Macular Edema
Conditions
Keywords
Diabetic Macular Edema, DME, VEGF Trap-Eye, best-corrected visual acuity (BCVA)
Brief summary
To determine the efficacy of intravitreally (IVT) administered VEGF Trap-Eye on the best-corrected visual acuity (BCVA) assessed by the early treatment diabetic retinopathy study (ETDRS) chart in subjects with diabetic macular edema (DME) with central involvement.
Interventions
BIOLOGICALAflibercept (Eylea, VEGF Trap-Eye, BAY86-5321)
Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks (2Q4).
PROCEDUREMacular Laser Photocoagulation
Participants received laser treatment at baseline and as needed at visits at which laser retreatment criteria were met, but no more frequently than every 12 weeks.
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
* Adults ≥ 18 years with type 1 or 2 diabetes mellitus * Subjects with diabetic macular edema (DME) secondary to diabetes mellitus involving the center of the macula in the study eye * Decrease in vision determined to be primarily the result of DME in the study eye * Best-corrected visual acuity (BCVA) early treatment diabetic retinopathy study (ETDRS) letter score of 73 to 24 (20/40 to 20/320) in the study eye
Exclusion criteria
* Laser photocoagulation (panretinal or macular) in the study eye within 90 days of Day 1 * More than 2 previous macular laser treatments in the study eye * Previous use of intraocular or periocular corticosteroids in the study eye within 120 days of Day 1 * Previous treatment with antiangiogenic drugs in either eye (pegaptanib sodium, bevacizumab, ranibizumab etc.) within 90 days of Day 1 * Active proliferative diabetic retinopathy (PDR) in the study eye * Uncontrolled diabetes mellitus, as defined by HbA1c \>12% * Only 1 functional eye even if that eye is otherwise eligible for the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Week 52 - Last Observation Carried Forward (LOCF) | Baseline up to week 52 | Visual function of the study eye was assessed using the ETDRS protocol, which is a widely accepted international standard for macular laser photocoagulation treatment. A higher score represents better functioning. LOCF censored measurements after additional treatment. |
Secondary
| 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 52 - LOCF | Baseline up to week 52 | Visual function of the study eye was assessed using the ETDRS protocol. A higher score represents better functioning. |
| Percentage of Participants With a Greater Than Equal (>=) Two-step Improvement From Baseline in the ETDRS Diabetic Retinopathy Severity Score (DRSS) as Assessed by Fundus Photography (FP) at Week 52 - LOCF | Baseline up to week 52 | ETDRS DRSS: None (level 10); Mild to moderate nonproliferative diabetic retinopathy (DR) (levels 14, 15, 20, 35, and 43); Moderately severe/severe nonproliferative DR (levels 47 and 53); Mild/moderate/high-risk/advanced proliferative DR (levels 61, 65, 71,75, 81, and 85) |
| Percentage of Participants Who Gained at Least 10 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 52 - LOCF | Baseline up to week 52 | Visual function of the study eye was assessed using the ETDRS protocol. A higher score represents better functioning. |
| Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Near Activities Subscale at Week 52 - LOCF | Baseline up to week 52 | 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 that are all scored from 0-100. Near activities are defined as reading ordinary print in newspapers, performing work or hobbies requiring near vision, or finding something on a crowded shelf. |
| Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Distance Activities Subscale at Week 52 - LOCF | Baseline up to week 52 | 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 that are all scored from 0-100. Distance activities are defined as reading street signs or names on stores, and going down stairs, steps, or curbs. |
| Change From Baseline in Central Retinal Thickness (CRT) at Week 52 as Assessed on Optical Coherence Tomography (OCT) - LOCF | Baseline up to week 52 | CRT was assessed using spectral domain optical coherence tomography (SD-OCT), a non-invasive diagnostic system providing high-resolution imaging sections of the retina. SD-OCT was performed in the study eye after pupil dilation. A negative change from Baseline indicated improvement. |
Countries
China, Hong Kong, Russia, South Korea
Participant flow
Recruitment details
The study was conducted at centers in China, Hong Kong, South Korea, and Russian Federation between 18 February 2013 (first participant first visit) and 09 March 2015 (last participant last visit) (data cut-off date).
