FROM THE EDITORS OF REVIEW OF OPHTHALMOLOGY:

Genentech Unveils Positive Phase II Results for Sustained-delivery of Ranibizumab Positive topline results from Genentech’s Phase II LADDER study evaluating the efficacy and safety of its investigational port delivery system with ranibizumab in people with wet age-related macular degeneration... Acucela Data On Emixustat Hydrochloride Acucela announced new data on the effect of emixustat hydrochloride on retinal thickness in diabetic retinopathy... And More...

Lessons From Recent Phase III Trial Failures

In a recent editorial, authors wrote that, over the past two years, the field has witnessed the failure of three Phase III clinical trials designed to test new treatments for age-related macular degeneration. This came as a surprise to many retinal specialists, who have enjoyed a large number of successful Phase III clinical trials over the past 12 years, the authors added. Although Phase III trial failures are unavoidable for a myriad of reasons in the high-risk drug approval process, the authors suggested that certain Phase III clinical trial designs should be avoided to optimize the likelihood of success.

Upon closer inspection of the three failed Phase III trials, the authors found that the trials didn’t adhere to certain rules of drug development that provide the best chance for success—one of which is to design a Phase III clinical trial based on an unambiguously successful Phase II clinical trial design. When Phase II trial results are equivocal or negative, authors wrote, there is a temptation to perform retrospective subgroup analyses of the Phase II trial and then design the Phase III trial based on a positive retrospective subgroup. The authors wrote that this practice should be avoided.

When designing a Phase III clinical trial, if a Phase II clinical trial is unambiguously positive, then the same core clinical trial design should be used in the subsequent Phase III clinical trial, authors recommended. And though the authors support subgroup analyses to help design future studies and identify populations that may benefit the most from a particular therapy, they stressed that the results from subgroup analyses must be validated by performing another Phase II prospective, randomized clinical trial before moving into a larger Phase III registration trial. They added that this extra step takes more time and more money, but helps avoid wasting more money and time when the Phase III study fails, and avoids putting patients at unnecessary risk during the trial.

SOURCE: Rosenfeld PJ, Feuer WJ, et al. Lessons from recent Phase 3 trial failures: Don’t design Phase 3 trials based on retrospective subgroup analyses from Phase 2 trials. Ophthalmology 2018; July 3. [Epub ahead of print].

Retinal Volume as OCT Biomarker for Disease Activity in nAMD

Researchers wrote that current algorithms for automated computer interpretation of optical coherence tomography imaging of individuals with neovascular age-related macular degeneration mainly rely on fluid detection. However, correct interpretation of the fluid currently limits diagnostic accuracy, they added. Therefore, researchers performed a detailed analysis of requirements that would have to be met to validate fluid detection approaches. They further investigated if monitoring retinal volume would be a viable alternative to detect disease activity.

The study included retrospective analysis and manual grading of 764 OCT volume scans of 44 individuals with exudative AMD treated with intravitreal anti-VEGF injections as part of a pro re nata treatment regimen for at least 24 months and reported their findings.


• Detection of subretinal fluid or intraretinal fluid alone wasn’t sufficient for disease detection. Researchers suggested that combining these findings with SRF and IRF could detect disease activity with a sensitivity of 98.6 percent and a specificity of 82 percent and that, with further characterization of IRF into exudative and degenerative cysts, specificity could be increased to 100 percent. They added that correct characterization is currently not achieved by published fluid detection approaches.
• Changes in macular retinal volume could reveal disease activity with sensitivity of 88.4 percent and specificity of 89.6 percent. Researchers found that combining this measurement SRF with detection could improve diagnostic accuracy to a specificity of 93.3 percent and sensitivity of 93.9 percent without relying on IRF or IRF characterization.

Researchers determined that fluid detection without further characterization wasn’t sufficient for AMD monitoring. They wrote that either additional distinctions between exudative and degenerative cysts would be necessary for monitoring or other activity markers would have to be taken into account. Researchers concluded that MRV offered the potential to fill this diagnostic gap and might become an important monitoring marker.

SOURCE: von der Burchard C, Treumer F, Ehlken C, et al. Retinal volume change is a reliable OCT biomarker for disease activity in neovascular AMD. Graefes Arch Clin Exp Ophthalmol 2018; June 18. [Epub ahead of print].

Intravitreal Aflibercept for Exudative AMD with Good VA

Researchers reported the two-year outcomes of intravitreal aflibercept for exudative age-related macular degeneration with good visual acuity, and examined the baseline factors associated with good visual outcome.

The multicenter, prospective study evaluated 39 eyes (39 individuals with AMD) enrolled from August 2013 to August 2014, at 12 and 24 months. Only individuals with initial best-corrected VA (BCVA) >0.3 logMAR (20/40 Snellen) were eligible. Three consecutive monthly IVA injections were followed by two monthly injections for 12 months. Thereafter, individuals received injections on a treat-and-extend regimen for up to 24 months. Outcome measures included BCVA and central macular thickness at 12 and 24 months. Researchers evaluated post hoc analysis, BCVA and CMT by AMD types (typical AMD [tAMD], type 1 and type 2 polypoidal choroidal vasculopathy). They evaluated baseline characteristics and BCVA associations with linear regression analysis and Student’s t-test.

