Diabetic Macular Edema, Type 1 Diabetes Mellitus, Type 2 Diabetes Mellitus
Conditions
Brief summary
The primary objective of the study is to determine if treatment with high-dose aflibercept (HD) at intervals of 12 or 16 weeks provides non-inferior best corrected visual acuity (BCVA) compared to aflibercept dosed every 8 weeks. The secondary objectives of the study are as follows: * To determine the effect of HD vs. aflibercept on anatomic and other visual measures of response * To evaluate the safety, immunogenicity, and pharmacokinetics (PK) of aflibercept
Interventions
DRUGaflibercept
Intravitreally (IVT) administered as a liquid formulation in a vial
Intravitreally (IVT) administered as a liquid formulation in a vial
Sponsors
Bayer
Regeneron Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Diabetic macular edema (DME) with central involvement in the study eye * Best corrected visual acuity (BCVA) early treatment diabetic retinopathy study (ETDRS) letter score of 78 to 24 (approximate Snellen equivalent of 20/32 to 20/320) in the study eye with decreased vision determined to be primarily the result of DME * Willing and able to comply with clinic visits and study-related procedures * Provide informed consent signed by study participant or legally acceptable representative Extension Phase: All randomized patients that complete visit 26, week 96, as long as the patient 1) provides informed consent and 2) no treatment for DME has been given in the study eye other than the randomized study treatment. Key
Exclusion criteria
* Evidence of macular edema due to any cause other than diabetes mellitus in either eye * Active proliferative diabetic retinopathy in the study eye * IVT anti-VEGF treatment (aflibercept, ranibizumab, bevacizumab, brolucizumab, pegaptanib sodium) or panretinal laser photocoagulation (PRP) /macular laser photocoagulation within 12 weeks (84 days) or intraocular or periocular corticosteroids within 16 weeks (112 days) of the screening visit in the study eye * Prior IVT investigational agents in either eye (eg, anti-ang-2/anti-VEGF bispecific monoclonal antibodies, gene therapy, etc.) at any time * Treatment with ocriplasmin (JETREA®) in the study eye at any time NOTE: Other Protocol Defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Best Corrected Visual Acuity (BCVA) (Early Treatment Diabetic Retinopathy Study [ETDRS] Letter Score) in the Study Eye at Week 48 | Baseline, Week 48 | Visual function of the study eye was assessed at a distance of 4 meters at every study visit using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. BCVA scale range is 0 (worst) to 100 (best). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Gaining ≥15 Letters in BCVA From Baseline at Week 48 | Baseline, Week 48 | Visual function of the study eye was assessed at a distance of 4 meters at every study visit using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. BCVA scale range is 0 (worst) to 100 (best). Only one study eye per participant was analyzed within the study |
| Percentage of Participants With BCVA ≥69 Letters at Week 48 | At Week 48 | Visual function of the study eye was assessed at a distance of 4 meters at every study visit using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. BCVA scale range is 0 (worst) to 100 (best). |
| Percentage of Participants Without Fluid at Foveal Center at Week 48 | At Week 48 | Retinal fluid status was evaluated using spectral domain optical coherence tomography (SD-OCT) on the study eye. |
| Change From Baseline in Central Retinal Thickness (CRT) in the Study Eye at Week 48 | Baseline, Week 48 | Central Retinal Thickness (CRT) was measured in the study eye by spectral domain optical coherence tomography (SD-OCT). |
| Percentage of Participants Without Leakage on Fluorescein Angiography (FA) at Week 48 | At Week 48 | Leakage is the release of fluorescein dye from diseased retinal vessels. |
| Change From Baseline in National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) Total Score at Week 48 | Baseline, Week 48 | Vision-specific quality of life is assessed with the NEI VFQ-25 (National Eye Institute Visual Function Questionnaire), i.e. a 25-item questionnaire that gives a score on a scale from 0 (worst) to 100 (best = no vision problems). |
