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HARBOR study shows sustained visual gains at 2 years
Mean gain in visual acuity was similar for patients who received 0.5-mg or 2-mg injections of ranibizumab as needed or monthly.
Visual and anatomic outcomes from ranibizumab injection for subfoveal neovascular age-related macular degeneration were maintained between 12 months and 24 months, according to the HARBOR study.
Monthly and as-needed injections of Lucentis (ranibizumab, Genentech) proved similarly effective, with safety profiles comparable to previous studies, according to Allen C. Ho, MD, the corresponding author and OSN Retina/Vitreous Board Member.
“The most significant findings from the HARBOR study included the efficacy results showing that patients in the less than monthly dosing arm maintained clinically significant visual acuity gains through month 12 and month 24,” Ho said in an interview with Ocular Surgery News. “These gains were not quite as good as monthly dosing. However, when you go to less than monthly dosing, you get almost as significant visual acuity gains and significantly fewer injections.”
Allen C. Ho
Results also showed that a 2-mg dose of ranibizumab was not significantly more effective than a 0.5-mg dose.
“The 0.5-mg dose is probably at the peak of the dose-response curve,” Ho said.
The results highlighted individualized dosing as a treatment option.
“I think the HARBOR study shows that you can’t fit everyone into one box or category,” Ho said.
Study results were published online ahead of print in Ophthalmology.
Patients and methods
The randomized, controlled, multicenter phase 2 study included 1,098 patients who had treatment-naïve subfoveal wet AMD.
Patients were randomized into four groups: 0.5 mg monthly injections, (276 patients, first group), 0.5 mg as needed (275 patients, second group), 2 mg monthly (274 patients, third group) and 2 mg as needed (273 patients, fourth group). As-needed injections were administered after patients received three monthly loading doses of ranibizumab.
Spectral-domain optical coherence tomography was used to assess central foveal thickness, choroidal neovascularization and other features.
“This was the first study to completely characterize the study population with SD-OCT, which is the higher-resolution OCT imaging. That is significant as well,” Ho said.
Outcome measures were mean change in best corrected visual acuity at 12 months and 24 months, percentage of patients who gained 15 or more letters of BCVA, mean number of injections, mean change in central foveal thickness, and ocular and systemic adverse events.
Outcomes and observations
The mean number of injections through 24 months was 21.4 in the first group, 13.3 in the second group, 21.6 in the third group and 11.2 in the fourth group.
In the second year, patients in the second group required a mean 5.6 injections and patients in the fourth group required a mean 4.3 injections.
Patients in the second group received injections an average of 9.9 weeks after the loading doses; 93% of those patients did not require monthly injections. Patients in the fourth group received injections an average of 12.5 weeks after the loading doses; 98% of those patients did not require monthly dosing.
At 24 months, the mean gain in BCVA from baseline was 9.1 letters in the first group, 7.9 letters in the second group, 8 letters in the third group and 7.6 letters in the fourth group.
The percentage of patients who gained at least 15 letters was 34.5% in the first group, 33.1% in the second group, 37.6% in the third group and 34.8% in the fourth group.
Snellen equivalent visual acuity was 20/40 or better in 44% of patients at 12 months and 52% at 24 months.
Central foveal thickness decreased rapidly in all groups by 7 days and was maintained up to 24 months. The mean change in central foveal thickness was 182.5 µm in the first group, 172 µm in the second group, 171.8 µm in the third group and 181 µm in the fourth group.
Systemic adverse events occurred in 6.6% of patients in the first group, 4.7% in the second group, 5.8% in the third group and 5.9% in the fourth group.
“Importantly, on the safety side, it was good to know that the 2-mg or higher dose evaluated in the study did not have any significant safety differences from the 0.5-mg current dose,” Ho said. “Specifically, the systemic safety was similar to the 0.5-mg dose. There was no increase in systemic adverse events.” – by Matt Hasson
Reference:
Ho AC, et al. Ophthalmology. 2014;doi:10.1016/j.ophtha.2014.05.009.
For more information:
Allen C. Ho, MD, can be reached at Mid Atlantic Retina, 4060 Butler Pike, Suite 200, Plymouth Meeting, PA 19462; 267-433-1108; email: acho@midatlanticretina.com.
Disclosure: Ho is a consultant for and receives research funding from Alcon, Allergan, Genentech, Janssen, Ophthotech and Regeneron.
Perspective
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Anti-VEGF therapy to treat neovascular AMD has revolutionized care. More than 90% of patients stabilize, and about one-third improve. But there are risks: The drugs may be costly, and with the need for repeat visits and injections, the care is burdensome. The HARBOR investigators tested a higher dose (2 mg) of ranibizumab in the hope that outcomes might be improved compared with those with the standard 0.5-mg dose. At 2 years, outcomes were similar with no apparent benefit to the higher dose.
While the original registration trials tested regular monthly injections, many retina specialists use an as-needed (PRN) injection schedule or a treat-and-extend approach. The HARBOR trial had four study arms: monthly 0.5 mg, monthly 2 mg or PRN after three monthly loading dose arms. While there were no meaningful differences in outcomes, the sponsor successfully petitioned the U.S. Food and Drug Administration for a label change to allow the less frequent PRN approach, so PRN 0.5 mg ranibizumab after three loading doses joins monthly ranibizumab as an on-label strategy to treat AMD.
Of course, the CATT study had shown similar outcomes for the PRN approach (a gain of seven letters at 1 year) without three required initial doses. More recently, the LUCAS investigators in Norway have compared ranibizumab and bevacizumab utilizing the treat-and-extend strategy and have achieved similar 1-year outcomes with about eight letters gained in each arm. The 1-year gains in HARBOR were about 10 letters for 0.5 mg ranibizumab monthly and eight letters for 0.5 mg ranibizumab PRN. For the 0.5 mg PRN ranibizumab patients, there were about 7.7 injections in year 1 and 5.6 in year 2. CATT, which did not require the initial trio of injections, required about 6.9 injections in year 1 with PRN ranibizumab.