Diabetic Macular Edema
Conditions
Brief summary
This is a Phase 2, doubled-masked, randomized study of the efficacy and safety of Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) in subjects with diabetic macular edema (DME). Approximately 200 subjects will be randomized in the US, Canada, Australia and EU.
Detailed description
Qualified subjects will be randomized to one of 5 treatment arms. The active (treatment) phase of the study will be 52 weeks, with a 6 month safety follow-up
Interventions
PROCEDURELaser Photocoagulation
laser every 16 weeks as needed
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
* Patients with clinically significant DME with central involvement * Adults 18 years or older with type 1 or 2 diabetes mellitus with diabetic macular edema * ETDRS BCVA: 20/40 to 20/320 (letter score of 73 to 24) in the study eye
Exclusion criteria
* History of vitreoretinal surgery in the study eye * Panretinal laser photocoagulation or macular laser photocoagulation in the study eye within 3 months of screening * Previous use of intraocular or periocular corticosteroids in the study eye within 3 months of screening * Previous treatment with anti-angiogenic drugs in either eye (pegaptanib sodium, anecortave acetate, bevacizumab, ranibizumab, etc) within 3 months of screening * Uncontrolled diabetes mellitus * Uncontrolled hypertension defined as systolic \> 180mmHg or \> 160 mmHg on 2 consecutive measurements or diastolic \> 100 mmHg on optimal medical regimen * Ocular disorders in the study eye, other than DME, that may confound interpretation of study results
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in BCVA From Baseline to Week 24 - Last Observation Carried Forward (LOCF) | At week 24 | Visual function of the study eye was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol at 4 meters. Measurements were taken at every study visit. Missing values were imputed with post-baseline values during on-treatment period by using last observation carried forward (LOCF). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in BCVA From Baseline to Week 52 - LOCF | At week 52 | Visual function of the study eye was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol at 4 meters. Missing values were imputed with post-baseline values during on-treatment period by using last observation carried forward (LOCF). |
| Participants With Gains in ETDRS Letter Score of at Least 15 Letters - LOCF | At week 24 and week 52 | Missing values were imputed with post-baseline values during on-treatment period by using last observation carried forward (LOCF). |
| Change From Baseline in Central Retinal Thickness (CRT) as Assessed by Optical Coherence Tomography (OCT) - LOCF | At week 24 and week 52 | Retinal thickness was evaluated using OCT at every visit except week 1. Missing values were imputed with post-baseline values during on-treatment period by using last observation carried forward (LOCF). |
| Number of Focal Laser Treatments | Week 1 to week 48 | — |
Countries
Austria, Canada, United States
Participant flow
Recruitment details
A total of 221 participants were randomized at 39 sites in the US, Canada, and Austria. After the 1 year treatment period, participants were to be followed for safety in a 6 mo. follow-up phase. The last visit for this study occurred in September, 2010.
Pre-assignment details
The study population consisted of men and women aged 18 or older with clinically significant diabetic macular edema (DME) with central involvement, and a best corrected visual acuity (BCVA) of 20/40 to 20/320 (letter score of 73 to 24) in the study eye.
