The addition of dexamethasone implant (Ozurdex, Allergan) to a continuing regimen of ranibizumab (Lucentis, Genentech) did not produce results in visual acuity outcomes that differed from those achieved with ranibizumab alone at 6 months. However, there was an improvement in the central macular thickness on OCT in patients.
By Lynda Charters;Reviewed by Sophie Bakri, MD
Because diabetic macular edema (DME) can persist in some patients despite anti-vascular endothelial growth factor (anti-VEGF) therapy, investigators looked to improve the outcomes for these patients and theorized that adding the dexamethasone implant (Ozurdex, Allergan) to anti-VEGF therapy with ranibizumab (Lucentis, Genentech) might solve the problem of the residual DME.
Diabetic Retinopathy Clinical Research (DRCR) investigators decided to add a dexamethasone implant to treat residual DME because it is FDA approved for the treatment of DME. After at least 6 months of monthly anti-VEGF therapy, between 32% and 66% of eyes can have residual DME, according to DRCR protocol T.
The question posed by the DRCR group was: Does the addition of the dexamethasone implant in patients treated with ranibizumab provide additional benefit to patients?
In this phase II, randomized clinical trial of the DRCR Network, the hopes for improved visual outcomes were not realized. When investigators compared the combination therapy of ranibizumab and dexamethasone with ranibizumab monotherapy, no significant differences in visual acuity were found between the 2 regimens at 6 months.
However, there was an improvement in the central macular thickness on optical coherence tomography (OCT) in patients who were randomized to the combination therapy, according to Sophie Bakri, MD. Dr. Bakri is a professor of ophthalmology, Mayo Clinic, Rochester, MN.
Protocol U was a phase II multicenter, randomized trial conducted from February 2014 to December 2016. A total of 129 eyes of 116 patients (median age, 65 years) with types 1 and 2 diabetes were included. The visual acuity levels ranged from 20/32 to 20/320.
Previous to inclusion in this trial, all patients had undergone treatment with a minimum of 3 anti-VEGF injections to treat DME during the preceding 20 weeks. Those drugs included aflibercept (Eylea Pharmaceuticals), ranibizumab, and bevacizumab (Avastin, Genentech).
Eyes with persistent DME that met the study inclusion criteria were entered into a run-in phase that lasted 12 weeks, during which another 3 injections of intravitreal ranibizumab (0.3 mg) were given–one injection when the patient was enrolled and injections at 4 and 8 weeks.
At the end of the 12-week period, the eyes that had been treated with the 3 additional injections and still had a central subfield thickness (CST) greater than the threshold defined by the protocol were then randomized to either an intravitreal injection of the combination of ranibizumab (0.3 mg) plus dexamethasone (700 µg) or to ranibizumab (0.3 mg) plus sham therapy.
The patients were examined every 4 weeks for 24 weeks. Besides an ocular examination, the examinations included spectral-domain OCT, measurement of the best-corrected visual acuity and intraocular pressure (IOP), Dr. Bakri explained.
The main outcome measure was the mean change in the visual acuity letter score at 24 weeks, and the secondary outcome was the change in the mean CST.
The DCRC Network investigators reported their findings in JAMA Ophthalmol (2018; 136: 29-38).
At 6 months, the mean improvement in visual acuity was 2.7 letters in the combination group and 3 letters in the ranibizumab-only cohort. Baseline visual acuity was similar at 66 letters in both groups.
There was also no difference found when controlling for confounding factors, such as lens status. The patients in the combination group had a greater chance of improving >15 letters (P = 0.03), but they also had an increased chance of losing 10 or more letters. At 24 weeks, the patients in the combination cohort had a greater decrease in CST (110 µm versus 62 µm).
In the dexamethasone group, 29% of patients experienced an increase in IOP, defined as any visit with an IOP > 30 mm Hg, a >10 mm Hg increase from baseline, or if the patient was initiated on an IOP-lowering agent (P <0.001).
One important aspect of interpreting results in steroid studies is understanding the contribution of cataract to visual acuity. There was limited follow-up to assess cataract progression, but the authors hypothesized that cataracts could be the reason that more patients had a >10-letter vision loss in the combination group.
The manuscript also mentioned that a subanalysis showed that pseudophakic eyes might have had increased vision in the combination cohort and that phakic eyes benefited more in the ranibizumab cohort.
“This is a short-term, 6 months randomized clinical trial in DME, whereas most clinical trials in DME run for a 3-year period,” Dr. Bakri said. “Therefore, we do not know the cumulative effect that differences in CST between groups may have on visual acuity in the long-term. For now, the conclusion from this trial is that it did not meet its primary endpoint in terms of visual acuity at 6 months.”
Sophie Bakri, MD