| Systemic Pharmacokinetics (PK) of Aflibercept as Assessed by Plasma Concentrations Through Week 48 | Through Week 48 | Concentrations of Free Aflibercept in Plasma by Time and Treatment Group |
| Percentage of Participants With a ≥2 Step Improvement From Baseline in Diabetic Retinopathy Severity Scale (DRSS) Score at Week 48 | Baseline, Week 48 | The DRSS was assessed according to the following scale: 10 = Diabetic retinopathy (DR) absent, 14 = DR questionable, 15 = DR questionable, 20 = Micro-aneurysms only, 35 = Mild Non-proliferative diabetic retinopathy (NPDR), 43 = Moderate NPDR, 47 = Moderately severe NPDR, 53 = Severe NPDR, 61 = Mild Proliferative diabetic retinopathy (PDR), 65 = Moderate PDR, 71 = High-risk PDR, 75 = High-risk PDR, 81 = Advanced PDR: fundus partially obscured, center of macula attached, 85 = Advanced PDR: posterior fundus obscured, or center of macula detached, 90 = cannot grade, even sufficiently for level 81 or 85. |
| Change From 8-weeks Post Initial Treatment Phase in BCVA in the Study Eye in Participants With Both 8-weeks Post Initial Treatment Phase BCVA and Week 48 BCVA | Baseline, Week 48 | Visual function of the study eye was assessed at a distance of 4 meters at every study visit using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. BCVA scale range is 0 (worst) to 100 (best). (Per SAP Version 2.0 Appendix 10.9 for US Only) |
| Change From Baseline in BCVA (Region-specific Analysis) in the Study Eye at Week 60 | Baseline, Week 60 | Visual function of the study eye was assessed at a distance of 4 meters at every study visit using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. BCVA scale range is 0 (worst) to 100 (best). |
| Assessment of Immunogenicity to Aflibercept by Measuring the Incidence of Treatment-emergent Anti-drug Antibodies (ADA) Response Through Week 96 | Through Week 96 | Number of participants with pre-existing immunoreactivity and treatment-emergent ADA response reported |
| Number of Participants With Any Treatment-emergent Adverse Event (TEAE) Through Week 96 | Through Week 96 | A TEAE is an AE starting after the first dose of study drug to the last dose of study drug (active or sham) plus 30 days. Additionally, for patients who are still participating in the study (ie, have not been withdrawn and are continuing in the extension phase of the study) as of the week 96 visit all AEs up through the date of the week 96 visit were considered treatment-emergent. |
| Number of Participants With Any Serious TEAE Through Week 96 | Through Week 96 | A TEAE is an AE starting after the first dose of study drug to the last dose of study drug (active or sham) plus 30 days. Additionally, for patients who are still participating in the study (ie, have not been withdrawn and are continuing in the extension phase of the study) as of the week 96 visit all AEs up through the date of the week 96 visit were considered treatment-emergent. |
| Number of Participants With Any TEAE Through Week 156 | Through Week 156 | TEAEs are defined as AEs starting after the first dose of study drug to the last dose of study drug (active or sham) plus 30 days or week 156 visit, whichever was later. |
| Number of Participants With Any Serious TEAE Through Week 156 | Through Week 156 | — |
| Change From Baseline in BCVA in the Study Eye in Participants With Both Baseline and Week 48 BCVA | Baseline, Week 48 | Visual function of the study eye was assessed at a distance of 4 meters at every study visit using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. BCVA scale range is 0 (worst) to 100 (best). (Per Statistical Analysis Plan (SAP) Version 2.0 Appendix 10.9 for US Only) |
Countries
Canada, Czechia, Germany, Hungary, Japan, Puerto Rico, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 970 participants were screened and 660 participants were randomized, of whom 658 participants received at least 1 dose of study treatment in the study eye. Fellow eye treatment was allowed with 2 mg aflibercept at the investigator's discretion for indications approved by governing authorities. The treated fellow eye was not considered an additional study eye. Only one study eye per participant was analyzed within the study.
