Diabetic Retinopathy, Macular Edema
Conditions
Keywords
Diabetes, Macular Edema, Diabetic Retinopathy
Brief summary
Treatment of diabetic macular edema with intravitreal aflibercept in subjects previously treated with intravitreal anti-Vascular endothelial growth factor (VEGF) agents (ranibizumab or bevacizumab)
Detailed description
This study is an investigator initiated interventional study for subjects with diabetic macular edema (DME) that have been previously treated with bevacizumab or ranibizumab. Intravitreal aflibercept 2mg will be given until OCT (ocular coherence tomography) demonstrates an absence of fluid. Continued intravitreal aflibercept 2mg will then take place every 2 months for a total of 24 months of treatment. This study is an interventional, single arm, investigator initiated study. Subjects will be given 2 mg (0.05 mL or 50 microliters) of intravitreal aflibercept injection (IAI) administered monthly until OCT demonstrates no evidence of fluid as defined by the protocol, followed by 2 mg (0.05 mL) once every 2 months. Each subject will be evaluated for 24 months. Thus, the study duration will be 24 months plus the recruitment period. Subjects will be evaluated for safety, efficacy as measured by Spectral Domain Optical Coherence Tomography (SDOCT) and best corrected visual acuity (BCVA) using the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) protocol. In additional, fundus photography, fluorescein angiography, and OCT angiography will be performed at baseline, month 6, month 12 and at the final visit. Only one eye per subject may be enrolled in the study. If a subject's fellow (non-study) eye requires treatment for at study entry, or during the subject's participation in the study, the fellow eye can receive IAI for DME.
Interventions
DRUGaflibercept
aflibercept 2mg given intravitreally every month until resolution of fluid in retina and then continued every 2 months for a total of 24 months of treatment
Sponsors
Regeneron Pharmaceuticals
Rishi Singh
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Men and women ≥ 18 years of age. 2. Foveal-involving retinal edema secondary to DME based on investigator review of clinical exam and SDOCT with central subfield thickness value of 325 microns by Zeiss Cirrus SD-OCT. 3. E-ETDRS best-corrected visual acuity of: 20/25 to 20/400 in the study eye. 4. History of previous treatment with anti-VEGF with at least 4 injections over the last 6 months. 5. Willing, committed, and able to return for all clinic visits and complete all study related procedures. 6. 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
1. Any prior or concomitant therapy with another investigational agent to treat DME in the study eye. 2. Prior panretinal photocoagulation in the study eye within the past 3 months. 3. Prior intravitreal anti-VEGF therapy in the study eye within 30 days of enrollment. 4. Prior systemic anti-VEGF therapy, investigational or FDA-approved, is only allowed up to 3 months prior to first dose, and will not be allowed during the study. 5. Previous treatment with intravitreal aflibercept injection 6. Significant vitreous hemorrhage obscuring view to the macula or the retinal periphery as determined by the investigator on clinical exam 7. Presence of other causes of macular edema, including pathologic myopia (spherical equivalent of -8 diopters or more negative, or axial length of 25 mm or more), ocular histoplasmosis syndrome, angioid streaks, choroidal rupture, choroidal neovascularization, age-related macular degeneration or multifocal choroiditis in the study eye. 8. Presence of macula-threatening traction retinal detachment. 9. Prior vitrectomy in the study eye. 10. History of retinal detachment or treatment or surgery for retinal detachment in the study eye. 11. Any history of macular hole of stage 2 and above in the study eye. 12. 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's unlikely to interfere with the injection. 13. Uncontrolled glaucoma at baseline evaluation 14. Active intraocular inflammation in either eye. 15. Active ocular or periocular infection in either eye. 16. Any ocular or periocular infection within the last 2 weeks prior to Screening in either eye. 17. Any history of uveitis in either eye. 18. History of corneal transplant or corneal dystrophy in the study eye. 19. Significant media opacities, including cataract, in the study eye which might interfere with visual acuity, assessment of safety, or fundus photography. 20. Any concurrent intraocular condition in the study eye (e.g. cataract) that, in the opinion of the investigator, could require either medical or surgical intervention during the 52 week study period. 21. Any concurrent ocular condition in the study eye which, in the opinion of the investigator, could either increase the risk to the subject beyond what is to be expected from standard procedures of intraocular injection, or which otherwise may interfere with the injection procedure or with evaluation of efficacy or safety. 22. Participation as a subject in any clinical study within the 12 weeks prior to Day 1. 23. Any systemic therapy with an investigational agent in the past 3 months prior to Day 1. 24. Any history of allergy to povidone iodine. 25. Pregnant or breast-feeding women 26. Women of childbearing potential who are unwilling to practice adequate contraception during the study -
