Nonproliferative Diabetic Retinopathy
Conditions
Brief summary
The primary objective of the study is to assess the efficacy of intravitreal (IVT) aflibercept compared to sham treatment in the improvement of moderately severe to severe nonproliferative diabetic retinopathy (NPDR). The secondary objectives of the study are: * To characterize the safety of IVT aflibercept in patients with moderately severe to severe NPDR * To determine if IVT aflibercept will prevent the worsening of diabetic retinopathy and reduce the incidence of DME * To determine the anatomic effects of IVT aflibercept in patients with moderately severe to severe NPDR
Interventions
DRUGIntravitreal aflibercept injection [IAI]
DRUGSham
Sponsors
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: 1. Men or women ≥18 years of age with type 1 or 2 diabetes mellitus who have moderately severe to severe nonproliferative diabetic retinopathy (NPDR) \[(diabetic retinopathy severity scale (DRSS) levels 47 or 53)\], confirmed by the central reading center, in whom panretinal photocoagulation (PRP) can be safely deferred for at least 6 months per the investigator 2. Best corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score in the study eye of ≥69 letters (approximate Snellen equivalent of 20/40 or better) Key
Exclusion criteria
1. Presence of diabetic macular edema (DME) threatening the center of the macula in the study eye 2. Evidence of retinal neovascularization on clinical examination or Fluorescein Angiography (FA) 3. Any prior focal or grid laser photocoagulation or any prior PRP in the study eye 4. Any prior systemic anti-vascular endothelial growth factor (VEGF) treatment or intravitreal (IVT) anti-VEGF treatment in the study eye 5. Any prior intraocular steroid injection in the study eye 6. Current anterior segment neovascularization (ASNV), vitreous hemorrhage, or tractional retinal detachment visible at the screening assessments in the study eye Note: Other inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Improved by ≥2 Steps From Baseline in the Diabetic Retinopathy Disease Severity Scale (DRSS) Score at Week 24 in the Combined 2Q16 and 2Q8 Groups | At Week 24 | The Diabetic Retinopathy Disease Severity Scale (DRSS) may be used to describe overall retinopathy severity as well as the change in severity over time. Severity range from level 10 (DR absent) to level 85 (advanced proliferative DR: posterior fundus obscured, or center of macula detached). Here, DRSS describes severity level 47 (moderately severe NPDR) and level 53 (severe NPDR) at week 24 from baseline. |
| Percentage of Participants With a ≥ 2-step Change at Week 52 in Diabetic Retinopathy Severity Scale (DRSS) From Baseline | At Week 52 | The Diabetic Retinopathy Disease Severity Scale (DRSS) may be used to describe overall retinopathy severity as well as the change in severity over time. Severity range from level 10 (DR absent) to level 85 (advanced proliferative DR: posterior fundus obscured, or center of macula detached). Here, DRSS describes severity level 47 (moderately severe NPDR) and level 53 (severe NPDR) at week 52 from baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Development of Any Neovascular Vision Threatening Complication (PDR/ASNV) Through Week 52 | Baseline through week 52 (day 365) | Vision-threatening complication (VTC) is defined as the composite outcome of proliferative diabetic retinopathy (PDR) (inclusive of participants who have vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and anterior segment neovascularization (ASNV) (participants with neovascularization of the iris \[at least 2 cumulative clock hours\], and/or definitive neovascularization of the iridocorneal angle). Vision Threatening Complications include PDR/ASNV identified by investigators and Diabetic Retinopathy Scale Score (DRSS) \>61. |
| Time to Development of Central Involved-Diabetic Macular Edema (CI-DME) Through Week 52 | Baseline through week 52 (day 365) | Time to develop Central Involved-Diabetic Macular Edema (CI-DME) through week 52 reported. |
| Percentage of Participants Who Developed a Vision-Threatening Complication Due to Diabetic Retinopathy at Week 52 | At Week 52 | Vision-threatening complications are defined as the composite outcome of proliferative diabetic retinopathy (PDR) (inclusive of participants who have vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and anterior segment neovascularization (ASNV) (participants with neovascularization of the iris \[at least 2 cumulative clock hours\], and/or definitive neovascularization of the iridocorneal angle). |
| Area Under the Curve (AUC) for Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52 | At week 52 | The area under the curve (AUC) is the area under the best corrected visual acuity (BCVA) versus time curve from baseline to week 52. 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 Who Received Panretinal Photocoagulation (PRP), Inclusive of Participants Undergoing Vitrectomy With Endolaser, at Week 52 | At Week 52 | The percentage of participants who received panretinal photocoagulation (PRP), inclusive of participants undergoing vitrectomy with endolaser, at week 52 were reported. |
| Percentage of Participants Who Developed Central Involved-Diabetic Macular Edema (CI-DME) at Week 52 | At Week 52 | The percentage of participants who developed CI-DME at week 52 were reported. |
Countries
Germany, Hungary, Japan, Puerto Rico, United Kingdom, United States
Participant flow
Recruitment details
Recruitment for this study was conducted in the following countries between 29 Mar 2016 and 07 Aug 2017: Germany, Hungary, Japan, the United Kingdom, and the United States. A total of 759 participants were screened.
