RAVE trial results

November 15, 2007

The Rubeosis Anti-VEGF (RAVE) trial is investigating intravitreal ranibizumab (Lucentis, Genentech) for the treatment of eyes with ischemic central retinal vein occlusion. After receiving nine monthly injections, retinal edema was resolved in nine of 10 eyes, six eyes gained 4 lines in ETDRS visual acuity, and no eyes developed neovascular glaucoma.

Key Points

Dr. Brown is the principal investigator for RAVE, a single-center, open-label, FDA-monitored investigational new drug trial launched 20 months ago. It was initially designed to enroll 10 patients who were randomly assigned to receive a once-monthly intravitreal injection of ranibizumab (Lucentis, Genentech) 0.3 or 0.5 mg, for 9 months. Thereafter, patients may be re-treated according to protocol-defined criteria based on the development of fluid recurrence or neovascularization.

Patients are being followed monthly, and the primary efficacy assessments are being made at 1 year. The endpoints include preservation of 5Ve Goldmann visual field compared with baseline and the proportion of patients with progression to neovascular glaucoma that requires panretinal photocoagulation (PRP) or glaucoma surgery. Secondary outcome measures are based on ETDRS visual acuity (VA), retinal thickness and volume measured with high-resolution optical coherence tomography, widefield (165°) angiography using a Staurenghi lens (Heidelberg Retinal Angiograph 2, Heidelberg), and changes in the electroretinogram (ERG) b wave component.

"Our expectations for outcomes in this study were that we could avoid performing panretinal photocoagulation (PRP), and so far it appears we have achieved that as long as ranibizumab treatment continues. We did not expect anyone would benefit from improved vision, and so the gains in VA associated with this intensive anti-VEGF treatment were a pleasant surprise," said Dr. Brown, a vitreoretinal specialist in private practice, Houston.

"However, like most trials, RAVE has already raised more questions than it has answered. As we continue to monitor these patients, we will see if the anti-VEGF treatment has simply reset the clock and provided a 9-month honeymoon period from rubeosis, and we will need to determine when to re-treat in eyes that begin to re-leak and what will be the role of targeted PRP."

Based on the results from the initial 10 eyes, Dr. Brown received permission from the FDA to enroll a total of 20 patients and to extend the trial to 2 years' duration; 16 patients have entered the study so far.

He noted that the RAVE trial is the only study specifically investigating treatment of eyes with ischemic CRVO.

"The development of anterior segment neovascularization and, subsequently, neovascular glaucoma is the most devastating complication of ischemic CRVO. Given the poor prognosis of neovascular glaucoma, eyes with ischemic disease have been excluded from National Eye Institute- and industry-sponsored CRVO clinical trials," he said.

To be eligible for entry into the RAVE trial, patients must have experienced the CRVO within the prior 3 months and have a diagnosis of ischemic disease based on the presence of at least three of the following four functional diagnostic criteria introduced by Sohan Hayreh, MD: VA 20/200 or worse, decreased b wave amplitude on ERG (<60% of the A wave), relative pupillary afferent defect of 0.9 log units or worse, and loss of the 1-2e isopter on the Goldmann visual field. Eyes with evidence of neovascular glaucoma or that received any previous intravitreal injection or retinal laser photocoagulation are excluded.

"Many eyes with CRVO will do fine without any treatment, especially if the vascular event was non-ischemic. To evaluate the efficacy of ranibizumab treatment, it was important to design our study so that it selected the high-risk patients," Dr. Brown said.

Findings from Dr. Hayreh's research also provided the rationale for the planned 9-month duration of monthly ranibizumab treatment.

"In his work, Dr. Hayreh found that most patients with ischemic CRVO develop collateral vessels able to shunt flow around the blocked vein, and these new vessels are usually seen by 9 months. If iris neovascularization is going to occur, it typically does so within the first 3 months after the occlusion, and by 9 months, mild iris neovascularization often regresses, even without PRP," Dr. Brown said.

"Hence the rationale of the RAVE trial is to eliminate the neovascular drive, which also mediates the retinal edema, to allow time for these collaterals to develop. Our initial results are extremely encouraging, but long-term follow-up is required to determine how much impact this therapy will have on the natural history of this devastating disease."