Pre-assignment details
Overall 539 participants were screened, of them 381 participants were randomized, and 378 participants were allocated to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Intravitreal Aflibercept Injection 2Q4 Participants received 2 mg Intravitreal aflibercept injection (IAI) (Eylea, VEGF \[vascular endothelial growth factor\] Trap-Eye, BAY86-5321) 2Q4 over 48 weeks. | 127 |
| Intravitreal Aflibercept Injection 2Q8 Participants received 2 mg Intravitreal aflibercept injection (IAI) (Eylea, VEGF Trap-Eye, BAY86-5321) every 4 weeks until Week 16 and every 8 weeks (2Q8) thereafter, over 48 weeks. | 127 |
| Macular Laser Photocoagulation Participants received laser treatment at baseline and as needed at visits at which laser retreatment criteria were met, but no more frequently than every 12 weeks over 48 weeks. | 124 |
| Total | 378 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 5 | 4 |
| Overall Study | Lost to Follow-up | 0 | 3 | 0 |
| Overall Study | Protocol deviation | 0 | 0 | 2 |
| Overall Study | Withdrawal of consent by participant | 1 | 3 | 4 |
Baseline characteristics
| Characteristic | Intravitreal Aflibercept Injection 2Q4 | Intravitreal Aflibercept Injection 2Q8 | Macular Laser Photocoagulation | Total |
|---|---|---|---|---|
| Age, Continuous | 59.3 years STANDARD_DEVIATION 10.3 | 57.6 years STANDARD_DEVIATION 10.1 | 58.8 years STANDARD_DEVIATION 10.5 | 58.5 years STANDARD_DEVIATION 10.3 |
| Region of Enrollment China | 101 participants | 101 participants | 99 participants | 301 participants |
| Region of Enrollment Other Asia-Pacific (Hong Kong, Korea) | 16 participants | 16 participants | 16 participants | 48 participants |
| Region of Enrollment Russia | 10 participants | 10 participants | 9 participants | 29 participants |
| Sex: Female, Male Female | 68 Participants | 60 Participants | 60 Participants | 188 Participants |
| Sex: Female, Male Male | 59 Participants | 67 Participants | 64 Participants | 190 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 87 / 127 | 83 / 127 | 89 / 124 |
| serious Total, serious adverse events | 19 / 127 | 22 / 127 | 24 / 124 |
Outcome results
Primary
Change From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Week 52 - Last Observation Carried Forward (LOCF)
Visual function of the study eye was assessed using the ETDRS protocol, which is a widely accepted international standard for macular laser photocoagulation treatment. A higher score represents better functioning. LOCF censored measurements after additional treatment.
Time frame: Baseline up to week 52
Population: Full analysis set (FAS) included all randomized participants who received any study treatment, had a baseline measurement of BCVA, and had at least 1 post-baseline assessment of BCVA. FAS with assessment for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intravitreal Aflibercept Injection 2Q4 | Change From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Week 52 - Last Observation Carried Forward (LOCF) | 13.7 Letters correctly read | Standard Deviation 8.4 |
| Intravitreal Aflibercept Injection 2Q8 | Change From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Week 52 - Last Observation Carried Forward (LOCF) | 12.8 Letters correctly read | Standard Deviation 9.5 |
| Macular Laser Photocoagulation | Change From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Week 52 - Last Observation Carried Forward (LOCF) | -0.2 Letters correctly read | Standard Deviation 13.5 |
p-value: <0.000197.5% CI: [10.9, 17.2]ANCOVA
p-value: <0.000197.5% CI: [10.2, 16.9]ANCOVA
Secondary
Change From Baseline in Central Retinal Thickness (CRT) at Week 52 as Assessed on Optical Coherence Tomography (OCT) - LOCF
CRT was assessed using spectral domain optical coherence tomography (SD-OCT), a non-invasive diagnostic system providing high-resolution imaging sections of the retina. SD-OCT was performed in the study eye after pupil dilation. A negative change from Baseline indicated improvement.
Time frame: Baseline up to week 52
Population: FAS with assessment for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intravitreal Aflibercept Injection 2Q4 | Change From Baseline in Central Retinal Thickness (CRT) at Week 52 as Assessed on Optical Coherence Tomography (OCT) - LOCF | -238.7 micrometer | Standard Deviation 172.5 |
| Intravitreal Aflibercept Injection 2Q8 | Change From Baseline in Central Retinal Thickness (CRT) at Week 52 as Assessed on Optical Coherence Tomography (OCT) - LOCF | -234.7 micrometer | Standard Deviation 160.8 |
| Macular Laser Photocoagulation | Change From Baseline in Central Retinal Thickness (CRT) at Week 52 as Assessed on Optical Coherence Tomography (OCT) - LOCF | -109.3 micrometer | Standard Deviation 206.9 |
p-value: <0.000197.5% CI: [-171.2, -89.9]ANCOVA
p-value: <0.000197.5% CI: [-172.8, -89.9]ANCOVA
Secondary
Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Distance Activities Subscale at Week 52 - 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 that are all scored from 0-100. Distance activities are defined as reading street signs or names on stores, and going down stairs, steps, or curbs.