Pre-assignment details
Out of 759, 402 participants were randomized to receive 1 of 3 treatment groups in a 1:1:1 ratio stratified based on their Diabetic Retinopathy Severity Scale (DRSS) score (level 47 vs. level 53). Only 1 eye was selected as the study eye.
Participants by arm
| Arm | Count |
|---|---|
| Sham Treatment All participants received sham injections in the study eye every 4 weeks (Q4) to week 16 (after 5 initial monthly sham injections), followed by sham injections Q8 to week 96. | 133 |
| Intravitreal Aflibercept Injection (IAI) 2Q16 All participants received a 2 milligram (mg) Intravitreal Aflibercept Injection (IAI) in the study eye every 16 weeks (2Q16) (after 3 initial monthly doses and one 8-week interval) to week 96. | 135 |
| Intravitreal Aflibercept Injection (IAI) 2Q8 All participants received 2 mg IAI in the study eye every 8 weeks (2Q8) from day 1 up to week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with IAI 2 mg to week 96. | 134 |
| Total | 402 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 9 | 0 |
| Overall Study | Death | 8 | 1 | 2 |
| Overall Study | Lost to Follow-up | 18 | 5 | 14 |
| Overall Study | Pregnancy | 1 | 0 | 0 |
| Overall Study | Protocol Deviation | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 9 | 6 |
Baseline characteristics
| Characteristic | Intravitreal Aflibercept Injection (IAI) 2Q16 | Intravitreal Aflibercept Injection (IAI) 2Q8 | Sham Treatment | Total |
|---|---|---|---|---|
| Age, Continuous | 55.4 Years STANDARD_DEVIATION 11.13 | 55.8 Years STANDARD_DEVIATION 10.19 | 55.8 Years STANDARD_DEVIATION 10.31 | 55.7 Years STANDARD_DEVIATION 10.53 |
| Baseline Diabetic Retinopathy Severity Score (DRSS) Level 47 (Moderately Severe) | 102 Participants | 101 Participants | 99 Participants | 302 Participants |
| Baseline Diabetic Retinopathy Severity Score (DRSS) Level 53 (Severe) | 33 Participants | 33 Participants | 34 Participants | 100 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 97 Participants | 93 Participants | 74 Participants | 264 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 37 Participants | 41 Participants | 58 Participants | 136 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 4 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) Asian | 12 Participants | 7 Participants | 4 Participants | 23 Participants |
| Race (NIH/OMB) Black or African American | 16 Participants | 12 Participants | 13 Participants | 41 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 5 Participants | 8 Participants | 18 Participants |
| Race (NIH/OMB) White | 99 Participants | 104 Participants | 107 Participants | 310 Participants |
| Sex: Female, Male Female | 60 Participants | 53 Participants | 64 Participants | 177 Participants |
| Sex: Female, Male Male | 75 Participants | 81 Participants | 69 Participants | 225 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 8 / 133 | 1 / 135 | 3 / 134 | 4 / 269 |
| other Total, other adverse events | 104 / 133 | 104 / 135 | 106 / 134 | 210 / 269 |
| serious Total, serious adverse events | 38 / 133 | 38 / 135 | 47 / 134 | 85 / 269 |
Outcome results
Primary
Percentage of Participants Who Improved by ≥2 Steps From Baseline in the Diabetic Retinopathy Disease Severity Scale (DRSS) Score at Week 24 in the Combined 2Q16 and 2Q8 Groups
The Diabetic Retinopathy Disease Severity Scale (DRSS) may be used to describe overall retinopathy severity as well as the change in severity over time. Severity range from level 10 (DR absent) to level 85 (advanced proliferative DR: posterior fundus obscured, or center of macula detached). Here, DRSS describes severity level 47 (moderately severe NPDR) and level 53 (severe NPDR) at week 24 from baseline.
