFQ questionnaire is organized as a collection of subscales which are all scored from 0-100. To reach the overall composite score, each sub-scale score is averaged in order to give each sub-scale equal weight |
| Change From Baseline in European Five-dimensional Health Scale (EQ-5D) Score at Week 24 - LOCF | Baseline and Week 24 | EQ-5D is a quality of life questionnaire based on a scale from -0.594 (worst) to 1.00 (best). |
Countries
Australia, Austria, France, Germany, Hungary, Italy, Japan, Latvia, Singapore, South Korea
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321) Participants received a 2 mg dose of Intravitreal Aflibercept Injection (IAI) administered every 4 weeks from Day 1 through Week 20, later as often as every 4 weeks depending on the study retreatment criteria from Week 24 through Week 48. Follow-up phase: Participants on IAI, who continued the study, received 2 mg dose of IAI depending on the study retreatment criteria at Week 60 and 68. | 104 |
| Sham Treatment Participants received sham treatment administered every 4 weeks from Day 1 through Week 52. Follow-up phase: Participants on sham treatment, who switched to Intravitreal Aflibercept Injection (IAI), received a 2 mg dose of IAI at week 52 and depending on the study retreatment criteria at Week 60 and 68. | 68 |
| Total | 172 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 5 |
| Overall Study | Increase in vis. acuity, never injected | 0 | 1 |
| Overall Study | Lack of Efficacy | 0 | 5 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | (Overseas travel - indefinite period) | 1 | 0 |
| Overall Study | Protocol Violation | 5 | 2 |
| Overall Study | Withdrawal by Subject | 4 | 6 |
Baseline characteristics
| Characteristic | Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321) | Sham Treatment | Total |
|---|---|---|---|
| Age, Continuous | 60.0 Years STANDARD_DEVIATION 12.3 | 63.8 Years STANDARD_DEVIATION 13.3 | 61.5 Years STANDARD_DEVIATION 12.8 |
| Baseline Best Corrected Visual Acuity (BCVA) letter scores | 53.5 Letters correctly read STANDARD_DEVIATION 15.7 | 50.9 Letters correctly read STANDARD_DEVIATION 15.4 | 52.5 Letters correctly read STANDARD_DEVIATION 15.6 |
| Baseline intraocular pressure | 15.2 mm Hg STANDARD_DEVIATION 2.8 | 14.4 mm Hg STANDARD_DEVIATION 2.7 | 14.9 mm Hg STANDARD_DEVIATION 2.8 |
| Baseline National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) total score | 79.66 scores on a scale STANDARD_DEVIATION 13.06 | 78.94 scores on a scale STANDARD_DEVIATION 14 | 79.38 scores on a scale STANDARD_DEVIATION 13.4 |
| Baseline Retinal Thickness by Optical Coherence Tomography (OCT) | 682.78 microns STANDARD_DEVIATION 233.36 | 638.66 microns STANDARD_DEVIATION 224.69 | 665.34 microns STANDARD_DEVIATION 230.33 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 1 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 100 Participants | 66 Participants | 166 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| European questionnaire 5 dimensions (EQ-5D) total score | 0.87 score on a scale STANDARD_DEVIATION 0.15 | 0.86 score on a scale STANDARD_DEVIATION 0.16 | 0.87 score on a scale STANDARD_DEVIATION 0.15 |
| Number of participants with baseline retinal perfusion Indeterminate | 7 Participants | 7 Participants | 14 Participants |
| Number of participants with baseline retinal perfusion Nonperfused | 7 Participants | 7 Participants | 14 Participants |
| Number of participants with baseline retinal perfusion Perfused | 90 Participants | 54 Participants | 144 Participants |
| Number of participants with time since Central retinal vein occlusion (CRVO) diagnosis < 2 months | 56 Participants | 35 Participants | 91 Participants |
| Number of participants with time since Central retinal vein occlusion (CRVO) diagnosis >= 2 months | 46 Participants | 33 Participants | 79 Participants |
| Number of participants with time since Central retinal vein occlusion (CRVO) diagnosis Missing | 2 Participants | 0 Participants | 2 Participants |
| Race Asian | 26 Participants | 15 Participants | 41 Participants |
| Race Unknown or Not Reported | 3 Participants | 4 Participants | 7 Participants |
| Race White | 75 Participants | 49 Participants | 124 Participants |
| Sex: Female, Male Female | 45 Participants | 31 Participants | 76 Participants |
| Sex: Female, Male Male | 59 Participants | 37 Participants | 96 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 52 / 104 | 44 / 68 | 66 / 97 | 30 / 57 | 38 / 91 | 19 / 52 |
| serious Total, serious adverse events | 8 / 104 | 8 / 68 | 14 / 97 | 7 / 57 | 4 / 91 | 3 / 52 |
Outcome results
Primary
Percentage of Participants Who Gained at Least 15 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 24 With Discontinued Participants Before Week 24 Evaluated as Failures
Defined study baseline range of Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score of 73 to 24 (= 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: Baseline and Week 24
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321) | Percentage of Participants Who Gained at Least 15 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 24 With Discontinued Participants Before Week 24 Evaluated as Failures | 60.2 Percentage of participants |
| Sham Treatment | Percentage of Participants Who Gained at Least 15 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 24 With Discontinued Participants Before Week 24 Evaluated as Failures | 22.1 Percentage of participants |
Comparison: Null hypothesis of difference of Eylea minus Sham of 0 was tested. In the database close after Week 24, basis for primary efficacy evaluation, 56 Sham / 96 Eylea subjects were considered as week 24 completers.p-value: <0.000195% CI: [24.4, 52.1]Cochran-Mantel-Haenszel
Secondary
Change From Baseline in BCVA as Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Week 24 - Last Observation Carried Forward (LOCF)
Defined study baseline range of ETDRS Best Corrected Visual Acuity letter score of 73 to 24 (= Acuity of 20/40 to 20/320) in the study eye; a higher score represents better functioning. However, because this was assessed at the screening visit, subjects may have had a higher BCVA recorded at the baseline visit and would not have been excluded from the study.