The mean age was 69 years, and 26 of 39 eyes were male. tAMD occurred in 18 eyes, type 1 occurred in 12 eyes and type 2 PCV occurred in nine eyes. Baseline mean BCVA was 0.097 logMAR (20/25 Snellen) and showed significant improvement to 0.058 (20/22 Snellen, p=0.03) at 12 months and 0.066 (20/23) at 24 months. CMT improved significantly from 320 ±99 µm to 250 ±93 µm (p=0.002) at 12 months and 240 ±93 µm (p=0.0005) at 24 months. BCVA and CMT weren’t significantly different among the three groups. Only subretinal hemorrhage was significantly associated with improved BCVA. BCVA change from baseline was -0.12 with SRH and -0.011 without SRH (p=0.017) at 12 months.

Researchers wrote that IVA showed good efficacy for exudative AMD with good VA at 24 months and that tAMD and type 1 and 2 PCV showed similar prognoses. They concluded that baseline SRH predicted favorable long-term vision in AMD with good VA.

SOURCE: Sakamoto S, Takahashi H, Inoue Y, et al. Intravitreal aflibercept for exudative age-related macular degeneration with good visual acuity: 2-year results of a prospective study. Clin Ophthalmol 2018;12:1137-47.

Evaluation of Multispectral Imaging in Diagnosing Diabetic Retinopathy

Scientists assessed multispectral imaging as a novel diagnostic approach for diabetic retinopathy in clinical settings.

A total of 50 type 2 diabetic patients (99 eyes) were enrolled in this cross-sectional study. All subjects underwent digital fundus photography, MSI and fundus fluorescein angiography. Scientists calculated total exact agreement, sensitivity, specificity, positive predictive value and negative predictive value of no DR/mild nonproliferative DR and severe NPDR/proliferative DR grading based on DFP and MSI, and compared the findings with fundus fluorescein angiography.

Compared with fundus fluorescein angiography:
• The exact agreement for MSI was 0.835; for DFP it was 0.614.
• The sensitivity for no DR/mild NPDR in MSI and DFP was 100 percent, and for severe NPDR/PDR it was 97.4 percent and 88.3 percent.
• The specificity for no DR/mild NPDR in MSI and DFP was 96.3 percent and 95 percent, and for severe NPDR/PDR it was 100 percent in both.
• The positive predictive value for no DR/mild NPDR in MSI and DFP was 86.4 percent and 82.6 percent, and for severe NPDR/PDR it was 100 percent in both.
• The negative predictive value for no DR/mild NPDR in MSI and DFP was 100 percent, and for severe NPDR/PDR it was 91.7 percent and 71 percent in both.

Scientists found that multispectral imaging displayed excellent agreement with fundus fluorescein angiography in DR grading, suggesting it might serve as a new diagnostic technique for evaluating DR.

SOURCE: Li L, Zhang P, Liu H, et al. Evaluation of multispectral imaging in diagnosing diabetic retinopathy. Retina 2018; Jun 12. [Epub ahead of print].

Quantitative Assessment of Macular Contraction & Vitreoretinal Alterations in Anti-VEGF-treated DME

Scientists evaluated macular contraction after anti-vascular endothelial growth factor injections for diabetic macular edema by documenting the displacement of macular capillary vessels and epiretinal membrane formation.

A total of 130 eyes were included in the retrospective study. The study group consisted of 63 eyes that had intravitreal anti-VEGF injections for DME, and the control group included 67 eyes without central DME. Both groups were balanced in terms of diabetes duration and HbA1c. Scientists measured the distances between the bifurcation of the macular capillary retinal vessels, and evaluated ERM status based on spectral-domain optical coherence tomography findings on initial and final visits.

In the study group, the mean number of injections was 4.7 ±2.6 (range: 3 to 14) and the mean follow-up time was 16.7 ±7.8 months vs. 20.7 ±10.9 months in the control group (p=0.132). The change in distance measurements between the reference points on macular capillary vessels was significant in all lines except line c (p<0.05 for lines a, b, d, e and f) in the study group, while this change was only significant in line e in controls (p=0.007, paired samples test). However, when the change in macular thickness was accounted for as a confounding factor, the change in distances between the reference points from the initial and final visits lost its significance (repeated measures ANCOVA, p>0.05). During follow-up, the number of cases with ERM formation changed from 10 to 12 in the study group although it remained three in the control group.

Scientists found a displacement of macular capillary vessels associated with a change in macular thickness in eyes having anti-VEGF injections for DME. They added that the number of ERM cases didn’t change significantly during the follow-up.

SOURCE: Cetin EN, Demirtaş Ö, Özbakış NC, et al. Quantitative assessment of macular contraction and vitreoretinal interface alterations in diabetic macular edema treated with intravitreal anti-VEGF injections. Graefes Arch Clin Exp Ophthalmol 2018; June 20. [Epub ahead of print].