Time frame: At Week 24
Population: FAS included all randomized participants who received any study treatment as assigned at baseline (as randomized). The missing data were imputed using last observation carried forward (LOCF) method.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sham Treatment | Percentage of Participants Who Improved by ≥2 Steps From Baseline in the Diabetic Retinopathy Disease Severity Scale (DRSS) Score at Week 24 in the Combined 2Q16 and 2Q8 Groups | 6.0 Percentage of participants |
| Intravitreal Aflibercept Injection (IAI) 2Q16 | Percentage of Participants Who Improved by ≥2 Steps From Baseline in the Diabetic Retinopathy Disease Severity Scale (DRSS) Score at Week 24 in the Combined 2Q16 and 2Q8 Groups | 61.5 Percentage of participants |
| Intravitreal Aflibercept Injection (IAI) 2Q8 | Percentage of Participants Who Improved by ≥2 Steps From Baseline in the Diabetic Retinopathy Disease Severity Scale (DRSS) Score at Week 24 in the Combined 2Q16 and 2Q8 Groups | 55.2 Percentage of participants |
| IAI 2 mg Groups Combined (2Q16 & 2Q8) | Percentage of Participants Who Improved by ≥2 Steps From Baseline in the Diabetic Retinopathy Disease Severity Scale (DRSS) Score at Week 24 in the Combined 2Q16 and 2Q8 Groups | 58.4 Percentage of participants |
p-value: <0.000195% CI: [45.2, 59.5]Cochran-Mantel-Haenszel
Primary
Percentage of Participants With a ≥ 2-step Change at Week 52 in Diabetic Retinopathy Severity Scale (DRSS) From Baseline
The Diabetic Retinopathy Disease Severity Scale (DRSS) may be used to describe overall retinopathy severity as well as the change in severity over time. Severity range from level 10 (DR absent) to level 85 (advanced proliferative DR: posterior fundus obscured, or center of macula detached). Here, DRSS describes severity level 47 (moderately severe NPDR) and level 53 (severe NPDR) at week 52 from baseline.
Time frame: At Week 52
Population: FAS included all randomized participants who received any study treatment as assigned at baseline (as randomized). The missing data were imputed using LOCF method.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sham Treatment | Percentage of Participants With a ≥ 2-step Change at Week 52 in Diabetic Retinopathy Severity Scale (DRSS) From Baseline | 15.0 Percentage of participants |
| Intravitreal Aflibercept Injection (IAI) 2Q16 | Percentage of Participants With a ≥ 2-step Change at Week 52 in Diabetic Retinopathy Severity Scale (DRSS) From Baseline | 65.2 Percentage of participants |
| Intravitreal Aflibercept Injection (IAI) 2Q8 | Percentage of Participants With a ≥ 2-step Change at Week 52 in Diabetic Retinopathy Severity Scale (DRSS) From Baseline | 79.9 Percentage of participants |
p-value: <0.000195% CI: [40.1, 60.1]Cochran-Mantel-Haenszel
p-value: <0.000195% CI: [55.8, 73.9]Cochran-Mantel-Haenszel
Secondary
Area Under the Curve (AUC) for Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52
The area under the curve (AUC) is the area under the best corrected visual acuity (BCVA) versus time curve from baseline to week 52. 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 52
Population: AUC was calculated as a weighted average based on total AUC (using the trapezoidal rule) divided by total duration in days. FAS included all randomized participants who received any study treatment as assigned at baseline (as randomized).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sham Treatment | Area Under the Curve (AUC) for Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52 | 0.5 scores on a scale | Standard Deviation 3.01 |
| Intravitreal Aflibercept Injection (IAI) 2Q16 | Area Under the Curve (AUC) for Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52 | 1.7 scores on a scale | Standard Deviation 3.5 |
| Intravitreal Aflibercept Injection (IAI) 2Q8 | Area Under the Curve (AUC) for Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52 | 1.3 scores on a scale | Standard Deviation 3.49 |
p-value: 0.005795% CI: [0.33, 1.94]ANOVA
p-value: 0.052995% CI: [-0.01, 1.6]ANOVA
Secondary
Percentage of Participants Who Developed a Vision-Threatening Complication Due to Diabetic Retinopathy at Week 52
Vision-threatening complications are defined as the composite outcome of proliferative diabetic retinopathy (PDR) (inclusive of participants who have vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and anterior segment neovascularization (ASNV) (participants with neovascularization of the iris \[at least 2 cumulative clock hours\], and/or definitive neovascularization of the iridocorneal angle).
Time frame: At Week 52
Population: FAS included all randomized participants who received any study treatment as assigned at baseline (as randomized).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sham Treatment | Percentage of Participants Who Developed a Vision-Threatening Complication Due to Diabetic Retinopathy at Week 52 | 20.3 Percentage of participants |
| Intravitreal Aflibercept Injection (IAI) 2Q16 | Percentage of Participants Who Developed a Vision-Threatening Complication Due to Diabetic Retinopathy at Week 52 | 3.7 Percentage of participants |
| Intravitreal Aflibercept Injection (IAI) 2Q8 | Percentage of Participants Who Developed a Vision-Threatening Complication Due to Diabetic Retinopathy at Week 52 | 3.0 Percentage of participants |
p-value: <0.000195% CI: [-24.7, -9.9]Cochran-Mantel-Haenszel
p-value: <0.000195% CI: [-24.2, -9.1]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Developed Central Involved-Diabetic Macular Edema (CI-DME) at Week 52
The percentage of participants who developed CI-DME at week 52 were reported.