Participants by arm
| Arm | Count |
|---|---|
| Laser Photocoagulation Focal laser at week 1, and one week after visits at which the participant met laser re-treatment criteria to the end of the study (week 52) starting at week 16; laser re- treatment was permitted no more than once every 16 weeks. | 44 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321).5Q4 Intravitreal Aflibercept Injection (IAI) 0.5mg every 4 weeks to week 52 | 44 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q4 Intravitreal Aflibercept Injection (IAI) 2mg every 4 weeks to week 52 | 44 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q8 Intravitreal Aflibercept Injection (IAI) 2mg every 4 weeks for 3 visits followed by every 8 weeks through week 52 | 42 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321)2PRN Intravitreal Aflibercept Injection (IAI) 2mg every 4 weeks for 3 visits followed by PRN dosing according to the re-treatment criteria to week 52 | 45 |
| Total | 219 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 3 | 1 | 0 | 0 |
| Overall Study | Death | 1 | 1 | 2 | 2 | 0 |
| Overall Study | Lack of Efficacy | 2 | 0 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 | 4 | 2 | 4 |
| Overall Study | Other | 2 | 0 | 1 | 3 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 3 | 2 | 3 |
Baseline characteristics
| Characteristic | Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321).5Q4 | Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q4 | Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q8 | Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321)2PRN | Laser Photocoagulation | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 62.3 years STANDARD_DEVIATION 10.7 | 62.1 years STANDARD_DEVIATION 10.5 | 62.5 years STANDARD_DEVIATION 11.49 | 60.7 years STANDARD_DEVIATION 8.66 | 64.0 years STANDARD_DEVIATION 8.12 | 62.3 years STANDARD_DEVIATION 9.92 |
| Sex: Female, Male Female | 20 Participants | 17 Participants | 20 Participants | 16 Participants | 17 Participants | 90 Participants |
| Sex: Female, Male Male | 24 Participants | 27 Participants | 22 Participants | 29 Participants | 27 Participants | 129 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 20 / 44 | 22 / 44 | 22 / 44 | 26 / 42 | 24 / 45 |
| serious Total, serious adverse events | 10 / 44 | 14 / 44 | 13 / 44 | 12 / 42 | 6 / 45 |
Outcome results
Primary
Change in BCVA From Baseline to Week 24 - Last Observation Carried Forward (LOCF)
Visual function of the study eye was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol at 4 meters. Measurements were taken at every study visit. Missing values were imputed with post-baseline values during on-treatment period by using last observation carried forward (LOCF).
Time frame: At week 24
Population: The FAS was used for the primary efficacy analysis. It included patients as randomized.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Laser Photocoagulation | Change in BCVA From Baseline to Week 24 - Last Observation Carried Forward (LOCF) | 2.5 letters correctly read | Standard Deviation 16.14 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321).5Q4 | Change in BCVA From Baseline to Week 24 - Last Observation Carried Forward (LOCF) | 8.6 letters correctly read | Standard Deviation 14.64 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q4 | Change in BCVA From Baseline to Week 24 - Last Observation Carried Forward (LOCF) | 11.4 letters correctly read | Standard Deviation 8.67 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q8 | Change in BCVA From Baseline to Week 24 - Last Observation Carried Forward (LOCF) | 8.5 letters correctly read | Standard Deviation 7.5 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321)2PRN | Change in BCVA From Baseline to Week 24 - Last Observation Carried Forward (LOCF) | 10.3 letters correctly read | Standard Deviation 7.52 |
Secondary
Change From Baseline in Central Retinal Thickness (CRT) as Assessed by Optical Coherence Tomography (OCT) - LOCF
Retinal thickness was evaluated using OCT at every visit except week 1. Missing values were imputed with post-baseline values during on-treatment period by using last observation carried forward (LOCF).
Time frame: At week 24 and week 52
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Laser Photocoagulation | Change From Baseline in Central Retinal Thickness (CRT) as Assessed by Optical Coherence Tomography (OCT) - LOCF | At week 24 | -67.9 microns | Standard Deviation 135.17 |
| Laser Photocoagulation | Change From Baseline in Central Retinal Thickness (CRT) as Assessed by Optical Coherence Tomography (OCT) - LOCF | At week 52 | -58.4 microns | Standard Deviation 177.6 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321).5Q4 | Change From Baseline in Central Retinal Thickness (CRT) as Assessed by Optical Coherence Tomography (OCT) - LOCF | At week 24 | -144.6 microns | Standard Deviation 110.65 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321).5Q4 | Change From Baseline in Central Retinal Thickness (CRT) as Assessed by Optical Coherence Tomography (OCT) - LOCF | At week 52 | -165.4 microns | Standard Deviation 135.72 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q4 | Change From Baseline in Central Retinal Thickness (CRT) as Assessed by Optical Coherence Tomography (OCT) - LOCF | At week 24 | -194.5 microns | Standard Deviation 143.04 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q4 | Change From Baseline in Central Retinal Thickness (CRT) as Assessed by Optical Coherence Tomography (OCT) - LOCF | At week 52 | -227.4 microns | Standard Deviation 148.96 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q8 | Change From Baseline in Central Retinal Thickness (CRT) as Assessed by Optical Coherence Tomography (OCT) - LOCF | At week 52 | -187.8 microns | Standard Deviation 135.01 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q8 | Change From Baseline in Central Retinal Thickness (CRT) as Assessed by Optical Coherence Tomography (OCT) - LOCF | At week 24 | -127.3 microns | Standard Deviation 141.78 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321)2PRN | Change From Baseline in Central Retinal Thickness (CRT) as Assessed by Optical Coherence Tomography (OCT) - LOCF | At week 24 | -153.3 microns | Standard Deviation 132.17 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321)2PRN | Change From Baseline in Central Retinal Thickness (CRT) as Assessed by Optical Coherence Tomography (OCT) - LOCF | At week 52 | -180.3 microns | Standard Deviation 124.43 |
Secondary
Change in BCVA From Baseline to Week 52 - LOCF
Visual function of the study eye was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol at 4 meters. Missing values were imputed with post-baseline values during on-treatment period by using last observation carried forward (LOCF).
