Macular Edema
Conditions
Keywords
Diabetic macular edema, DME
Brief summary
To evaluate the efficacy of long-term treatment with 2 mg aflibercept via different intravitreal (IVT) treatment regimens to participants with DME pretreated with 2 mg aflibercept every 8 weeks after 5 initial monthly injections for approximately 1 year or more (according to the EU label for the first year of treatment)
Interventions
DRUGAflibercept (Eylea, VEGF Trap-Eye, BAY86-5321)
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
The subject's history of aflibercept treatment met all of the following: * Treatment in the study eye was initiated with five monthly (-1 week /+2 weeks) doses of 2 mg aflibercept and improvements of visual and anatomic outcomes were observed and documented. * Following the above initiation phase, the intervals between treatments were between 6 weeks and 12 weeks (one exception was allowed). * The interval between the last 2 pre-study injections was ≥ 8 weeks, and visual and anatomic outcomes had been stable over this interval. * The subject received the last intravitreal (IVT) injection of aflibercept in the study eye 8 weeks (±10 days) before the first planned treatment /randomization in this study. * Total prior treatment duration with aflibercept (i.e. from first aflibercept treatment ever to enrollment into this study) was 1 year or longer. To be met at initiation of pre-study aflibercept treatment: * Type 1 or 2 diabetes mellitus (DM) * Diagnosis of diabetic macular edema (DME) secondary to DM involving the center of the macula (defined as the area of the center subfield on optical coherence tomography \[OCT\]) in the study eye * Decrease in vision determined to be primarily the result of DME in the study eye * Best corrected visual acuity (BCVA) in the study eye of Early Treatment Diabetic Retinopathy Study (ETDRS) letter score 73 to 24
Exclusion criteria
At initiation of pre-study aflibercept treatment: \- Previous treatment with anti-angiogenic drugs in study eye (e.g., pegaptanib sodium, bevacizumab, ranibizumab, or aflibercept) within the last 12 weeks before initiation of aflibercept pre-study treatment At initiation of pre-study aflibercept treatment, screening for this study, and baseline for this study: * Prior treatment of the study eye with long acting steroids, either periocular or intraocular, in the preceding 120 days or Iluvien intravitreal implant at any time * Active proliferative diabetic retinopathy, current iris neovascularization, vitreous hemorrhage, or tractional retinal detachment in the study eye * Cataract surgery or any other intraocular surgery within 90 days of aflibercept treatment in the study eye * Ocular inflammation (including trace or above) or history of uveitis in the study eye * Structural damage to the center of the macula in the study eye that was likely to preclude improvement in BCVA following the resolution of macular edema including atrophy of the retinal pigment epithelium, subretinal fibrosis or scar, significant macular ischemia or organized hard exudates * Concurrent disease in the study eye, other than DME, that could compromise visual acuity, require medical or surgical intervention during the study period, or could confound interpretation of the results (including advanced glaucoma, retinal vascular occlusion, retinal detachment, macular hole, or choroidal neovascularization of any cause) * Uncontrolled DM as defined by hemoglobin (Hb) A1c \> 12.0% at screening and baseline for this study * Any ocular or periocular infection in the preceding 4 weeks in either eye * History of either cerebral vascular accident and/or myocardial infarction within 180 days before aflibercept treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52 | From baseline to Week 52 | Best Corrected Visual Acuity (BCVA) was measured in the study eye by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. The ETDRS chart includes 70 letters in total and the letter score ranges from 0 to 100. More letters read correctly results in a higher letter score, which represents better visual acuity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Central Retinal Thickness (CRT) at Week 52 | From baseline to week 52 | Central Retinal Thickness (CRT) was measured in the study eye by spectral domain optical coherence tomography (SD-OCT). |
| Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52 | From baseline to week 52 | Best Corrected Visual Acuity (BCVA) was measured in the study eye by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. The ETDRS chart includes 70 letters in total and the letter score ranges from 0 to 100. More letters read correctly results in a higher letter score, which represents better visual acuity |
| Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 100 | From baseline to Week 100 | Best Corrected Visual Acuity (BCVA) was measured in the study eye by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. The ETDRS chart includes 70 letters in total and the letter score ranges from 0 to 100. More letters read correctly results in a higher letter score, which represents better visual acuity. |
| Mean Change From Baseline in Central Retinal Thickness (CRT) at Week 100 | From baseline to Week 100 | Central Retinal Thickness (CRT) was measured in the study eye by spectral domain optical coherence tomography (SD-OCT). |
| Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 100 | From baseline to Week 100 | Best Corrected Visual Acuity (BCVA) was measured in the study eye by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. The ETDRS chart includes 70 letters in total and the letter score ranges from 0 to 100. More letters read correctly results in a higher letter score, which represents better visual acuity |
| Number of Participants With Treatment-emergent Adverse Event (TEAE) | Up to Week 100 | AEs that started after the first application of aflibercept under this protocol until 30 days after the last dose of study drug administration |
Countries
Austria, Canada, Czechia, France, Germany, Hungary, Italy, Lithuania, Poland, Portugal, Slovakia, Spain, Switzerland, United Kingdom
Participant flow
Recruitment details
Study was conducted at multiple centers in 14 countries between 16-Nov-2016 (first participant first visit) and 24-Sep-2019 (last participant last visit).