Time frame: Baseline and Week 24
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321) | Change From Baseline in BCVA as Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Week 24 - Last Observation Carried Forward (LOCF) | 71.6 Letters correctly read | Standard Deviation 17.1 |
| Sham Treatment | Change From Baseline in BCVA as Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Week 24 - Last Observation Carried Forward (LOCF) | 54.3 Letters correctly read | Standard Deviation 20.2 |
Comparison: Null hypothesis was equality in change from baseline to Week 24 in BCVA total letter score between Eylea and Sham. If primary efficacy was successful, secondary efficacy endpoints were tested in a pre-specified fixed sequence testing procedure. Change in BCVA letter score was to be tested first in this sequence.p-value: <0.000195% CI: [10.8, 18.7]ANOVA
Secondary
Change From Baseline in Central Retinal Thickness (CRT) at Week 24 - LOCF
Time frame: Baseline and Week 24
Population: Full-Analysis Set with assessment for this outcome measure; imputation technique: LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321) | Change From Baseline in Central Retinal Thickness (CRT) at Week 24 - LOCF | -448.58 microns | Standard Deviation 256.02 |
| Sham Treatment | Change From Baseline in Central Retinal Thickness (CRT) at Week 24 - LOCF | -169.27 microns | Standard Deviation 224.72 |
Comparison: Null hypothesis was equality in change from baseline to Week 24 in central retinal thickness between Eylea and Sham. If primary efficacy was successful, secondary efficacy end points were to be tested in a pre-specified fixed sequence testing procedure. Change in central retinal thickness was to be tested at second place in this sequence.p-value: <0.000195% CI: [-286.31, -192.53]ANCOVA
Secondary
Change From Baseline in European Five-dimensional Health Scale (EQ-5D) Score at Week 24 - LOCF
EQ-5D is a quality of life questionnaire based on a scale from -0.594 (worst) to 1.00 (best).
Time frame: Baseline and Week 24
Population: Full-Analysis Set with assessment for this outcome measure; imputation technique: LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321) | Change From Baseline in European Five-dimensional Health Scale (EQ-5D) Score at Week 24 - LOCF | 0.029 Scores on a scale | Standard Deviation 0.139 |
| Sham Treatment | Change From Baseline in European Five-dimensional Health Scale (EQ-5D) Score at Week 24 - LOCF | -0.002 Scores on a scale | Standard Deviation 0.195 |
95% CI: [-0.002, 0.09]
Secondary
Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Total Score at Week 24 - LOCF
The NEI VFQ-25 total score ranges from 0-100 with a score of 0 being the worst outcome and 100 being the best outcome. The NEI VFQ questionnaire is organized as a collection of subscales which are all scored from 0-100. To reach the overall composite score, each sub-scale score is averaged in order to give each sub-scale equal weight
Time frame: Baseline and Week 24
Population: Full-Analysis Set with assessment for this outcome measure; imputation technique: LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321) | Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Total Score at Week 24 - LOCF | 7.46 Scores on a scale | Standard Deviation 9.55 |
| Sham Treatment | Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Total Score at Week 24 - LOCF | 3.55 Scores on a scale | Standard Deviation 9.74 |
95% CI: [1.7, 6.8]
Secondary
Percentage of Participants Who Developed Neovascularization During the First 24 Weeks
Formation of blood vessels in the anterior segment, optic disc, or elsewhere in the fundus up to Week 24
Time frame: From baseline until Week 24
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321) | Percentage of Participants Who Developed Neovascularization During the First 24 Weeks | Any neovascularization | 2.9 Percentage of participants |
| Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321) | Percentage of Participants Who Developed Neovascularization During the First 24 Weeks | Anterior segment neovascularization | 1.9 Percentage of participants |
| Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321) | Percentage of Participants Who Developed Neovascularization During the First 24 Weeks | Neovascularization of the optic disc (NVD) | 0.0 Percentage of participants |
| Aflibercept Injection (EYLEA, VEGF Trap-Eye, BAY86-5321) | Percentage of Participants Who Developed Neovascularization During the First 24 Weeks | Neovascularization elsewhere in the fundus (NVE) | 1.0 Percentage of participants |
| Sham Treatment | Percentage of Participants Who Developed Neovascularization During the First 24 Weeks | Neovascularization elsewhere in the fundus (NVE) | 2.9 Percentage of participants |
| Sham Treatment | Percentage of Participants Who Developed Neovascularization During the First 24 Weeks | Any neovascularization | 4.4 Percentage of participants |
| Sham Treatment | Percentage of Participants Who Developed Neovascularization During the First 24 Weeks | Neovascularization of the optic disc (NVD) | 0.0 Percentage of participants |
| Sham Treatment | Percentage of Participants Who Developed Neovascularization During the First 24 Weeks | Anterior segment neovascularization | 1.5 Percentage of participants |
Comparison: Nullhypothesis of no difference in development of neovascularizations between Eylea and Sham group was tested. (Any neovascularization)p-value: 0.594795% CI: [-7.4, 4.4]Cochran-Mantel-Haenszel