Time frame: At week 52
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Laser Photocoagulation | Change in BCVA From Baseline to Week 52 - LOCF | -1.3 letters correctly read | Standard Deviation 20.72 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321).5Q4 | Change in BCVA From Baseline to Week 52 - LOCF | 11.0 letters correctly read | Standard Deviation 15.4 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q4 | Change in BCVA From Baseline to Week 52 - LOCF | 13.1 letters correctly read | Standard Deviation 10.54 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q8 | Change in BCVA From Baseline to Week 52 - LOCF | 9.7 letters correctly read | Standard Deviation 8.93 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321)2PRN | Change in BCVA From Baseline to Week 52 - LOCF | 12.0 letters correctly read | Standard Deviation 11.09 |
Secondary
Number of Focal Laser Treatments
Time frame: Week 1 to week 48
Population: For the first 24 weeks, the Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) groups did not receive laser treatment. From week 24 onward, participants in the Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) groups were allowed to receive laser rescue treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Laser Photocoagulation | Number of Focal Laser Treatments | 2.5 Treatments | Standard Deviation 0.87 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321).5Q4 | Number of Focal Laser Treatments | 0.8 Treatments | Standard Deviation 0.93 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q4 | Number of Focal Laser Treatments | 0.5 Treatments | Standard Deviation 0.66 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q8 | Number of Focal Laser Treatments | 0.8 Treatments | Standard Deviation 0.86 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321)2PRN | Number of Focal Laser Treatments | 0.7 Treatments | Standard Deviation 0.77 |
Secondary
Participants With Gains in ETDRS Letter Score of at Least 15 Letters - LOCF
Missing values were imputed with post-baseline values during on-treatment period by using last observation carried forward (LOCF).
Time frame: At week 24 and week 52
Population: FAS
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Laser Photocoagulation | Participants With Gains in ETDRS Letter Score of at Least 15 Letters - LOCF | At week 24 | 9 participants | 135.17 |
| Laser Photocoagulation | Participants With Gains in ETDRS Letter Score of at Least 15 Letters - LOCF | At week 52 | 5 participants | — |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321).5Q4 | Participants With Gains in ETDRS Letter Score of at Least 15 Letters - LOCF | At week 24 | 15 participants | 110.65 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321).5Q4 | Participants With Gains in ETDRS Letter Score of at Least 15 Letters - LOCF | At week 52 | 18 participants | — |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q4 | Participants With Gains in ETDRS Letter Score of at Least 15 Letters - LOCF | At week 24 | 14 participants | 143.04 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q4 | Participants With Gains in ETDRS Letter Score of at Least 15 Letters - LOCF | At week 52 | 20 participants | — |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q8 | Participants With Gains in ETDRS Letter Score of at Least 15 Letters - LOCF | At week 52 | 10 participants | — |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321) 2Q8 | Participants With Gains in ETDRS Letter Score of at Least 15 Letters - LOCF | At week 24 | 7 participants | 141.78 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321)2PRN | Participants With Gains in ETDRS Letter Score of at Least 15 Letters - LOCF | At week 24 | 12 participants | 132.17 |
| Intravitreal Aflibercept Injection (IAI;EYLEA®;BAY86-5321)2PRN | Participants With Gains in ETDRS Letter Score of at Least 15 Letters - LOCF | At week 52 | 19 participants | — |