Participants by arm
| Arm | Count |
|---|---|
| Aflibercept 2 mg Every 8 Weeks (2q8) Participants received 2 milligrams (mg) aflibercept every 8 weeks (2q8), following 5 initial monthly doses | 167 |
| High-dose (HD) Aflibercept Every 12 Weeks (HDq12) Participants received HD aflibercept (8 mg) every 12 weeks (HDq12) following 3 initial monthly doses | 328 |
| HD Aflibercept Every 16 Weeks (HDq16) Participants received HD aflibercept (8mg) every 16 weeks (HDq16) following 3 initial monthly doses | 163 |
| Total | 658 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Extension Phase (Wk 96 to Wk 156) | Adverse Event | 0 | 0 | 0 | 1 | 1 | 1 |
| Extension Phase (Wk 96 to Wk 156) | Death | 0 | 0 | 0 | 2 | 7 | 2 |
| Extension Phase (Wk 96 to Wk 156) | Decision by the Investigator/Sponsor | 0 | 0 | 0 | 0 | 3 | 2 |
| Extension Phase (Wk 96 to Wk 156) | Lost to Follow-up | 0 | 0 | 0 | 3 | 6 | 6 |
| Extension Phase (Wk 96 to Wk 156) | Protocol Violation | 0 | 0 | 0 | 1 | 0 | 0 |
| Extension Phase (Wk 96 to Wk 156) | Withdrawal by Subject | 0 | 0 | 0 | 5 | 10 | 5 |
| Main Study (Up to Wk 96) | Adverse Event | 1 | 9 | 2 | 0 | 0 | 0 |
| Main Study (Up to Wk 96) | Death | 9 | 18 | 5 | 0 | 0 | 0 |
| Main Study (Up to Wk 96) | Decision by the investigator/sponsor | 2 | 9 | 3 | 0 | 0 | 0 |
| Main Study (Up to Wk 96) | Lost to Follow-up | 5 | 19 | 7 | 0 | 0 | 0 |
| Main Study (Up to Wk 96) | Non-compliance with protocol by the subject | 2 | 1 | 0 | 0 | 0 | 0 |
| Main Study (Up to Wk 96) | Withdrawal by Subject | 9 | 17 | 8 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Aflibercept 2 mg Every 8 Weeks (2q8) | High-dose (HD) Aflibercept Every 12 Weeks (HDq12) | HD Aflibercept Every 16 Weeks (HDq16) | Total |
|---|---|---|---|---|
| Age, Continuous | 63.0 Years STANDARD_DEVIATION 9.78 | 62.1 Years STANDARD_DEVIATION 11.13 | 61.9 Years STANDARD_DEVIATION 9.5 | 62.3 Years STANDARD_DEVIATION 10.41 |
| Best Corrected Visual Acuity (BCVA) in the Study Eye | 61.5 Letters STANDARD_DEVIATION 11.22 | 63.6 Letters STANDARD_DEVIATION 10.1 | 61.4 Letters STANDARD_DEVIATION 11.76 | 62.5 Letters STANDARD_DEVIATION 10.86 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 31 Participants | 54 Participants | 34 Participants | 119 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 133 Participants | 266 Participants | 126 Participants | 525 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 8 Participants | 3 Participants | 14 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 30 Participants | 48 Participants | 23 Participants | 101 Participants |
| Race/Ethnicity, Customized Black or African American | 18 Participants | 35 Participants | 9 Participants | 62 Participants |
| Race/Ethnicity, Customized Multiple | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Reported | 3 Participants | 4 Participants | 2 Participants | 9 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 6 Participants | 1 Participants | 11 Participants |
| Race/Ethnicity, Customized White | 112 Participants | 231 Participants | 128 Participants | 471 Participants |
| Sex: Female, Male Female | 75 Participants | 118 Participants | 64 Participants | 257 Participants |
| Sex: Female, Male Male | 92 Participants | 210 Participants | 99 Participants | 401 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 | 9 / 167 | 18 / 328 | 5 / 163 | 2 / 70 | 7 / 130 | 3 / 65 |
| other Total, other adverse events | 98 / 167 | 190 / 328 | 116 / 163 | 50 / 70 | 99 / 130 | 50 / 65 |
| serious Total, serious adverse events | 46 / 167 | 84 / 328 | 45 / 163 | 27 / 70 | 46 / 130 | 23 / 65 |
Outcome results
Primary
Change From Baseline in Best Corrected Visual Acuity (BCVA) (Early Treatment Diabetic Retinopathy Study [ETDRS] Letter Score) in the Study Eye at Week 48
Visual function of the study eye was assessed at a distance of 4 meters at every study visit using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. BCVA scale range is 0 (worst) to 100 (best).
