STUDY SUBJECTS

Major inclusion criteria:

• Type 1 or 2 diabetes mellitus with clinically significant DME
• Center involvement of the fovea (central retinal thickness (CRT) of 250 μm or more)
• 20/40 to 20/320 vision

Major exclusion criteria:

• History of vitreoretinal surgery
• Panretinal or macular laser photocoagulation within 3 months of screening
• Intraocular or periocular steroid injection within 3 months of screening
• Treatment with other antiangiogenic drugs within 3 months of the study

Randomization scheme and interventions:

Randomized 1:1:1:1:1 to

1. (a) 0.5 mg VEGF Trap-Eye every 4 weeks (0.5q4)
2. (b) 2 mg VEGF Trap-Eye every 4 weeks (2q4)
3. (c) 2 mg VEGF Trap-Eye every 8 weeks after 3 monthly doses (2q8)
4. (d) 2 mg VEGF Trap-Eye as needed after 3 monthly doses (2PRN)
   • (eyes in the PRN arm received a sham injection if no treatment was indicated)
5. (e) laser photocoagulation using a modified ETDRS protocol at baseline and hen as needed (eyes in the laser group also received a sham injection every 4 weeks)

Retreatment with VEGF Trap-Eye was indicated if any of the following criteria were present:

• A >50 μm increase in CRT
• New or persistent cystoid retinal changes, subretinal fluid, or persistent diffuse edema >250 μm
• A loss of 5 or more letters in conjunction with any increase in CRT

Retreatment with laser photocoagulation was indicated if any of the following criteria were present starting at week 16 in the laser photocoagulation group:

• An increase in retinal thickness at or lt;500 μm of the center of the macula
• Hard exudates at or lt;500 μm of the center of the macula and associated with retinal thickening
• Zone of retinal thickening 1 disc diameter or larger

Rescue with laser photocoagulation was indicated if any of the 3 criteria above were present starting at week 24 in the VEGF Trap-Eye groups.

RESULTS (52 weeks)

Study population

• 221 eyes were randomized, 219 were treated, and 200 completed the study

Mean Visual acuity change from baseline to 24 weeks

• Laser: 2.5 letter gain (comparison)
• 0.5q4: 8.6 letter gain (p = 0.0054
• 2q4: 11.4 letter gain (p < 0.0001)
• 2q8: 8.5 letter gain (p = 0.0085)
• 2prn: 10.3 letter gain (p = 0.0004)

Visual acuity end-points

• Gain of > 15 letter: VEGF Trap-Eye 34% vs. laser 21%
• Gain of > 10 letters: VEGF Trap-Eye 64% vs. laser 32%
• Gain of ≥ 0 letters: VEGF Trap-Eye 93% vs. laser 68%
• Loss of > 15 letters: all 2mg groups 0% vs 0.5q4 4.5% vs laser 9.1%

Mean Central Retinal Thickness change from baseline to 24 weeks

• Laser: -67.9 µm (comparison)
• 0.5q4: -144.6 µm (p = 0.0002)
• 2q4: -194.5 µm (p < 0.0001)
• 2q8: -127.3 µm (p = 0.0066)
• 2prn: -153.3 µm (p < 0.0001)

Treatment Exposure, mean number of treatments at week 24

• Laser: 1.7 laser treatments
• 0.5q4: 5.6 injections
• 2q4: 5.5 injection
• 2q8: 3.8 injections
• 2prn: 4.4 injections

Adverse events

• Ocular adverse events for VEGF Trap-Eye were deemed consistent with events reported for other intravitreal anti-VEGF agents and intravitreal injections.
• Serious adverse events included 2 patients with endophthalmitis (1.1% of all VEGF Trap-Eye) and 1 patient with uveitis (0.6% of all VEGF Trap-Eye), which were not seen in the laser group
• Systemic adverse events in the VEGF Trap-Eye groups included 2 myocardial infarctions, 2 cerebrovascular accidents, and 3 deaths, none of which occurred in the laser group.

Conclusions

• Regardless of the dosing schedule, Intravitreal VEGF Trap-Eye is superior to macular laser for the treatment of DME over a 24 week period as measured by visual acuity and retinal thickness outcomes.
• Among the different arms, those with extended intervals (2q8 and 2prn) were similarly efficacious compared to those with shorter intervals (0.5q4 and 2q4). The mechanism of action for VEGF Trap-Eye, which differs from other monoclonal antibodies that block VEGF-A, may prolong the treatment effect.