Design:

• Weeks 0 through 24:
  • Subjects were randomly assigned in a 3:2 ratio to receive 2 mg of intravitreal aflibercept (IAI) or sham injections every 4 weeks up to week 24
• Weeks 24 through 52:
  • Patients from both groups were evaluated monthly and received an as needed (PRN) IAI if certain pre-determined re-treatment criteria were met. If re-treatment criteria not met, a sham injection as given
• Weeks 52 through 100:
  • All patients were evaluated at least quarterly (and more frequently if needed, at the discretion of the treating physician) and received IAI PRN if they met the same re-treatment criteria. Subjects were no longer masked.
• Any subject could receive panretinal photocoagulation (PRP) at any time for neovascularization

Endpoints:

• Primary efficacy endpoint: Proportion of eyes with a gain of 15 ETDRS letters or more from baseline to week 24. Results were also reported for weeks 52 and 100.
• Secondary endpoints: Change from baseline to week 24 in BCVA, central retinal thickness (CRT), proportion of eyes progressing to ocular neovascularization, and National Eye Institute (NEI) Visual Function Questionnaire score.

STUDY SUBJECTS

Adult patients with center-involved macular edema secondary to CRVO with mean central subfield retinal thickness of 250 microns or more and ETDRS BCVA of 20/40 to 20/320

Key exclusion criteria: History of vitreoretinal surgery, current bilateral retinal vein occlusion, previous PRP or macular laser photocoagulation, age-related macular degeneration, diabetic macular edema or retinopathy, intraocular or periocular steroids or antiangiogenic agents within three months, iris neovascularization, vitreous hemorrhage, uveitis, other causes of decreased vision, and other conditions that may interfere with interpretation of results.

RESULTS

Study population:

• 15 eyes randomized to IAI and 74 eyes to sham injection
  • 97% and 81.1% of eyes in the IAI and sham groups completed 24 weeks
  • 93.0% and 77.0% of eyes in the IAI and sham groups completed 52 weeks
  • 88.7% and 67.6% of eyes in the IAI and sham groups completed 100 weeks
• No difference in baseline characteristics between study and control groups

Results at 24 weeks:

Visual Outcomes

• At 24 weeks, 56.1% of eyes in the IAI gained 15 or more letters from baseline, compared to 12.3% of eyes in the sham injection group (p<0.001)
• By week 24, eyes in the IAI group had a mean gain of +17.3 ± 12.8 letters, and eyes in the sham group had a mean loss of -4.0 ± 18.0 letters
• Improvement in vision in the IAI group and decline in vision in the sham group was evident at week 4, after the first IAI or sham injection, and continued through 24 weeks

Anatomic Outcomes

• At week 24, mean change in CRT was -457.2 microns in the IAI group and -144.8 microns in the sham group (adjusted least squares mean difference = -311.9, p<0.001)
• No eyes in the IAI group and 5 eyes (6.8%) in the sham group developed neovascularization (p = 0.006)

Patient Reported Outcomes

• Patients in the IAI group had a significantly greater improvement in the NEI Visual Function Questionnaire score compared to sham injection eyes

Safety:

• Serious adverse events (SAEs) were uncommon, occurring in 3.5% and 13.5% of the IAI and sham groups, respectively.
  • IAI group: one event each of reduced vision, retinal artery occlusion, endophthalmitis, and corneal abrasion.
  • Sham group: Mostly complications consistent with natural history of RVO

Results at 52 weeks:

Mean (SD) number of PRN injections between weeks 24 to 52 was 2.7 (1.7) in eyes in the IAI-randomized group (IAI + PRN) and 3.9 (2.0) in eyes in the sham injection-randomized group (sham + PRN)

Visual Outcomes

• At 52 weeks, 55.3% of eyes in the IAI + PRN group gained 15 or more letters from baseline, compared to 30.1% of eyes in the sham + PRN group
• At 52 weeks, IAI + PRN eyes had a mean change in vision of +16.2 letters from baseline
• When the sham group switched to a PRN regimen at 24 weeks, change in vision from baseline improved from -4.0 letters (at 24 weeks) to +3.8 letters (at 52 weeks)

Anatomic Outcomes

• CRT reduction maintained in the IAI + PRN group (-413 microns from baseline at 52 weeks)
• When the sham group switched to a PRN regimen, CRT was reduced -381 microns from baseline at 52 weeks (compared to -144.8 microns at 24 weeks)

Patient Reported Outcomes

• At 52 weeks, both groups had improved visual function scores compared to baseline, with no difference in the score between the groups

Safety:

• SAEs occurred in 3 patients in the IAI + PRN group and 2 patients in the sham group between weeks 24-52

Results at 100 weeks:

• Mean (SD) number of PRN injections between weeks 52 to 100 was 3.3 (2.1) in the IAI + PRN group and 2.9 (2.0) in the sham + PRN group

Visual Outcomes

• At 100 weeks, 49.1% of eyes in the IAI + PRN group gained 15 or more letters from baseline, compared to 23.3 % of eyes in the sham + PRN (p<0.001)
• Decline in visual improvement compared to results at 52 weeks
• Mean change from baseline was +13.0 letters in the IAI + PRN group and +1.5 letters in the sham + PRN group (p<0.0001)

Anatomic Outcomes

• Mean CRT reduction from baseline at week 100 was -390.3 and -343.3 microns in the IAI + PRN and sham + PRN groups, respectively
• CRT reduced from baseline, but increased from week 52 results
• Between weeks 52 and 100, neovascularization developed in 6 eyes (5.3%) in the IAI + PRN group and 6 eyes (8.2%) in the sham + PRN group
• From the start of the trial to week 100, 1.8% versus 8.1% of eyes in the IAI + PRN group and sham + PRN group, respectively, required PRP (p=0.0355)

Patient Reported Outcomes

• Both groups had improved visual function scores compared to baseline but declined from the scores at 52 weeks, with no difference in the score between the groups

Safety:

• SAEs occurred in no sham + PRN and in 7 IAI + PRN patients from weeks 52 to 100

CONCLUSIONS

• 24 week (6 month) results:
• In eyes with CRVO-related macular edema, monthly intravitreal aflibercept reduced macular edema, improved vision, reduced neovascularization, and improved vision-related function at 24 weeks compared to sham injections
• 52 week (1 year) results:
• Gains in vision observed at 6 months in eyes initially treated with monthly aflibercept injections can be maintained after transition to a PRN dosing strategy with close monitoring for up to an additional six months
• Week 100 (2 year) results:
• PRN dosing regimen with at least quarterly evaluation may be insufficient to sustain improvements in vision and anatomic outcomes. More frequent monitoring may be necessary for some eyes to optimize visual outcomes.