Time frame: Baseline, Week 48
Population: Full analysis set (FAS): All randomized participants who received at least 1 dose of study drug; it was based on the treatment assigned to the participant at baseline (as randomized); Only one study eye per participant was analyzed within the study.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept 2 mg Every 8 Weeks (2q8) | Change From Baseline in Best Corrected Visual Acuity (BCVA) (Early Treatment Diabetic Retinopathy Study [ETDRS] Letter Score) in the Study Eye at Week 48 | 8.67 Letters | Standard Error 0.73 |
| High-dose (HD) Aflibercept Every 12 Weeks (HDq12) | Change From Baseline in Best Corrected Visual Acuity (BCVA) (Early Treatment Diabetic Retinopathy Study [ETDRS] Letter Score) in the Study Eye at Week 48 | 8.10 Letters | Standard Error 0.61 |
| HD Aflibercept Every 16 Weeks (HDq16) | Change From Baseline in Best Corrected Visual Acuity (BCVA) (Early Treatment Diabetic Retinopathy Study [ETDRS] Letter Score) in the Study Eye at Week 48 | 7.23 Letters | Standard Error 0.71 |
p-value: <0.000195% CI: [-2.26, 1.13]Mixed Model for Repeated Measurements
p-value: 0.003195% CI: [-3.27, 0.39]Mixed Model for Repeated Measurements
Secondary
Assessment of Immunogenicity to Aflibercept by Measuring the Incidence of Treatment-emergent Anti-drug Antibodies (ADA) Response Through Week 96
Number of participants with pre-existing immunoreactivity and treatment-emergent ADA response reported
Time frame: Through Week 96
Population: ADA analysis set (AAS): All treated participants who received any amount of study drug and had at least 1 non-missing anti-aflibercept antibody result following the first dose of study drug. The AAS is based on the actual treatment received (as treated) rather than as randomized
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aflibercept 2 mg Every 8 Weeks (2q8) | Assessment of Immunogenicity to Aflibercept by Measuring the Incidence of Treatment-emergent Anti-drug Antibodies (ADA) Response Through Week 96 | Pre-existing Immunoreactivity | 4 Participants |
| Aflibercept 2 mg Every 8 Weeks (2q8) | Assessment of Immunogenicity to Aflibercept by Measuring the Incidence of Treatment-emergent Anti-drug Antibodies (ADA) Response Through Week 96 | Treatment-Emergent | 2 Participants |
| High-dose (HD) Aflibercept Every 12 Weeks (HDq12) | Assessment of Immunogenicity to Aflibercept by Measuring the Incidence of Treatment-emergent Anti-drug Antibodies (ADA) Response Through Week 96 | Pre-existing Immunoreactivity | 11 Participants |
| High-dose (HD) Aflibercept Every 12 Weeks (HDq12) | Assessment of Immunogenicity to Aflibercept by Measuring the Incidence of Treatment-emergent Anti-drug Antibodies (ADA) Response Through Week 96 | Treatment-Emergent | 7 Participants |
| HD Aflibercept Every 16 Weeks (HDq16) | Assessment of Immunogenicity to Aflibercept by Measuring the Incidence of Treatment-emergent Anti-drug Antibodies (ADA) Response Through Week 96 | Pre-existing Immunoreactivity | 2 Participants |
| HD Aflibercept Every 16 Weeks (HDq16) | Assessment of Immunogenicity to Aflibercept by Measuring the Incidence of Treatment-emergent Anti-drug Antibodies (ADA) Response Through Week 96 | Treatment-Emergent | 4 Participants |
Secondary
Change From 8-weeks Post Initial Treatment Phase in BCVA in the Study Eye in Participants With Both 8-weeks Post Initial Treatment Phase BCVA and Week 48 BCVA
Visual function of the study eye was assessed at a distance of 4 meters at every study visit using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. BCVA scale range is 0 (worst) to 100 (best). (Per SAP Version 2.0 Appendix 10.9 for US Only)