Pre-assignment details
A total of 500 participants were screened in this study. Of these, 37 participants did not enter the treatment period (31 were screening failures; 3 were lost to follow-up; 2 had an adverse event (AE) and 1 was not randomized due to an other reason). A total of 463 participants were randomized and received treatment.
Participants by arm
| Arm | Count |
|---|---|
| Aflibercept 2 mg Fixed Participants received fixed dosing of 2 mg aflibercept at injection intervals of 8 weeks | 155 |
| Aflibercept 2 mg Extended Participants received flexible dosing of 2 mg aflibercept at injection intervals of ≥8 weeks | 154 |
| Aflibercept 2 mg PRN Participants received monthly monitoring with 2 mg aflibercept injection pro re nata (PRN, as needed) | 154 |
| Total | 463 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 2 | 1 |
| Overall Study | Death | 3 | 6 | 8 |
| Overall Study | Lost to Follow-up | 4 | 1 | 2 |
| Overall Study | Physician Decision | 1 | 0 | 0 |
| Overall Study | Withdrawal by sponsor | 0 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 7 | 6 | 6 |
Baseline characteristics
| Characteristic | Aflibercept 2 mg Extended | Aflibercept 2 mg PRN | Aflibercept 2 mg Fixed | Total |
|---|---|---|---|---|
| Age, Continuous | 64.8 Years STANDARD_DEVIATION 10.1 | 65.4 Years STANDARD_DEVIATION 9.3 | 64.3 Years STANDARD_DEVIATION 8.7 | 64.8 Years STANDARD_DEVIATION 9.4 |
| Best Corrected Visual Acuity (BCVA) | 72.5 Scores on a scale STANDARD_DEVIATION 11.35 | 71.0 Scores on a scale STANDARD_DEVIATION 10.87 | 72.8 Scores on a scale STANDARD_DEVIATION 10.38 | 72.1 Scores on a scale STANDARD_DEVIATION 10.88 |
| Central Retinal Thickness (CRT) | 285.3 Microns STANDARD_DEVIATION 76.01 | 294.5 Microns STANDARD_DEVIATION 80.72 | 289.8 Microns STANDARD_DEVIATION 66.46 | 289.9 Microns STANDARD_DEVIATION 74.55 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 4 Participants | 1 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 142 Participants | 142 Participants | 144 Participants | 428 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 10 Participants | 8 Participants | 10 Participants | 28 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 9 Participants | 7 Participants | 11 Participants | 27 Participants |
| Race (NIH/OMB) White | 144 Participants | 147 Participants | 141 Participants | 432 Participants |
| Sex: Female, Male Female | 59 Participants | 64 Participants | 55 Participants | 178 Participants |
| Sex: Female, Male Male | 95 Participants | 90 Participants | 100 Participants | 285 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 155 | 6 / 154 | 8 / 154 |
| other Total, other adverse events | 97 / 155 | 85 / 154 | 98 / 154 |
| serious Total, serious adverse events | 35 / 155 | 38 / 154 | 37 / 154 |
Outcome results
Primary
Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52
Best Corrected Visual Acuity (BCVA) was measured in the study eye by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. The ETDRS chart includes 70 letters in total and the letter score ranges from 0 to 100. More letters read correctly results in a higher letter score, which represents better visual acuity.