Time frame: Baseline up to week 52
Population: FAS with assessment for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intravitreal Aflibercept Injection 2Q4 | Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Distance Activities Subscale at Week 52 - LOCF | 3.93 Scores on a scale | Standard Deviation 22.36 |
| Intravitreal Aflibercept Injection 2Q8 | Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Distance Activities Subscale at Week 52 - LOCF | 10.25 Scores on a scale | Standard Deviation 21.44 |
| Macular Laser Photocoagulation | Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Distance Activities Subscale at Week 52 - LOCF | 0.04 Scores on a scale | Standard Deviation 23.14 |
p-value: 0.268897.5% CI: [-2.9, 8.53]ANCOVA
p-value: 0.000997.5% CI: [2.64, 13.37]ANCOVA
Secondary
Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Near Activities Subscale at Week 52 - 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 that are all scored from 0-100. Near activities are defined as reading ordinary print in newspapers, performing work or hobbies requiring near vision, or finding something on a crowded shelf.
Time frame: Baseline up to week 52
Population: FAS with assessment for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intravitreal Aflibercept Injection 2Q4 | Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Near Activities Subscale at Week 52 - LOCF | 6.65 Scores on a scale | Standard Deviation 23.86 |
| Intravitreal Aflibercept Injection 2Q8 | Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Near Activities Subscale at Week 52 - LOCF | 7.28 Scores on a scale | Standard Deviation 22.95 |
| Macular Laser Photocoagulation | Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Near Activities Subscale at Week 52 - LOCF | 0.04 Scores on a scale | Standard Deviation 24.39 |
p-value: 0.036497.5% CI: [-0.41, 11.97]ANCOVA
p-value: 0.011397.5% CI: [0.8, 12.94]ANCOVA
Secondary
Percentage of Participants Who Gained at Least 10 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 52 - LOCF
Visual function of the study eye was assessed using the ETDRS protocol. A higher score represents better functioning.
Time frame: Baseline up to week 52
Population: FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intravitreal Aflibercept Injection 2Q4 | Percentage of Participants Who Gained at Least 10 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 52 - LOCF | 70.9 Percentage of participants |
| Intravitreal Aflibercept Injection 2Q8 | Percentage of Participants Who Gained at Least 10 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 52 - LOCF | 62.7 Percentage of participants |
| Macular Laser Photocoagulation | Percentage of Participants Who Gained at Least 10 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 52 - LOCF | 23.4 Percentage of participants |
p-value: <0.000197.5% CI: [35, 59.9]Cochran-Mantel-Haenszel
p-value: <0.000197.5% CI: [26.3, 52.1]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Gained at Least 15 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 52 - LOCF
Visual function of the study eye was assessed using the ETDRS protocol. A higher score represents better functioning.
Time frame: Baseline up to week 52
Population: FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intravitreal Aflibercept Injection 2Q4 | Percentage of Participants Who Gained at Least 15 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 52 - LOCF | 43.3 Percentage of participants |
| Intravitreal Aflibercept Injection 2Q8 | Percentage of Participants Who Gained at Least 15 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 52 - LOCF | 36.5 Percentage of participants |
| Macular Laser Photocoagulation | Percentage of Participants Who Gained at Least 15 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 52 - LOCF | 12.1 Percentage of participants |
p-value: <0.000197.5% CI: [19.2, 43]Cochran-Mantel-Haenszel
p-value: <0.000197.5% CI: [12.6, 35.9]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With a Greater Than Equal (>=) Two-step Improvement From Baseline in the ETDRS Diabetic Retinopathy Severity Score (DRSS) as Assessed by Fundus Photography (FP) at Week 52 - LOCF
ETDRS DRSS: None (level 10); Mild to moderate nonproliferative diabetic retinopathy (DR) (levels 14, 15, 20, 35, and 43); Moderately severe/severe nonproliferative DR (levels 47 and 53); Mild/moderate/high-risk/advanced proliferative DR (levels 61, 65, 71,75, 81, and 85)
Time frame: Baseline up to week 52
Population: FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intravitreal Aflibercept Injection 2Q4 | Percentage of Participants With a Greater Than Equal (>=) Two-step Improvement From Baseline in the ETDRS Diabetic Retinopathy Severity Score (DRSS) as Assessed by Fundus Photography (FP) at Week 52 - LOCF | 60.7 Percentage of participants |
| Intravitreal Aflibercept Injection 2Q8 | Percentage of Participants With a Greater Than Equal (>=) Two-step Improvement From Baseline in the ETDRS Diabetic Retinopathy Severity Score (DRSS) as Assessed by Fundus Photography (FP) at Week 52 - LOCF | 62.3 Percentage of participants |
| Macular Laser Photocoagulation | Percentage of Participants With a Greater Than Equal (>=) Two-step Improvement From Baseline in the ETDRS Diabetic Retinopathy Severity Score (DRSS) as Assessed by Fundus Photography (FP) at Week 52 - LOCF | 21.7 Percentage of participants |
p-value: <0.000197.5% CI: [26, 52.2]Cochran-Mantel-Haenszel
p-value: <0.000197.5% CI: [27.6, 53.7]Cochran-Mantel-Haenszel