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of Treatment Outcomes by Change in Visual Acuity From Baseline | Baseline and 12 months | Subjects were evaluated for efficacy by the change in best corrected visual acuity from baseline. Best Corrected Visual Acuity (BCVA) was measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. More letters read correctly results in a higher letter score, which represents better visual acuity. |
| Mean Absolute Change on Central Foveal Thickness | Baseline and 12 months | Mean absolute Central Foveal Thickness change from baseline at month 12 as measured by Spectral Domain Optical Coherence Tomography (SD-OCT), defined as the average thickness within the central 1 mm subfield of the central retina. Thicker measures can represent more macular edema |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change on Visual Acuity Score | Baseline, 6 months, 12 months, 24 months | The mean change from baseline in best-corrected visual acuity score at months 6,12 and 24. Best Corrected Visual Acuity was measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. More letters read correctly results in a higher letter score, which represents better visual acuity. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Foveal Avascular Zone (FAZ) Changes | Baseline, 12 months, and 24 months | FAZ Area change at month 12 and month 24 by OCT angiography. |
| Optical Coherence Tomography (OCT) Perfusion | Baseline, 12 months,and 24 months | Change in macular OCT perfusion (whole deep capillary perfusion density) at months 12 and 24 by OCT angiography |
| Number of Participants That Gained or Lost Letters of Visual Acuity. | 12 months | The percentage of participants who gained or lost 5, 10, and 15 letters or more of vision at month 12. Visual Acuity (BCVA) was measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. |
| Number of Participants With Absence of Retinal Fluid as Measured by OCT | Baseline, 6 months, and 12 months | The percentage of participants that were considered anatomically 'dry' by SDOCT at months 6 and 12 and transitioned to the every-8-weeks treatment regimen. |
| Number of Participants With Diabetic Retinopathy (DR) Classified by Severity | Baseline, 6 months, and 12 months | The diabetic retinopathy severity changes from baseline at months 6 and 12. DR severity was judged clinically at the fundus examination. |
| Retinal Vascular Changes by OCT Angiography | Baseline, 12 months, and 24 months | Capillary Perfusion Density change at month 12 and month 24 by OCT angiography. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Single Arm Aflibercept 2mg given intravitreally every month until resolution of fluid in retina and then continued every 2 months for a total of 24 months of treatment | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Single Arm |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 13 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants |
| Age, Continuous | 63.7 years STANDARD_DEVIATION 13.5 |
| Early Treatment Diabetic Retinopathy Study (ETDRS) letters scores Fellow Eye | 73.65 letters |
| Early Treatment Diabetic Retinopathy Study (ETDRS) letters scores Study Eye | 69.95 letters |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| OCT - Average Thickness | 300.2 µm |
| OCT - Cube Volume | 11.5 mm3 |
| Optical Coherence Tomography (OCT) - Central Subfield Thickness (CST) | 419 µm |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 20 |
| other Total, other adverse events | 0 / 20 |
| serious Total, serious adverse events | 4 / 20 |
Outcome results
Primary
Efficacy of Treatment Outcomes by Change in Visual Acuity From Baseline
Subjects were evaluated for efficacy by the change in best corrected visual acuity from baseline. Best Corrected Visual Acuity (BCVA) was measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. More letters read correctly results in a higher letter score, which represents better visual acuity.
Time frame: Baseline and 12 months
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Single Arm | Efficacy of Treatment Outcomes by Change in Visual Acuity From Baseline | Baseline | 69.95 letters |
| Single Arm | Efficacy of Treatment Outcomes by Change in Visual Acuity From Baseline | 12 Months | 74 letters |
Primary
Mean Absolute Change on Central Foveal Thickness
Mean absolute Central Foveal Thickness change from baseline at month 12 as measured by Spectral Domain Optical Coherence Tomography (SD-OCT), defined as the average thickness within the central 1 mm subfield of the central retina. Thicker measures can represent more macular edema
Time frame: Baseline and 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Single Arm | Mean Absolute Change on Central Foveal Thickness | Baseline | 419.7 μm | Standard Deviation 92 |
| Single Arm | Mean Absolute Change on Central Foveal Thickness | 12 months | 287.2 μm | Standard Deviation 80.2 |
Secondary
Mean Change on Visual Acuity Score
The mean change from baseline in best-corrected visual acuity score at months 6,12 and 24. Best Corrected Visual Acuity was measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. More letters read correctly results in a higher letter score, which represents better visual acuity.