Time frame: From baseline to Week 52
Population: Full Analysis Set (FAS): included all randomized participants who received any study drug and had a baseline BCVA assessment and at least one post-baseline BCVA assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept 2 mg Fixed | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52 | 0.4 Scores on a scale | Standard Deviation 6.7 |
| Aflibercept 2 mg Extended | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52 | 0.5 Scores on a scale | Standard Deviation 6.7 |
| Aflibercept 2 mg PRN | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52 | 1.7 Scores on a scale | Standard Deviation 6.8 |
Comparison: Aflibercept 2 mg fixed was regarded as the reference armp-value: <0.000195% CI: [-1.46, 1.47]ANCOVA
Comparison: Aflibercept 2 mg fixed was regarded as the reference armp-value: <0.000195% CI: [-0.52, 2.42]ANCOVA
Secondary
Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 100
Best Corrected Visual Acuity (BCVA) was measured in the study eye by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. The ETDRS chart includes 70 letters in total and the letter score ranges from 0 to 100. More letters read correctly results in a higher letter score, which represents better visual acuity.
Time frame: From baseline to Week 100
Population: Full Analysis Set (FAS): included all randomized participants who received any study drug and had a baseline BCVA assessment and at least one post-baseline BCVA assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept 2 mg Fixed | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 100 | 0.1 Scores on a scale | Standard Deviation 7.2 |
| Aflibercept 2 mg Extended | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 100 | -0.1 Scores on a scale | Standard Deviation 9.1 |
| Aflibercept 2 mg PRN | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 100 | 1.8 Scores on a scale | Standard Deviation 9 |
Comparison: Aflibercept 2 mg fixed was regarded as the reference armp-value: <0.000195% CI: [-2.13, 1.52]ANCOVA
Comparison: Aflibercept 2 mg fixed was regarded as the reference armp-value: <0.000195% CI: [-0.4, 3.19]ANCOVA
Secondary
Mean Change From Baseline in Central Retinal Thickness (CRT) at Week 100
Central Retinal Thickness (CRT) was measured in the study eye by spectral domain optical coherence tomography (SD-OCT).
Time frame: From baseline to Week 100
Population: Participants in FAS taken into account for this analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept 2 mg Fixed | Mean Change From Baseline in Central Retinal Thickness (CRT) at Week 100 | -15.5 Microns | Standard Deviation 64.3 |
| Aflibercept 2 mg Extended | Mean Change From Baseline in Central Retinal Thickness (CRT) at Week 100 | 2.3 Microns | Standard Deviation 81.8 |
| Aflibercept 2 mg PRN | Mean Change From Baseline in Central Retinal Thickness (CRT) at Week 100 | -13.9 Microns | Standard Deviation 74.4 |
Comparison: Aflibercept 2 mg fixed was regarded as the reference armp-value: 0.041695% CI: [0.62, 31.66]ANCOVA
Comparison: Aflibercept 2 mg fixed was regarded as the reference armp-value: 0.552495% CI: [-9.52, 17.77]ANCOVA
Secondary
Mean Change From Baseline in Central Retinal Thickness (CRT) at Week 52
Central Retinal Thickness (CRT) was measured in the study eye by spectral domain optical coherence tomography (SD-OCT).
Time frame: From baseline to week 52
Population: Participants in FAS taken into account for this analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept 2 mg Fixed | Mean Change From Baseline in Central Retinal Thickness (CRT) at Week 52 | -18.8 Microns | Standard Deviation 45.5 |
| Aflibercept 2 mg Extended | Mean Change From Baseline in Central Retinal Thickness (CRT) at Week 52 | -2.1 Microns | Standard Deviation 56.2 |
| Aflibercept 2 mg PRN | Mean Change From Baseline in Central Retinal Thickness (CRT) at Week 52 | 2.2 Microns | Standard Deviation 77.8 |
Comparison: Aflibercept 2 mg fixed was regarded as the reference armp-value: 0.010595% CI: [3.39, 25.37]ANCOVA
Comparison: Aflibercept 2 mg fixed was regarded as the reference armp-value: 0.002395% CI: [7.65, 34.8]ANCOVA
Secondary
Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 100
Best Corrected Visual Acuity (BCVA) was measured in the study eye by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. The ETDRS chart includes 70 letters in total and the letter score ranges from 0 to 100. More letters read correctly results in a higher letter score, which represents better visual acuity
Time frame: From baseline to Week 100
Population: Full analysis set (FAS)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aflibercept 2 mg Fixed | Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 100 | ≥10 letter gain | 10 Participants |
| Aflibercept 2 mg Fixed | Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 100 | ≥15 letter gain | 3 Participants |