Time frame: Baseline, Week 48
Population: Full Analysis Set (FAS) - for participants who had both BCVA at 8 weeks post initial treatment and week 48 BCVA; Only one study eye per participant was analyzed within the study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept 2 mg Every 8 Weeks (2q8) | Change From 8-weeks Post Initial Treatment Phase in BCVA in the Study Eye in Participants With Both 8-weeks Post Initial Treatment Phase BCVA and Week 48 BCVA | 1.63 Letters | Standard Deviation 6.65 |
| High-dose (HD) Aflibercept Every 12 Weeks (HDq12) | Change From 8-weeks Post Initial Treatment Phase in BCVA in the Study Eye in Participants With Both 8-weeks Post Initial Treatment Phase BCVA and Week 48 BCVA | 1.68 Letters | Standard Deviation 5.54 |
| HD Aflibercept Every 16 Weeks (HDq16) | Change From 8-weeks Post Initial Treatment Phase in BCVA in the Study Eye in Participants With Both 8-weeks Post Initial Treatment Phase BCVA and Week 48 BCVA | 1.64 Letters | Standard Deviation 4.75 |
Secondary
Change From Baseline in BCVA in the Study Eye in Participants With Both Baseline and Week 48 BCVA
Visual function of the study eye was assessed at a distance of 4 meters at every study visit using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. BCVA scale range is 0 (worst) to 100 (best). (Per Statistical Analysis Plan (SAP) Version 2.0 Appendix 10.9 for US Only)
Time frame: Baseline, Week 48
Population: Full Analysis Set (FAS) - for participants who had both baseline BCVA and week 48 BCVA; Only one study eye per participant was analyzed within the study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept 2 mg Every 8 Weeks (2q8) | Change From Baseline in BCVA in the Study Eye in Participants With Both Baseline and Week 48 BCVA | 9.11 Letters | Standard Deviation 8.94 |
| High-dose (HD) Aflibercept Every 12 Weeks (HDq12) | Change From Baseline in BCVA in the Study Eye in Participants With Both Baseline and Week 48 BCVA | 9.14 Letters | Standard Deviation 8.35 |
| HD Aflibercept Every 16 Weeks (HDq16) | Change From Baseline in BCVA in the Study Eye in Participants With Both Baseline and Week 48 BCVA | 9.11 Letters | Standard Deviation 7.3 |
Secondary
Change From Baseline in BCVA (Region-specific Analysis) in the Study Eye at Week 60
Visual function of the study eye was assessed at a distance of 4 meters at every study visit using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. BCVA scale range is 0 (worst) to 100 (best).
Time frame: Baseline, Week 60
Population: FAS: All randomized participants who received at least 1 dose of study drug; it was based on the treatment assigned to the participant at baseline (as randomized); Here, Number of Participants Analyzed = Number of participants with week 60 data. Only one study eye per participant was analyzed within the study
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept 2 mg Every 8 Weeks (2q8) | Change From Baseline in BCVA (Region-specific Analysis) in the Study Eye at Week 60 | 9.40 Letters | Standard Error 0.77 |
| High-dose (HD) Aflibercept Every 12 Weeks (HDq12) | Change From Baseline in BCVA (Region-specific Analysis) in the Study Eye at Week 60 | 8.52 Letters | Standard Error 0.63 |
| HD Aflibercept Every 16 Weeks (HDq16) | Change From Baseline in BCVA (Region-specific Analysis) in the Study Eye at Week 60 | 7.64 Letters | Standard Error 0.75 |
Secondary
Change From Baseline in Central Retinal Thickness (CRT) in the Study Eye at Week 48
Central Retinal Thickness (CRT) was measured in the study eye by spectral domain optical coherence tomography (SD-OCT).