Time frame: Baseline, 6 months, 12 months, 24 months
Population: A total of 20 participants were enrolled; 20 completed 6 and 12 months and 16 completed the study (24 months)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Single Arm | Mean Change on Visual Acuity Score | Baseline | 69.95 letters |
| Single Arm | Mean Change on Visual Acuity Score | 6 months | 71.5 letters |
| Single Arm | Mean Change on Visual Acuity Score | 12 months | 74 letters |
| Single Arm | Mean Change on Visual Acuity Score | 24 months | 75 letters |
Other Pre-specified
Foveal Avascular Zone (FAZ) Changes
FAZ Area change at month 12 and month 24 by OCT angiography.
Time frame: Baseline, 12 months, and 24 months
Population: A total of 20 participants were enrolled; 20 completed the 12 months and 16 completed the study (24 months). 15 OCT angiography out of 16 that completed the study were available for the 24-month analysis.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Single Arm | Foveal Avascular Zone (FAZ) Changes | Baseline | 0.30 mm2 |
| Single Arm | Foveal Avascular Zone (FAZ) Changes | 12 Months | 0.34 mm2 |
| Single Arm | Foveal Avascular Zone (FAZ) Changes | 24 Months | 0.40 mm2 |
Other Pre-specified
Number of Participants That Gained or Lost Letters of Visual Acuity.
The percentage of participants who gained or lost 5, 10, and 15 letters or more of vision at month 12. Visual Acuity (BCVA) was measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters.
Time frame: 12 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Single Arm | Number of Participants That Gained or Lost Letters of Visual Acuity. | Lost 15 letters | 5 percentage of participants |
| Single Arm | Number of Participants That Gained or Lost Letters of Visual Acuity. | Lost 14 to 10 letters | 5 percentage of participants |
| Single Arm | Number of Participants That Gained or Lost Letters of Visual Acuity. | Lost 9 to 5 letters | 10 percentage of participants |
| Single Arm | Number of Participants That Gained or Lost Letters of Visual Acuity. | Lost 1 to 4 letters | 5 percentage of participants |
| Single Arm | Number of Participants That Gained or Lost Letters of Visual Acuity. | Gained 0 to 4 letters | 30 percentage of participants |
| Single Arm | Number of Participants That Gained or Lost Letters of Visual Acuity. | Gained 5 to 9 letters | 10 percentage of participants |
| Single Arm | Number of Participants That Gained or Lost Letters of Visual Acuity. | Gained 10 to 14 letters | 25 percentage of participants |
| Single Arm | Number of Participants That Gained or Lost Letters of Visual Acuity. | Gained more than 15 letters | 10 percentage of participants |
Other Pre-specified
Number of Participants With Absence of Retinal Fluid as Measured by OCT
The percentage of participants that were considered anatomically 'dry' by SDOCT at months 6 and 12 and transitioned to the every-8-weeks treatment regimen.
Time frame: Baseline, 6 months, and 12 months
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Single Arm | Number of Participants With Absence of Retinal Fluid as Measured by OCT | Baseline | every-4-weeks regimen | 20 Participants |
| Single Arm | Number of Participants With Absence of Retinal Fluid as Measured by OCT | Baseline | every-8-weeks regimen | 0 Participants |
| Single Arm | Number of Participants With Absence of Retinal Fluid as Measured by OCT | 6 Months | every-4-weeks regimen | 13 Participants |
| Single Arm | Number of Participants With Absence of Retinal Fluid as Measured by OCT | 6 Months | every-8-weeks regimen | 7 Participants |
| Single Arm | Number of Participants With Absence of Retinal Fluid as Measured by OCT | 12 Months | every-4-weeks regimen | 5 Participants |
| Single Arm | Number of Participants With Absence of Retinal Fluid as Measured by OCT | 12 Months | every-8-weeks regimen | 15 Participants |
Other Pre-specified
Number of Participants With Diabetic Retinopathy (DR) Classified by Severity
The diabetic retinopathy severity changes from baseline at months 6 and 12. DR severity was judged clinically at the fundus examination.
