Center-involved Diabetic Macular Edema Research Articles

Phase 1b Dose Escalation Study of Sozinibercept Inhibition of Vascular Endothelial Growth Factors C and D With Aflibercept for Diabetic Macular Edema.

Sozinibercept inhibits vascular endothelial growth factors (VEGFs) C and D. This study evaluated outcomes following switching from anti-VEGF-A monotherapy to intravitreal injections of three dose levels of sozinibercept in combination with aflibercept in patients with diabetic macular edema (DME). A phase 1b, open-label, multicenter dose-escalation study with a 24-week follow-up. Patients received 3 loading doses of aflibercept (2 mg) in combination with sozinibercept (0.3, 1, or 2 mg) once every 4 weeks and were followed through week 24. The primary endpoint was safety, and secondary endpoints included mean change from baseline in best-corrected visual acuity (BCVA) and anatomic changes on imaging. Nine patients received sozinibercept in combination with aflibercept after a mean (SD) of 6.3 (2.4) injections of previous anti-VEGF-A. Sozinibercept combination therapy was well tolerated with no dose-limiting toxicities. Mean change in BCVA at week 12 was +7.7 letters (95% confidence interval [CI], 2-13.3) from baseline (65 letters [SD 5.5]) with a dose response for increasing doses of sozinibercept. At week 12, central subfield thickness (CST) was decreased by -71 µm (95% CI, -117 to -26) from baseline (434 µm [SD 58]), and 6 of 9 (67%) patients had a ≥50% reduction in excess foveal thickness. In prior-treated patients with center-involved DME, switching to sozinibercept in combination with aflibercept was well tolerated with improved visual and anatomic outcomes. This first-in-human study builds upon basic research by providing safety and preliminary efficacy of sozinibercept (anti-VEGF-C/-D) in combination with aflibercept for DME.

Resolution of Angiographic Macular Leakage with Faricimab Versus Aflibercept in Patients with Diabetic Macular Edema in YOSEMITE/RHINE

To evaluate if dual angiopoietin-2 (Ang-2)/vascular endothelial growth factor-A (VEGF-A) inhibition with faricimab resulted in greater macular leakage resolution versus aflibercept in patients with diabetic macular edema (DME). Post hoc analysis of macular leakage assessments prespecified in the YOSEMITE/RHINE (NCT03622580/NCT03622593) phase 3 trials. Adults with visual acuity loss due to center-involving DME. Patients were randomized 1:1:1 to faricimab 6.0 mg every 8 weeks (Q8W), faricimab 6.0 mg according to a personalized treat-and-extend-based regimen (T&E), or aflibercept 2.0 mg Q8W. This analysis included the first 16 weeks (head-to-head dosing period) when all patients received assigned study drug Q4W; patients were assessed 4 weeks after receiving 4 doses of assigned study drug Q4W. Macular leakage area on fluorescein angiography assessed by a reading center; proportion of patients with resolution of macular leakage (defined as macular leakage area 0-1 mm2) and high macular leakage (defined as macular leakage area ≥ 10 mm2) at baseline and week 16; and the proportion of faricimab T&E patients receiving Q16W dosing at week 52 among those with resolution of and high macular leakage at week 16. Among patients with macular leakage data available at baseline, there were 1216 patients in the pooled faricimab (Q8W + T&E) arms and 593 patients in the aflibercept arm. Baseline median macular leakage area was similar between the faricimab (24.6 mm2) and aflibercept arms (25.6 mm2). At week 16, median macular leakage area was 3.6 mm2 with faricimab versus 7.6 mm2 with aflibercept (nominal P < 0.0001). More faricimab-treated patients (28%) achieved resolution of macular leakage versus aflibercept at week 16 (15%; nominal P < 0.0001). In the faricimab T&E arm, 63% of patients with resolution of macular leakage and 45% of patients with high macular leakage at week 16 achieved Q16W dosing at week 52 (nominal P < 0.01). Faricimab demonstrated greater macular leakage resolution versus aflibercept during head-to-head dosing. These findings suggest that dual Ang-2/VEGF-A inhibition promotes vascular stability beyond VEGF inhibition alone, supporting faricimab's potential to offer greater disease control and extend durability for patients with DME.

Subthreshold Micropulse Laser for Eyes With Center Involving Diabetic Macular Edema With Good Visual Acuity: The PULSE Study, a Randomized Clinical Trial.

