STUDY SUBJECTS

Major Inclusion criteria:

• ≧ 50 years old
• Treatment naive neovascular AMD (nAMD)- confirmed by fluorescein angiography
• Best corrected visual acuity (BCVA) > 25 letters on ETDRS
• Subfoveal (within 200 um) choroidal neovascular (CNV) lesion or extrafoveal CNV with foveal sub retinal fluid or subfoveal serous pigment epithelial detachment (PED)

Major exclusion criteria:

• CNV lesion comprising >50% fibrosis or blood
• Greatest linear diameter of CNV lesion > 6000 um

RANDOMIZATION SCHEME AND INTERVENTIONS

Randomized 1:1:1 to

(a) Ranibizumab (0.5 mg) monthly

(b) Ranibizumab (0.5 mg) as-needed

(c) Bevacizumab (1.25 mg) monthly

(d) Bevacizumab (1.25 mg) as-needed

All participants attended monthly visits with clinical examination, optical coherence tomography (OCT), and funds photography. All patients were treated at visits 0, 1, and 2. The continuous arm was treated monthly thereafter. The as-needed group were not treated unless they met pre-specified clinical and OCT criteria for active disease. If re-treatment was-needed, then a cycle of 3 monthly doses were required. Subjects and assessment teams were masked; treatment teams were unmasked (14 out of 23 sites).

Amendment later allowed for PDT for any subtype of CNVM if lesion > 4 DA and accompanied by loss of 20 letters of vision.

Re-Treatment Criteria:

OCT Findings: presence of sub retinal fluid, increasing intraretinal fluid, fresh hemorrhage

VA Findings: A visual acuity drop in > 10 letters if OCT parameters were equivocal

FA Findings: >25% fluorescein leakage of the lesion size or expansion of the CNV lesion if VA or OCT did not qualify

PRIMARY ENDPOINT

• Distance BCVA at 1 year—measured by ETDRS

Secondary Endpoints

• Adverse events
• EQ-SD (generic health-related quality of life assessment)
• Cumulative resource use and costs
• Contrast sensitivity
• Nearly visual acuity and reading index
• Lesion morphology and metrics from OCT and FAs
• Serum VEGF levels

RESULTS (12 months)

Study population

• 610 patients – ranibizumab monthly (n=157), ranibizumab as-needed (n=155), monthly bevacizumab (n=149), as-needed (n=138)

PRIMARY OUTCOME: Distance BCVA at 1 year

• Inconclusive by drug type (neither non inferior or nor equivalent)- did not reach 3.5 letter difference requirement to be classified as non inferior (-2.00 letters ranibiz, 95% CI, -4.04-0.06)
• Monthly versus as-needed treatment were equivalent

SECONDARY OUTCOMES

• VA: Near visual acuity worse by 8% in bevacizumab group, but no difference by treatment regimen
• OCT: Mean foveal thickness: 9% less for monthly group; no difference by drug type
• Statistically more FA leakage (36% vs 24%, p=0.002) and larger lesion size in as- needed group
• Lower serum VEGF concentrations in bevacizumab group and monthly group
• No difference in contrast sensitivity, reading index, EQ-SD score for drug type or treatment regimen
• Cost (greatest to least): Monthly ranibizumab most costly (9656 pounds)—>as-needed ranibizumab (3258 pounds)—> Bevacizumab monthly or as-needed (least costly)
• No statistical difference in cost of monthly bevacizumab versus as-needed bevacizumab

Adverse events

• No difference in mortality or serious systemic adverse events by drug type or treatment regimen
• Higher arteriothrombotic or heart failure events in ranibizumab group compared to bevacizumab (2.9% vs 0.7%; OR 0.23, p = 0.003); no difference in treatment regimens

CONCLUSIONS

• There were inconclusive results when comparing VA between ranibizumab and bevacizumab at 1 year
• There was no difference in VA based on treatment regimen (monthly or as-needed) at 1 year
• There were overall similar safety and efficacy outcomes, with the exception of a small statistical increase in arteriothrombotic event or heart failure in the ranibizumab group at 1 year.