| Aflibercept 2 mg Fixed | Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 100 | ≥30 letter loss | 1 Participants |
| Aflibercept 2 mg Extended | Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 100 | ≥10 letter gain | 17 Participants |
| Aflibercept 2 mg Extended | Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 100 | ≥15 letter gain | 4 Participants |
| Aflibercept 2 mg Extended | Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 100 | ≥30 letter loss | 2 Participants |
| Aflibercept 2 mg PRN | Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 100 | ≥15 letter gain | 6 Participants |
| Aflibercept 2 mg PRN | Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 100 | ≥30 letter loss | 2 Participants |
| Aflibercept 2 mg PRN | Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 100 | ≥10 letter gain | 22 Participants |
Comparison: ≥ 15 letter gain: Aflibercept 2 mg fixed was regarded as the reference arm95% CI: [-2.72, 4.05]Cochran-Mantel-Haenszel
Comparison: ≥10 letter gain: Aflibercept 2 mg fixed was regarded as the reference arm95% CI: [-1.73, 10.98]Cochran-Mantel-Haenszel
Comparison: ≥30 letter loss: Aflibercept 2 mg fixed was regarded as the reference arm95% CI: [-1.56, 2.87]Cochran-Mantel-Haenszel
Comparison: ≥15 letter gain: Aflibercept 2 mg fixed was regarded as the reference arm95% CI: [-1.89, 5.69]Cochran-Mantel-Haenszel
Comparison: ≥10 letter gain: Aflibercept 2 mg fixed was regarded as the reference arm95% CI: [0.81, 14.28]Cochran-Mantel-Haenszel
Comparison: ≥30 letter loss: Aflibercept 2 mg fixed was regarded as the reference arm95% CI: [-1.61, 2.88]Cochran-Mantel-Haenszel
Secondary
Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52
Best Corrected Visual Acuity (BCVA) was measured in the study eye by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. The ETDRS chart includes 70 letters in total and the letter score ranges from 0 to 100. More letters read correctly results in a higher letter score, which represents better visual acuity
Time frame: From baseline to week 52
Population: Full Analysis Set (FAS): included all randomized participants who received any study drug and had a baseline BCVA assessment and at least one post-baseline BCVA assessment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aflibercept 2 mg Fixed | Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52 | ≥10 letter gain | 10 Participants |
| Aflibercept 2 mg Fixed | Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52 | ≥15 letter gain | 4 Participants |
| Aflibercept 2 mg Fixed | Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52 | ≥30 letter loss | 1 Participants |
| Aflibercept 2 mg Extended | Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52 | ≥10 letter gain | 14 Participants |
| Aflibercept 2 mg Extended | Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52 | ≥15 letter gain | 5 Participants |
| Aflibercept 2 mg Extended | Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52 | ≥30 letter loss | 0 Participants |
| Aflibercept 2 mg PRN | Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52 | ≥15 letter gain | 4 Participants |
| Aflibercept 2 mg PRN | Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52 | ≥30 letter loss | 0 Participants |
| Aflibercept 2 mg PRN | Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52 | ≥10 letter gain | 13 Participants |
Comparison: ≥ 15 letter gain: Aflibercept 2 mg fixed was regarded as the reference arm95% CI: [-3.14, 4.49]Cochran-Mantel-Haenszel
Comparison: ≥10 letter gain: Aflibercept 2 mg fixed was regarded as the reference arm95% CI: [-3.4, 8.73]Cochran-Mantel-Haenszel
Comparison: ≥30 letter loss: Aflibercept 2 mg fixed was regarded as the reference arm95% CI: [-1.94, 0.63]Cochran-Mantel-Haenszel
Comparison: ≥15 letter gain: Aflibercept 2 mg fixed was regarded as the reference arm95% CI: [-3.68, 3.41]Cochran-Mantel-Haenszel
Comparison: ≥10 letter gain: Aflibercept 2 mg fixed was regarded as the reference arm95% CI: [-4.1, 7.54]Cochran-Mantel-Haenszel
Comparison: ≥30 letter loss: Aflibercept 2 mg fixed was regarded as the reference arm95% CI: [-2, 0.65]Cochran-Mantel-Haenszel
Secondary
Number of Participants With Treatment-emergent Adverse Event (TEAE)
AEs that started after the first application of aflibercept under this protocol until 30 days after the last dose of study drug administration
Time frame: Up to Week 100
Population: Safety analysis set (SAF): included all participants who received any study drug under the protocol.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aflibercept 2 mg Fixed | Number of Participants With Treatment-emergent Adverse Event (TEAE) | 129 Participants |
| Aflibercept 2 mg Extended | Number of Participants With Treatment-emergent Adverse Event (TEAE) | 128 Participants |
| Aflibercept 2 mg PRN | Number of Participants With Treatment-emergent Adverse Event (TEAE) | 129 Participants |