To determine if sub-threshold micropulse laser (SML) therapy can prevent or delay vision loss in diabetic macular edema (DME) with good visual acuity (VA). Prospective, single-masked, sham-controlled trial in 27 eyes of 19 adult patients with treatment-naïve, center-involved DME, and VA of 20/25 or better. Measures included best-corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), contrast sensitivity (CS), average threshold on microperimetry, and central subfield thickness (CST). The primary outcome measure was median time to vision loss of 10 letters at any visit or 5 to 9 letters at two consecutive visits ≤ 28 days apart. Eight eyes met vision loss criteria during the 2-year study, with similar proportions for SML (n = 5) and sham (n = 3). Median time to vision loss was 5 months for both groups. At 6 months, there were no statistical differences in BCVA, LLVA, CS, microperimetry threshold, and CST between SML and sham arms (P > 0.05 in all measures). In eyes with center-involved DME and good VA, SML did not prevent or delay the vision loss threshold for initiating anti-VEGF therapy. However, these results may be affected by a high rate of early participant dropout from the study. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Short pulse grid and subthreshold micropulse laser (the sandwich grid) plus intravitreal ranibizumab for the treatment of diabetic macular edema

ObjectiveTo investigate the effects of two laser treatment procedures combined, short pulse grid laser (SP) and subthreshold micropulse laser (MP) (the sandwich grid [SWG] technique), plus intravitreal ranibizumab (IVR) on central subfield thickness (CSFT), best-corrected visual acuity (BCVA) and macular sensitivity in patients with diabetic macular edema (DME).MethodsForty-five eyes (of 33 patients) with center-involving DME were treated with the SWG laser technique plus IVR and followed for 12 months. Laser treatment was performed at baseline: SP laser spots were placed in a grid pattern in the macular area (500 µm from the fovea) according to the extension of DME; subsequently, MP laser was delivered up to the edge of the fovea. MP laser re-treatment sessions could be performed every 3 months if DME was present and CSFT was ≥ 300 μm on SD-OCT. IVR injection was performed at baseline and repeated monthly if CSFT > 300µm. Preoperatively and monthly, ophthalmological examination was performed including measurements of BCVA, CSFT, and macular sensitivity.ResultsOne-year follow-up data is available for 37 eyes of 27 patients. Mean ± SE CSFT (µm) was 509.36 ± 25.14 and 325.76 ± 15.34 at baseline and 12 months, respectively. A significant reduction in mean CSFT was observed at all study visits compared to baseline (p < 0.001). Mean ± SE BCVA (logMAR) was 0.62 ± 0.04 and 0.45 ± 0.04 at baseline and 12 months, respectively. A significant improvement in mean BCVA was observed at all study visits compared to baseline (p < 0.001). Mean ± SE macular sensitivity (dB) was 17.85 ± 0.80 and improved to 19.05 ± 0.59 after one year of follow-up (p = 0.006). The mean number of IVR injections was 8.29 ± 0.63. The mean number of MP laser procedures including the initial SWG laser session was 3.67 ± 0.22. No ocular or systemic adverse effects were observed.ConclusionThe SWG laser technique plus IVR was associated with significant improvement in macular edema, BCVA, and macular sensitivity in patients with center-involving DME.Clinical Trial Number (CAAE)22969019.4.0000.5440.

Evaluation of Foveal Vasculature by Optical Coherence Tomography Angiography after Pan-Retinal Photocoagulation versus Intravitreal Anti-VEGF Injections.

This study aimed to compare macular vascular changes one and three months after treatment with either panretinal photocoagulation (PRP) or intravitreal bevacizumab (IVB). A total of 62 eyes with very severe non-proliferative diabetic retinopathy or early proliferative diabetic retinopathy without center-involved diabetic macular edema, were included in this retrospective study. Thirty-nine eyes were allocated to the PRP group, while 23 eyes were treated with IVB. Optical coherence tomography angiography (OCTA) was performed to measure foveal avascular zone (FAZ) characteristics as well as the densities of superficial and deep capillary plexuses (SCP and DCP). In the IVB group, the FAZ area and perimeter expanded at month one but returned to baseline level after three months. In the PRP group, however, the FAZ area and perimeter were rather steady. Changes in the FAZ area were significantly different between the treatment groups at month one (P = 0.02), but not at month three (P = 0.31). There was no significant difference in the change in FAZ circularity index between the two groups at each time point (P = 0.55 and P = 0.31). Similarly, changes in SCP density were not statistically significant between the two groups at both time points (all Ps 0.05). A comparison of the two treatment arms based on the mean change in DCP density revealed a significant difference at month one, but not at month three (P = 0.01 and P = 0.49, respectively). Although bevacizumab and PRP have different short-term macular vascular responses, both therapies have the ability to normalize or stabilize vascular measures over time.

Dual pathway inhibition with faricimab for previously treated neovascular age-related macular degeneration and diabetic macular oedema: guidance from a UK panel of retina specialists

Background/objectivesSome eyes with neovascular age-related macular degeneration (nAMD) and centre-involving diabetic macular oedema (DMO) fail to respond sufficiently or lose response over time to standard of care intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy. This paper explores clinical scenarios for switching to dual action angiopoietin-2 (Ang-2)/VEGF-A inhibitor faricimab (Vabysmo, Roche Products Limited) in previously anti-VEGF-treated patients.MethodsA national steering group meeting of UK retina specialists was held in London on 27 October 2023. Clinician practice and experience were reviewed together with pivotal clinical trial data and early findings from real-world settings. Roche Products Limited facilitated and funded the meeting.ResultsWhile there is no standardised protocol for identifying suboptimal response, the authors review relevant clinical biomarkers of disease activity used in routine clinical practice to determine patient response and guide treatment decisions. Common reasons identified for considering a change of treatment were lack of efficacy demonstrated by suboptimal anatomic or visual improvement and insufficient durability of response. The panel outline strategies for switching to faricimab among eligible patients with a prior anti-VEGF treatment history, with initial monthly loading doses or maintaining the previous treatment interval before attempting to extend, that may be integrated into current treat-and-extend (T&E) clinical pathways for treating patients with nAMD and DMO. General considerations for switching between treatments are also reviewed.ConclusionClinicians may consider a treatment switch to faricimab in nAMD and DMO patients who have suboptimal disease control or insufficient durability of response on initial anti-VEGF therapy.