Time frame: Baseline, Week 48
Population: Full analysis set (FAS): All randomized participants who received at least 1 dose of study drug; it was based on the treatment assigned to the participant at baseline (as randomized). Only one study eye per participant was analyzed within the study.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept 2 mg Every 8 Weeks (2q8) | Change From Baseline in Central Retinal Thickness (CRT) in the Study Eye at Week 48 | -164.85 Microns | Standard Error 8.79 |
| High-dose (HD) Aflibercept Every 12 Weeks (HDq12) | Change From Baseline in Central Retinal Thickness (CRT) in the Study Eye at Week 48 | -176.77 Microns | Standard Error 5.73 |
| HD Aflibercept Every 16 Weeks (HDq16) | Change From Baseline in Central Retinal Thickness (CRT) in the Study Eye at Week 48 | -148.84 Microns | Standard Error 9.45 |
Secondary
Change From Baseline in National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) Total Score at Week 48
Vision-specific quality of life is assessed with the NEI VFQ-25 (National Eye Institute Visual Function Questionnaire), i.e. a 25-item questionnaire that gives a score on a scale from 0 (worst) to 100 (best = no vision problems).
Time frame: Baseline, Week 48
Population: Full analysis set (FAS): All randomized participants who received at least 1 dose of study drug; it was based on the treatment assigned to the participant at baseline (as randomized)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept 2 mg Every 8 Weeks (2q8) | Change From Baseline in National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) Total Score at Week 48 | 2.82 Score on a Scale | Standard Error 1.1 |
| High-dose (HD) Aflibercept Every 12 Weeks (HDq12) | Change From Baseline in National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) Total Score at Week 48 | 4.06 Score on a Scale | Standard Error 0.8 |
| HD Aflibercept Every 16 Weeks (HDq16) | Change From Baseline in National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) Total Score at Week 48 | 2.94 Score on a Scale | Standard Error 0.93 |
Secondary
Number of Participants With Any Serious TEAE Through Week 156
Time frame: Through Week 156
Population: Extension Safety Analysis Set (eSAF): All participants in the SAF who enrolled in the extension phase and completed the extension baseline visit.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aflibercept 2 mg Every 8 Weeks (2q8) | Number of Participants With Any Serious TEAE Through Week 156 | 27 Participants |
| High-dose (HD) Aflibercept Every 12 Weeks (HDq12) | Number of Participants With Any Serious TEAE Through Week 156 | 41 Participants |
| HD Aflibercept Every 16 Weeks (HDq16) | Number of Participants With Any Serious TEAE Through Week 156 | 22 Participants |
Secondary
Number of Participants With Any Serious TEAE Through Week 96
A TEAE is an AE starting after the first dose of study drug to the last dose of study drug (active or sham) plus 30 days. Additionally, for patients who are still participating in the study (ie, have not been withdrawn and are continuing in the extension phase of the study) as of the week 96 visit all AEs up through the date of the week 96 visit were considered treatment-emergent.
Time frame: Through Week 96
Population: Safety analysis set (SAF): All randomized participants who received any study treatment; it was based on the treatment received (as treated)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aflibercept 2 mg Every 8 Weeks (2q8) | Number of Participants With Any Serious TEAE Through Week 96 | 46 Participants |
| High-dose (HD) Aflibercept Every 12 Weeks (HDq12) | Number of Participants With Any Serious TEAE Through Week 96 | 81 Participants |
| HD Aflibercept Every 16 Weeks (HDq16) | Number of Participants With Any Serious TEAE Through Week 96 | 44 Participants |
Secondary
Number of Participants With Any TEAE Through Week 156
TEAEs are defined as AEs starting after the first dose of study drug to the last dose of study drug (active or sham) plus 30 days or week 156 visit, whichever was later.