Time frame: Baseline, 6 months, and 12 months
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Single Arm | Number of Participants With Diabetic Retinopathy (DR) Classified by Severity | Baseline | Mild nonproliferative diabetic retinopathy (NPDR) | 0 Participants |
| Single Arm | Number of Participants With Diabetic Retinopathy (DR) Classified by Severity | Baseline | Moderate NPDR | 9 Participants |
| Single Arm | Number of Participants With Diabetic Retinopathy (DR) Classified by Severity | Baseline | Severe NPDR | 5 Participants |
| Single Arm | Number of Participants With Diabetic Retinopathy (DR) Classified by Severity | Baseline | Proliferative diabetic retinopathy (PDR) | 6 Participants |
| Single Arm | Number of Participants With Diabetic Retinopathy (DR) Classified by Severity | 6 Months | Mild nonproliferative diabetic retinopathy (NPDR) | 0 Participants |
| Single Arm | Number of Participants With Diabetic Retinopathy (DR) Classified by Severity | 6 Months | Moderate NPDR | 9 Participants |
| Single Arm | Number of Participants With Diabetic Retinopathy (DR) Classified by Severity | 6 Months | Severe NPDR | 5 Participants |
| Single Arm | Number of Participants With Diabetic Retinopathy (DR) Classified by Severity | 6 Months | Proliferative diabetic retinopathy (PDR) | 6 Participants |
| Single Arm | Number of Participants With Diabetic Retinopathy (DR) Classified by Severity | 12 Months | Mild nonproliferative diabetic retinopathy (NPDR) | 2 Participants |
| Single Arm | Number of Participants With Diabetic Retinopathy (DR) Classified by Severity | 12 Months | Moderate NPDR | 7 Participants |
| Single Arm | Number of Participants With Diabetic Retinopathy (DR) Classified by Severity | 12 Months | Severe NPDR | 5 Participants |
| Single Arm | Number of Participants With Diabetic Retinopathy (DR) Classified by Severity | 12 Months | Proliferative diabetic retinopathy (PDR) | 6 Participants |
Other Pre-specified
Optical Coherence Tomography (OCT) Perfusion
Change in macular OCT perfusion (whole deep capillary perfusion density) at months 12 and 24 by OCT angiography
Time frame: Baseline, 12 months,and 24 months
Population: A total of 20 participants were enrolled; 20 completed the 12 months and 16 completed the study (24 months). 15 OCT angiography out of 16 that completed the study were available for the 24-month analysis.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Single Arm | Optical Coherence Tomography (OCT) Perfusion | Baseline | 50.82 percentage perfusion density |
| Single Arm | Optical Coherence Tomography (OCT) Perfusion | 12 months | 47.6 percentage perfusion density |
| Single Arm | Optical Coherence Tomography (OCT) Perfusion | 24 months | 46.40 percentage perfusion density |
Other Pre-specified
Retinal Vascular Changes by OCT Angiography
Capillary Perfusion Density change at month 12 and month 24 by OCT angiography.
Time frame: Baseline, 12 months, and 24 months
Population: A total of 20 participants were enrolled; 20 completed the 12 months and 16 completed the study (24 months). 15 OCT angiography out of 16 that completed the study were available for the 24-month analysis.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Single Arm | Retinal Vascular Changes by OCT Angiography | Baseline : Super - Whole | 45.98 percentage perfusion density |
| Single Arm | Retinal Vascular Changes by OCT Angiography | Baseline : Super - Fovea | 31.15 percentage perfusion density |
| Single Arm | Retinal Vascular Changes by OCT Angiography | Baseline : Super - Parafovea | 47.34 percentage perfusion density |
| Single Arm | Retinal Vascular Changes by OCT Angiography | Baseline : Deep - Whole | 50.82 percentage perfusion density |
| Single Arm | Retinal Vascular Changes by OCT Angiography | Baseline : Deep - Fovea | 24.56 percentage perfusion density |
| Single Arm | Retinal Vascular Changes by OCT Angiography | Baseline : Deep - Parafovea | 53.71 percentage perfusion density |
| Single Arm | Retinal Vascular Changes by OCT Angiography | 12 Months : Super - Whole | 43.56 percentage perfusion density |
| Single Arm | Retinal Vascular Changes by OCT Angiography | 12 Months : Super - Fovea | 24.30 percentage perfusion density |
| Single Arm | Retinal Vascular Changes by OCT Angiography | 12 Months : Super - Parafovea | 45.08 percentage perfusion density |
| Single Arm | Retinal Vascular Changes by OCT Angiography | 12 Months : Deep - Whole | 47.63 percentage perfusion density |
| Single Arm | Retinal Vascular Changes by OCT Angiography | 12 Months : Deep - Fovea | 24.92 percentage perfusion density |
| Single Arm | Retinal Vascular Changes by OCT Angiography | 12 Months : Deep - Parafovea | 49.88 percentage perfusion density |
| Single Arm | Retinal Vascular Changes by OCT Angiography | 24 Months : Super - Whole | 40.68 percentage perfusion density |
| Single Arm | Retinal Vascular Changes by OCT Angiography | 24 Months : Super - Fovea | 18.51 percentage perfusion density |
| Single Arm | Retinal Vascular Changes by OCT Angiography | 24 Months : Super - Parafovea | 42.93 percentage perfusion density |
| Single Arm | Retinal Vascular Changes by OCT Angiography | 24 Months : Deep - Whole | 46.40 percentage perfusion density |
| Single Arm | Retinal Vascular Changes by OCT Angiography | 24 Months : Deep - Fovea | 23.69 percentage perfusion density |
| Single Arm | Retinal Vascular Changes by OCT Angiography | 24 Months : Deep - Parafovea | 48.83 percentage perfusion density |