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Eric Chen, Angeline F. Mariani, David M. Brown; The Superdose Anti-VEGF (SAVE) Trial: 2.0-mg Intravitreal Ranibizumab for Recalcitrant Neovascular AMD, Two Year Endpoint Results. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2032.
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Many patients with neovascular AMD have persistent edema on OCT or fluorescein leakage despite monthly anti-VEGF intravitreal injections. As the MARINA and ANCHOR trials both demonstrated a dose-response curve favoring 0.5 mg ranibizumab over 0.3 mg ranibizumab dosing, this study was designed to test whether a higher dose of ranibizumab might lead to further anatomic and visual acuity improvements.
In this Phase I-II multicenter open label controlled clinical trial, 50 patients with recalcitrant neovascular AMD (defined as having leakage on SD OCT despite monthly 0.5 mg ranibizumab injections) were treated with 2.0 mg ranibizumab injections monthly for 3 loading doses followed by randomization to either 4 week (Cohort A) or 6 week (Cohort B) follow-up exams. All patients in the follow-up period received a "capped PRN" treatment with 2.0 mg ranibizumab injections mandated at each quarterly visit and 2.0 mg ranibizumab PRN injections given at follow-up visits (treatment given if any evidence of CNVM activity on OCT, FFA, or clinical exam). At every visit, all patients had ETDRS 4 meter refractions, clinical exam, Stratus OCT, Cirrus HD OCT, and Spectralis OCT. Patient demographics between the two Cohorts were well matched.
50 patients with evidence of fluid on OCT (intraretinal, subretinal, or sub-RPE) were enrolled. Patients had (on average) 24 ranibizumab injections prior to enrollment. Mean refracted VA was 69.6 ETDRS letters at baseline and mean central subfield was 419.9μ. Anatomically, mean OCT central subfield thickness improvement from baseline was: -48.5μ at day 7, -37.5μ at month one, -43.4μ at month two, and -38.4μ at month three. Mean visual acuity gain (ETDRS) over baseline was +2.5 letters at day 7, +3.7 letters at month 1, +4.0 letters at month 2, and +3.5 letters at month three. Upon randomization to different follow-up intervals, Cohorts A and B had OCT improvement from baseline of -49.0μ and -18.8μ at month 8, -59.9μ and -43.8μ at month 12, and -25.0μ and -25.6μ at month 18 respectively. Visual acuity gains were at 5.1 and 3.7 letters at month 8, 5.1 and 3.0 letters at month 12, and 6.5 and 4.1 letters at month 18.
By the year two data endpoint, a higher dose of ranibizumab appeared to promote and maintain improvements in both visual acuity and central macular thickness in patients with recalcitrant neovascular AMD. The difference between these results and those seen in the HARBOR study for treatment-naïve patients (no added benefit with 2.0mg ranibizumab compared to standard dose ranibizumab at one year) imply there may be some different mechanisms involved in these different patients, including tachyphylaxis or increased drug clearance.
http://www.clinicaltrials.gov FDA IND 106985
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