Time frame: Through Week 156
Population: Extension Safety Analysis Set (eSAF): All participants in the SAF who enrolled in the extension phase and completed the extension baseline visit.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aflibercept 2 mg Every 8 Weeks (2q8) | Number of Participants With Any TEAE Through Week 156 | 64 Participants |
| High-dose (HD) Aflibercept Every 12 Weeks (HDq12) | Number of Participants With Any TEAE Through Week 156 | 122 Participants |
| HD Aflibercept Every 16 Weeks (HDq16) | Number of Participants With Any TEAE Through Week 156 | 59 Participants |
Secondary
Number of Participants With Any Treatment-emergent Adverse Event (TEAE) Through Week 96
A TEAE is an AE starting after the first dose of study drug to the last dose of study drug (active or sham) plus 30 days. Additionally, for patients who are still participating in the study (ie, have not been withdrawn and are continuing in the extension phase of the study) as of the week 96 visit all AEs up through the date of the week 96 visit were considered treatment-emergent.
Time frame: Through Week 96
Population: Safety analysis set (SAF): All randomized participants who received any study treatment; it was based on the treatment received (as treated)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aflibercept 2 mg Every 8 Weeks (2q8) | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) Through Week 96 | 134 Participants |
| High-dose (HD) Aflibercept Every 12 Weeks (HDq12) | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) Through Week 96 | 277 Participants |
| HD Aflibercept Every 16 Weeks (HDq16) | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) Through Week 96 | 143 Participants |
Secondary
Percentage of Participants Gaining ≥15 Letters in BCVA From Baseline at Week 48
Visual function of the study eye was assessed at a distance of 4 meters at every study visit using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. BCVA scale range is 0 (worst) to 100 (best). Only one study eye per participant was analyzed within the study
Time frame: Baseline, Week 48
Population: Full analysis set (FAS): All randomized participants who received at least 1 dose of study drug; it was based on the treatment assigned to the participant at baseline (as randomized)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aflibercept 2 mg Every 8 Weeks (2q8) | Percentage of Participants Gaining ≥15 Letters in BCVA From Baseline at Week 48 | 23.0 Percentage of Participants |
| High-dose (HD) Aflibercept Every 12 Weeks (HDq12) | Percentage of Participants Gaining ≥15 Letters in BCVA From Baseline at Week 48 | 18.7 Percentage of Participants |
| HD Aflibercept Every 16 Weeks (HDq16) | Percentage of Participants Gaining ≥15 Letters in BCVA From Baseline at Week 48 | 16.6 Percentage of Participants |
Secondary
Percentage of Participants With a ≥2 Step Improvement From Baseline in Diabetic Retinopathy Severity Scale (DRSS) Score at Week 48
The DRSS was assessed according to the following scale: 10 = Diabetic retinopathy (DR) absent, 14 = DR questionable, 15 = DR questionable, 20 = Micro-aneurysms only, 35 = Mild Non-proliferative diabetic retinopathy (NPDR), 43 = Moderate NPDR, 47 = Moderately severe NPDR, 53 = Severe NPDR, 61 = Mild Proliferative diabetic retinopathy (PDR), 65 = Moderate PDR, 71 = High-risk PDR, 75 = High-risk PDR, 81 = Advanced PDR: fundus partially obscured, center of macula attached, 85 = Advanced PDR: posterior fundus obscured, or center of macula detached, 90 = cannot grade, even sufficiently for level 81 or 85.
Time frame: Baseline, Week 48
Population: Full analysis set (FAS): All randomized participants who received at least 1 dose of study drug; it was based on the treatment assigned to the participant at baseline (as randomized); Only one study eye per participant was analyzed within the study,
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aflibercept 2 mg Every 8 Weeks (2q8) | Percentage of Participants With a ≥2 Step Improvement From Baseline in Diabetic Retinopathy Severity Scale (DRSS) Score at Week 48 | 26.6 Percentage of Participants |
| High-dose (HD) Aflibercept Every 12 Weeks (HDq12) | Percentage of Participants With a ≥2 Step Improvement From Baseline in Diabetic Retinopathy Severity Scale (DRSS) Score at Week 48 | 29.0 Percentage of Participants |
| HD Aflibercept Every 16 Weeks (HDq16) | Percentage of Participants With a ≥2 Step Improvement From Baseline in Diabetic Retinopathy Severity Scale (DRSS) Score at Week 48 | 19.6 Percentage of Participants |
95% CI: [-6.61, 10.57]
95% CI: [-16.88, 1.84]
Secondary
Percentage of Participants With BCVA ≥69 Letters at Week 48
Visual function of the study eye was assessed at a distance of 4 meters at every study visit using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. BCVA scale range is 0 (worst) to 100 (best).