Fixation Status After Resolution of Macular Edema Associated with BRVO

Researchers say that fixation status of eyes with branch retinal vein occlusion is associated with vision and other clinical parameters.

The researchers looked at 57 consecutive eyes with BRVO after resolution of macular edema. They used microperimetry to determine fixation status. Defect length of the foveal ellipsoid zone band was measured by optical coherence tomography, and retinal perfusion status was assessed by OCT angiography.

In microperimetry, researchers found the mean fixation rate around the gravitational center of all fixation points (defined as the fixation center) to be 79.8 ±18.9 percent, which was significantly associated with defect length of the foveal ellipsoid zone band (p<0.001) and the distance between the foveal and fixation centers (p=0.012). The integrity of the ellipsoid zone band at the fixation center was intact in 55 eyes (96.5 percent). Fixation centers were located within and outside the foveal avascular zone in 33 (57.9 percent) and 24 (42.1 percent) eyes, respectively; in the latter group, all fixation centers were perfused. Downward deviation of fixation points was rare, despite variations in the occluded area; there was a significant difference in distribution of deviation between eyes with superotemporal and inferotemporal BRVO (p<0.001).

In eyes with BRVO, fixation status was strongly associated with visual acuity, morphologic damage, and retinal perfusion status both in the foveal area and at the fixation center after resolution of macular edema. This information regarding fixation status could facilitate vision management in patients with BRVO.

SOURCE: Kogo T, Muraoka Y, Ooto S, et al. Fixation status after resolution of macular edema associated with branch retinal vein occlusion. Retina 2018; July 13. [Epub ahead of print].

Risk of POAG Following Vitreoretinal Surgery

Scientists determined the risk of primary open-angle glaucoma following vitreoretinal surgery, as part of a retrospective, population-based cohort study.

All residents of Olmsted County, Minn., undergoing scleral buckle and/or vitrectomy between 2004 and 2015 were included in the operative cohort. Fellow non-operative eyes were included in the comparison cohort. The study cohort consisted of 344 eyes and the comparison cohort consisted of 277 eyes. The main outcome measure was the development of POAG. Secondary glaucomas were excluded. Scientists compared the probability of glaucoma in operative eyes and nonoperative fellow eyes. The observed rate of POAG in operative eyes was also compared to the rate of POAG in the population.

The mean patient age was 64.7 years, and the median follow-up period was 4.9 years. A total of 58 eyes were in the scleral-buckle cohort, 57 eyes were in the scleral-buckle-with-vitrectomy cohort and 229 eyes were in the vitrectomy-only cohort.
• The 10-year cumulative probability of developing glaucoma was significantly greater in the operative group (CI, 3.8 to 14 percent) compared with the nonoperative group (1 percent, CI 0 to 2.4 percent; p=0.02).
• No eyes in the scleral buckle group developed glaucoma.
• The 10-year probability of POAG was 17.5 percent (CI 0 to 34.9 percent) in scleral buckle-with-vitrectomy and 10 percent (CI, 3 to 17 percent) in vitrectomy-alone cohorts.
• Rates of POAG in operative eyes undergoing scleral buckle with vitrectomy and vitrectomy alone were significantly greater than those of POAG for the general population (1 percent, p<0.001).

Scientists determined that the risk of POAG was increased after vitrectomy in this population.

SOURCE: Mansukhani SA, Barkmeier AJ, Bakri SJ, M, et al. The risk of primary open angle glaucoma following vitreoretinal surgery—a population-based study. Am J Ophthalmol 2018; June 22. [Epub ahead of print].

Resolution, Depth of Field and Physician Satisfaction During Digitally Assisted Vitreoretinal Surgery

Investigators evaluated depth of field, lateral resolution and image quality of a heads-up 3D visualization system for vitreoretinal surgery using physician survey and optical measurement outcomes. One of the investigators is employed by TrueVision Systems, which makes heads-up 3D viewing systems.

They compared depth of field and lateral resolution between the standard ocular viewing system and the digital 3D system at ×5, ×13 and ×18 magnification by six retinal surgeons. They also used optical techniques and a survey of surgeon impressions, performed after six weeks of surgical use. Their findings included:

• Physician questionnaire survey scores for depth of field at high magnification were better for the digital 3D system and equivalent for all other categories.
• Measured lateral resolution was, for digital 3D and oculars, respectively: 36.7 mm and 16.6 mm at ×5 magnification (p<0.001); 14.3 mm and 6.4 mm at ×13 magnification (p<0.001); and 9.8 mm and 4.2 mm (p<0.001) at ×18 magnification.
• Measured depth of field was 6.78 mm and 4 mm at ×5 magnification (p=0.027), 0.86 mm and 0.72 mm at ×13 (p=0.311), and 0.40 mm and 0.28 mm at ×18 magnification (p=0.235) for digital 3D and oculars, respectively.

Investigators concluded that lateral resolution of the digital 3D system was half that of the ocular viewing system, and depth of field showed some improvement with the digital system.

SOURCE: Freeman WR, Chen KC, Ho J, et al. Resolution, depth of field and physician satisfaction during digitally assisted vitreoretinal surgery. Retina 2018; June 27. [Epub ahead of print].