Diabetes Mellitus, 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
BIOLOGICALVEGF Trap-Eye (BAY86-5321)
Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks (2Q4).
PROCEDUREMacular Laser Photocoagulation (Control)
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 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 * BCVA 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, with the exception of inactive, regressed PDR * 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 BCVA (Best Corrected Visual Acuity) 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. A higher score represents better functioning. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| Percentage of Participants With a ≥2-step Improvement From Baseline in the ETDRS DRSS (Diabetic Retinopathy Severity Score) as Assessed by FP (Fundus Photography) at Week 52 - LOCF | Baseline up to Week 52 | Baseline ETDRS DRSS: None (level 10); Mild to moderate nonproliferative 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 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. |
| 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 | — |
Countries
Australia, Austria, Czechia, Denmark, France, Germany, Hungary, Italy, Japan, Poland, Spain
Participant flow
Recruitment details
Participants with diabetic macular edema (DME) secondary to diabetes mellitus involving the center of the macula in the study eye could participate in the study. The study was conducted at 73 study centers in Japan, European Countries and Australia between 09 May 2011(first participant first visit) and 30 Mar 2015 (last participant last visit).
Pre-assignment details
Of 604 participants who were screened for inclusion in the study, 406 were randomized, and 404 received treatment.
Participants by arm
| Arm | Count |
|---|---|
| Intravitreal Aflibercept Injection 2Q4 Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks (2Q4). | 136 |
| Intravitreal Aflibercept Injection 2Q8 Participants received 2mg Intravitreal aflibercept injection (IAI) (EYLEA, VEGF Trap-Eye, BAY86-5321) every 4 weeks for 5 visits followed by injections every 8 weeks (2Q8). | 135 |
| Control 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. | 133 |
| Total | 404 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 10 | 13 | 10 |
| Overall Study | Death | 6 | 6 | 2 |
| Overall Study | Lack of Efficacy | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 2 | 4 | 1 |
| Overall Study | Not Received Study Treatment | 0 | 0 | 2 |
| Overall Study | Physician Decision | 2 | 0 | 4 |
| Overall Study | Protocol Violation | 1 | 1 | 0 |
| Overall Study | Sponsor decision | 1 | 1 | 0 |
| Overall Study | Switching to other therapy | 0 | 0 | 1 |
| Overall Study | Therapeutic procedure required | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 12 | 8 | 15 |
Baseline characteristics
| Characteristic | Intravitreal Aflibercept Injection 2Q4 | Intravitreal Aflibercept Injection 2Q8 | Control | Total |
|---|---|---|---|---|
| Age, Continuous | 62.6 Years STANDARD_DEVIATION 8.6 | 64.2 Years STANDARD_DEVIATION 7.8 | 63.9 Years STANDARD_DEVIATION 8.6 | 63.6 Years STANDARD_DEVIATION 8.3 |
| Sex: Female, Male Female | 53 Participants | 47 Participants | 54 Participants | 154 Participants |
| Sex: Female, Male Male | 83 Participants | 88 Participants | 79 Participants | 250 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 | 117 / 136 | 122 / 135 | 113 / 133 |
| serious Total, serious adverse events | 63 / — | 60 / — | 51 / — |
Outcome results
Primary
Change From Baseline in BCVA (Best Corrected Visual Acuity) 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. A higher score represents better functioning.