Time frame: At Week 48
Population: Full analysis set (FAS): All randomized participants who received at least 1 dose of study drug; it was based on the treatment assigned to the participant at baseline (as randomized); Only one study eye per participant was analyzed within the study,
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aflibercept 2 mg Every 8 Weeks (2q8) | Percentage of Participants With BCVA ≥69 Letters at Week 48 | 63.0 Percentage of Participants |
| High-dose (HD) Aflibercept Every 12 Weeks (HDq12) | Percentage of Participants With BCVA ≥69 Letters at Week 48 | 65.3 Percentage of Participants |
| HD Aflibercept Every 16 Weeks (HDq16) | Percentage of Participants With BCVA ≥69 Letters at Week 48 | 62.6 Percentage of Participants |
Secondary
Percentage of Participants Without Fluid at Foveal Center at Week 48
Retinal fluid status was evaluated using spectral domain optical coherence tomography (SD-OCT) on the study eye.
Time frame: At Week 48
Population: Full analysis set (FAS): All randomized participants who received at least 1 dose of study drug; it was based on the treatment assigned to the participant at baseline (as randomized)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aflibercept 2 mg Every 8 Weeks (2q8) | Percentage of Participants Without Fluid at Foveal Center at Week 48 | 54.5 Percentage of Participants |
| High-dose (HD) Aflibercept Every 12 Weeks (HDq12) | Percentage of Participants Without Fluid at Foveal Center at Week 48 | 58.5 Percentage of Participants |
| HD Aflibercept Every 16 Weeks (HDq16) | Percentage of Participants Without Fluid at Foveal Center at Week 48 | 43.8 Percentage of Participants |
Secondary
Percentage of Participants Without Leakage on Fluorescein Angiography (FA) at Week 48
Leakage is the release of fluorescein dye from diseased retinal vessels.
Time frame: At Week 48
Population: Full analysis set (FAS): All randomized participants who received at least 1 dose of study drug; it was based on the treatment assigned to the participant at baseline (as randomized)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aflibercept 2 mg Every 8 Weeks (2q8) | Percentage of Participants Without Leakage on Fluorescein Angiography (FA) at Week 48 | 2.5 Percentage of Participants |
| High-dose (HD) Aflibercept Every 12 Weeks (HDq12) | Percentage of Participants Without Leakage on Fluorescein Angiography (FA) at Week 48 | 7.6 Percentage of Participants |
| HD Aflibercept Every 16 Weeks (HDq16) | Percentage of Participants Without Leakage on Fluorescein Angiography (FA) at Week 48 | 0.7 Percentage of Participants |
Secondary
Systemic Pharmacokinetics (PK) of Aflibercept as Assessed by Plasma Concentrations Through Week 48
Concentrations of Free Aflibercept in Plasma by Time and Treatment Group
Time frame: Through Week 48
Population: Pharmacokinetic analysis set (PKAS): All treated participants who received any amount of study drug and had at least 1 non-missing free or bound aflibercept measurement following the first dose of study drug as applicable. The PKAS is based on the actual treatment received (as treated) rather than as randomized.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aflibercept 2 mg Every 8 Weeks (2q8) | Systemic Pharmacokinetics (PK) of Aflibercept as Assessed by Plasma Concentrations Through Week 48 | 0.00102 milligram/Litre (mg/L) | Standard Deviation 0.0058 |
| High-dose (HD) Aflibercept Every 12 Weeks (HDq12) | Systemic Pharmacokinetics (PK) of Aflibercept as Assessed by Plasma Concentrations Through Week 48 | 0.0111 milligram/Litre (mg/L) | Standard Deviation 0.0157 |
| HD Aflibercept Every 16 Weeks (HDq16) | Systemic Pharmacokinetics (PK) of Aflibercept as Assessed by Plasma Concentrations Through Week 48 | 0.00105 milligram/Litre (mg/L) | Standard Deviation 0.00477 |