Time frame: At Week 52
Population: FAS included all randomized participants who received any study treatment as assigned at baseline (as randomized).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sham Treatment | Percentage of Participants Who Developed Central Involved-Diabetic Macular Edema (CI-DME) at Week 52 | 25.6 Percentage of participants |
| Intravitreal Aflibercept Injection (IAI) 2Q16 | Percentage of Participants Who Developed Central Involved-Diabetic Macular Edema (CI-DME) at Week 52 | 6.7 Percentage of participants |
| Intravitreal Aflibercept Injection (IAI) 2Q8 | Percentage of Participants Who Developed Central Involved-Diabetic Macular Edema (CI-DME) at Week 52 | 8.2 Percentage of participants |
p-value: =0.000295% CI: [-26.2, -8.5]Cochran-Mantel-Haenszel
p-value: <0.000195% CI: [-27.5, -10.4]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Received Panretinal Photocoagulation (PRP), Inclusive of Participants Undergoing Vitrectomy With Endolaser, at Week 52
The percentage of participants who received panretinal photocoagulation (PRP), inclusive of participants undergoing vitrectomy with endolaser, at week 52 were reported.
Time frame: At Week 52
Population: FAS included all randomized participants who received any study treatment as assigned at baseline (as randomized).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sham Treatment | Percentage of Participants Who Received Panretinal Photocoagulation (PRP), Inclusive of Participants Undergoing Vitrectomy With Endolaser, at Week 52 | 6.8 Percentage of participants |
| Intravitreal Aflibercept Injection (IAI) 2Q16 | Percentage of Participants Who Received Panretinal Photocoagulation (PRP), Inclusive of Participants Undergoing Vitrectomy With Endolaser, at Week 52 | 0.7 Percentage of participants |
| Intravitreal Aflibercept Injection (IAI) 2Q8 | Percentage of Participants Who Received Panretinal Photocoagulation (PRP), Inclusive of Participants Undergoing Vitrectomy With Endolaser, at Week 52 | 0.7 Percentage of participants |
p-value: 0.008995% CI: [-10.5, -1.6]Cochran-Mantel-Haenszel
p-value: 0.009695% CI: [-10.5, -1.5]Cochran-Mantel-Haenszel
Secondary
Time to Development of Any Neovascular Vision Threatening Complication (PDR/ASNV) Through Week 52
Vision-threatening complication (VTC) is defined as the composite outcome of proliferative diabetic retinopathy (PDR) (inclusive of participants who have vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and anterior segment neovascularization (ASNV) (participants with neovascularization of the iris \[at least 2 cumulative clock hours\], and/or definitive neovascularization of the iridocorneal angle). Vision Threatening Complications include PDR/ASNV identified by investigators and Diabetic Retinopathy Scale Score (DRSS) \>61.
Time frame: Baseline through week 52 (day 365)
Population: FAS included all randomized participants who received any study treatment as assigned at baseline (as randomized). Participants who did not have an event were censored at their last visit at or before the week 52 visit.~Here, the value NA = Not evaluable due to small number of VTC events.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sham Treatment | Time to Development of Any Neovascular Vision Threatening Complication (PDR/ASNV) Through Week 52 | NA Days |
| Intravitreal Aflibercept Injection (IAI) 2Q16 | Time to Development of Any Neovascular Vision Threatening Complication (PDR/ASNV) Through Week 52 | NA Days |
| Intravitreal Aflibercept Injection (IAI) 2Q8 | Time to Development of Any Neovascular Vision Threatening Complication (PDR/ASNV) Through Week 52 | NA Days |
Secondary
Time to Development of Central Involved-Diabetic Macular Edema (CI-DME) Through Week 52
Time to develop Central Involved-Diabetic Macular Edema (CI-DME) through week 52 reported.
Time frame: Baseline through week 52 (day 365)
Population: FAS included all randomized participants who received any study treatment as assigned at baseline (as randomized). Participants who did not have an event were censored at their last visit, at or before the week 52 visit. Here, the value NA = Not evaluable due to small number of CI-DME events.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sham Treatment | Time to Development of Central Involved-Diabetic Macular Edema (CI-DME) Through Week 52 | NA Days |
| Intravitreal Aflibercept Injection (IAI) 2Q16 | Time to Development of Central Involved-Diabetic Macular Edema (CI-DME) Through Week 52 | NA Days |
| Intravitreal Aflibercept Injection (IAI) 2Q8 | Time to Development of Central Involved-Diabetic Macular Edema (CI-DME) Through Week 52 | NA Days |