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intravitreal Aflibercept Injection 2Q4 | Change From Baseline in BCVA (Best Corrected Visual Acuity) as Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Week 52 - Last Observation Carried Forward (LOCF) | 10.5 Letters correctly read | Standard Deviation 9.55 |
| Intravitreal Aflibercept Injection 2Q8 | Change From Baseline in BCVA (Best Corrected Visual Acuity) as Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Week 52 - Last Observation Carried Forward (LOCF) | 10.7 Letters correctly read | Standard Deviation 9.32 |
| Control | Change From Baseline in BCVA (Best Corrected Visual Acuity) as Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Week 52 - Last Observation Carried Forward (LOCF) | 1.2 Letters correctly read | Standard Deviation 10.65 |
Comparison: Hypothesis: Mean change identical in both groupsp-value: <0.000197.5% CI: [6.5, 12]ANCOVA
Comparison: Hypothesis: Mean change identical in both groupsp-value: <0.000197.5% CI: [6.3, 11.8]ANCOVA
Secondary
Change From Baseline in Central Retinal Thickness (CRT) at Week 52 as Assessed on Optical Coherence Tomography (OCT) - LOCF
Time frame: Baseline up to Week 52
Population: Full-Analysis Set 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 | -195.0 micrometer | Standard Deviation 146.59 |
| Intravitreal Aflibercept Injection 2Q8 | Change From Baseline in Central Retinal Thickness (CRT) at Week 52 as Assessed on Optical Coherence Tomography (OCT) - LOCF | -192.4 micrometer | Standard Deviation 149.89 |
| Control | Change From Baseline in Central Retinal Thickness (CRT) at Week 52 as Assessed on Optical Coherence Tomography (OCT) - LOCF | -66.2 micrometer | Standard Deviation 138.99 |
Comparison: Hypothesis: Mean change identical in both groupsp-value: <0.000197.5% CI: [-190.9, -123.1]ANCOVA
Comparison: Hypothesis: Mean change identical in both groupsp-value: <0.000197.5% CI: [-179.3, -106.3]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: Full-Analysis Set 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 | 0.94 Scores on a scale | Standard Deviation 16.487 |
| 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 | 5.32 Scores on a scale | Standard Deviation 18.475 |
| Control | Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Distance Activities Subscale at Week 52 - LOCF | 2.26 Scores on a scale | Standard Deviation 15.923 |
Comparison: Hypothesis: Mean change identical in both groupsp-value: 0.513897.5% CI: [-5.29, 2.91]ANCOVA
Comparison: Hypothesis: Mean change identical in both groupsp-value: 0.849897.5% CI: [-4.79, 4.05]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: Full-Analysis Set 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 | 5.73 Scores on a scale | Standard Deviation 18.932 |
| 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 | 5.29 Scores on a scale | Standard Deviation 19.058 |
| Control | Change From Baseline in National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) Near Activities Subscale at Week 52 - LOCF | 3.54 Scores on a scale | Standard Deviation 16.768 |
Comparison: Hypothesis: Mean change identical in both groupsp-value: 0.220897.5% CI: [-2.01, 6.82]ANCOVA
Comparison: Hypothesis: Mean change identical in both groupsp-value: 0.553797.5% CI: [-5.79, 3.37]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 | 54.4 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 | 53.3 Percentage of participants |
| Control | Percentage of Participants Who Gained at Least 10 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 52 - LOCF | 25.8 Percentage of participants |
Comparison: Hypothesis: Probability to gain \>= 10 letters identical in both groupsp-value: <0.000197.5% CI: [15.8, 41.6]Cochran-Mantel-Haenszel
Comparison: Hypothesis: Probability to gain \>= 10 letters identical in both groupsp-value: <0.000197.5% CI: [14.6, 40.5]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 | 32.4 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 | 33.3 Percentage of participants |
| Control | Percentage of Participants Who Gained at Least 15 Letters in BCVA as Measured by ETDRS Letter Score Compared With Baseline at Week 52 - LOCF | 9.1 Percentage of participants |
Comparison: Hypothesis: Probability to gain \>= 15 letters identical in both groupsp-value: <0.000197.5% CI: [12.6, 33.9]Cochran-Mantel-Haenszel
Comparison: Hypothesis: Probability to gain \>= 15 letters identical in both groupsp-value: <0.000197.5% CI: [13.5, 34.9]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With a ≥2-step Improvement From Baseline in the ETDRS DRSS (Diabetic Retinopathy Severity Score) as Assessed by FP (Fundus Photography) at Week 52 - LOCF
Baseline ETDRS DRSS: None (level 10); Mild to moderate nonproliferative 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: Full-Analysis Set with assessment for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intravitreal Aflibercept Injection 2Q4 | Percentage of Participants With a ≥2-step Improvement From Baseline in the ETDRS DRSS (Diabetic Retinopathy Severity Score) as Assessed by FP (Fundus Photography) at Week 52 - LOCF | 33.3 Percentage of participants |
| Intravitreal Aflibercept Injection 2Q8 | Percentage of Participants With a ≥2-step Improvement From Baseline in the ETDRS DRSS (Diabetic Retinopathy Severity Score) as Assessed by FP (Fundus Photography) at Week 52 - LOCF | 27.7 Percentage of participants |
| Control | Percentage of Participants With a ≥2-step Improvement From Baseline in the ETDRS DRSS (Diabetic Retinopathy Severity Score) as Assessed by FP (Fundus Photography) at Week 52 - LOCF | 7.5 Percentage of participants |
Comparison: Hypothesis: Probability to improve by \>= 2 steps identical in both groupsp-value: <0.000197.5% CI: [12.2, 39.4]Cochran-Mantel-Haenszel
Comparison: Hypothesis: Probability to improve by \>= 2 steps identical in both groupsp-value: 0.000697.5% CI: [6.6, 32.1]Cochran-Mantel-Haenszel