Clinical Trial Spotlight

LAST but not least


LAST But Not Least

Can high-dose ranibizumab resolve persistent fluid in advanced AMD?


Anti–vascular endothelial growth factor drugs have been a godsend in treating age-related macular degeneration, but the fact is that they do not help every patient. Despite the impressive improvements in visual acuity and central retinal thickness seen with ranibizumab, the FDA-approved dose of monthly 0.5 mg intravitreal injection may not be enough for everyone.

Responding to this reality, several researchers have taken up the mantle and are looking into the feasibility of combination therapies and higher doses of anti-VEGF agents. Among the trials looking at high-dose (2.0 mg) ranibizumab is the LAST study (Pilot Study to evaLuate the Role of High-dose rAnibizumab in the Management of AMD in Patients With perSistent/recurrenT Macular Fluid Less Than 30 Days Following Treatment With Intravitreal Anti-VEGF Therapy), being undertaken at New York's Vitreous-Retina-Macula Consultants. The trial's principal investigator, K. Bailey Freund, MD, spoke with Retinal Physician.


To participate in the LAST trial, patients must have either subretinal fluid or cystoid macular edema on spectraldomain OCT less than 30 days following at least six months of anti-VEGF therapy. Dr. Freund explained that length of disease may be a determining factor in why these patients have not responded.

"Many of the patients for whom we cannot achieve a fluid-free macula with monthly anti-VEGF therapy have longstanding disease that appears less responsive to these agents," Dr. Freund said. "These patients have often received prior bevacizumab, pegaptanib sodium, or both. Our hope is that high-dose ranibizumab will give better anatomic and visual results in these patients."

As it is likely that macular degeneration patients with persistent submacular fluid have been previously treated with anti-VEGF drugs, it is not necessary that patients in this trial be treatment-naïve.


Among the concerns of researchers looking at high-dose ranibizumab has been the possibility of adverse events. However, Dr. Freund noted that the LAST study's exclusion criteria should mitigate this worry somewhat.

"Potential risks include a greater chance of ocular and systemic side effects, which would include a theoretically increased risk of thromboembolic events," Dr. Freund said. "A history of cerebral vascular accident, myocardial infarction or transient ischemic attacks within three months of study enrollment are exclusion criteria for our study."

Dr. Freund also noted that clinical experience has been accumulating. "Along with other retina practices, we have been performing bilateral, same-day injections of 0.5 mg ranibizumab in hundreds of patients for several years," he said. "It is reassuring that, to my knowledge, there have been no increased systemic safety issues identified in these patients receiving bilateral treatments."


Of 30 patients to be enrolled in the LAST study, twice as many will receive high-dose ranibizumab than the standard dose.

Dr. Freund explained the reasoning behind this style of enrollment. "We had initially planned on an open-label, non randomized trial for patients with persistent fluid despite six months of intravitreal anti-VEGF treatment," Dr. Freund said. "Through discussion with the FDA, it was decided to include a 0.5 mg control arm. As our hope is to achieve better outcomes with the high-dose ranibizumab, it seemed reasonable to randomize two to one to allow more patients to receive the higher dose."

The LAST study has already begun enrolling. Patients must not have undergone prior treatment with laser or photodynamic therapy or with triamcinolone for a sixmonth period to qualify for enrollment. More information about this clinical trial can be found on "Clinical Trials Update" of this issue. RP