Subfoveal neurosensory detachment flattening and observe (SNF-Ob) approach for the management of Ci-DMO - a multicentric study.

To understand subfoveal neurosensory detachment flattening and observe (SNF-Ob) strategy and its relationship with visual acuity in the management of centre-involved diabetic macular oedema (Ci-DMO). This was a multicentric retrospective observational study. We reviewed data of 188 eyes of 130 patients who presented with Ci-DMO with subfoveal neurosensory detachment (NSD) and treated with intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents or steroids. The primary outcome was best corrected visual acuity (BCVA) measured at the time of the first subfoveal neurosensory detachment flattening (SNF) and at the end of follow-up. Eyes that achieved 20/50 (LogMAR = 0.40) or better at first SNF had mean LogMAR BCVA 0.38 ± 0.21, 0.24 ± 0.11 and 0.21 ± 0.15 at baseline, at the time of first SNF, and at the end of the last follow-up respectively. Mean LogMAR BCVA significantly improved from baseline to first SNF (p < 0.0001; 95% CI 0.115-0.183) and at the end of the last follow-up (p < 0.0001; 95% CI 0.126-0.213) with a change of Early Treatment Diabetic Retinopathy Study (ETDRS) 10 letters. There was no significant difference in improvement in BCVA from the first SNF and at the end of the last follow-up (p = 0.0781; 95% CI -0.002 to 0.046). Eyes presenting with Ci-DMO and subfoveal NSD are unlikely to improve at SNF with BCVA > 20/50 (LogMAR = 0.40). Further evidence is needed before the combination of good BCVA and SNF may be considered as endpoint of pharmacological therapy for DMO.

ROBIN: a randomised, double-masked, placebo-controlled Phase IIa study of the AOC3 inhibitor BI 1467335 in diabetic retinopathy

ObjectiveTo evaluate the safety and efficacy of BI 1467335 in patients with non-proliferative diabetic retinopathy (NPDR).MethodsROBIN is a Phase IIa, double-masked, randomised, placebo-controlled study (NCT03238963). Patients with NPDR and without centre-involved diabetic macular oedema were included; all had a best corrected visual acuity letter score of ≥70 Early Treatment Diabetic Retinopathy Study letters in the study eye at screening. Patients received oral BI 1467335 10 mg or placebo once daily for 12 weeks. Post-treatment follow-up was 12 weeks. The primary endpoint was the proportion of patients over the 24 weeks with ocular adverse events (AEs). Secondary endpoints were the proportion of patients with ≥2-step improvement from baseline in DRSS severity level at Week 12 and the proportion of patients with non-ocular AEs at 24 weeks.ResultsSeventy-nine patients entered the study (BI 1467335, n = 40; placebo, n = 39). The proportion of patients with ocular AEs over 24 weeks was greater in the BI 1467335 versus the placebo group (35.0% vs 23.1%, respectively). Treatment-related AEs were reported for similar numbers of patients in the placebo and BI 1467335 group (7.7% vs 7.5%, respectively). At Week 12, 5.7% (n = 2) of patients in the BI 1467335 group had a 2-step improvement in DRSS severity level from baseline, compared with 0% in the placebo group.ConclusionsBI 1467335 was well tolerated by patients with NPDR. There was a high variability in DRSS levels for individual patients over time, with no clear efficacy signal.

Beyond VEGF: Angiopoietin-Tie Signaling Pathway in Diabetic Retinopathy.

Complications from diabetic retinopathy such as diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) constitute leading causes of preventable vision loss in working-age patients. Since vascular endothelial growth factor (VEGF) plays a major role in the pathogenesis of these complications, VEGF inhibitors have been the cornerstone of their treatment. Anti-VEGF monotherapy is an effective but burdensome treatment for DME. However, due to the intensive and burdensome treatment, most patients in routine clinical practice are undertreated, and therefore, their outcomes are compromised. Even in adequately treated patients, persistent DME is reported anywhere from 30% to 60% depending on the drug used. PDR is currently treated by anti-VEGF, panretinal photocoagulation (PRP) or a combination of both. Similarly, a number of eyes, despite these treatments, continue to progress to tractional retinal detachment and vitreous hemorrhage. Clearly there are other molecular pathways other than VEGF involved in the pathogenesis of DME and PDR. One of these pathways is the angiopoietin-Tie signaling pathway. Angiopoietin 1 (Ang1) plays a major role in maintaining vascular quiescence and stability. It acts as a molecular brake against vascular destabilization and inflammation that is usually promoted by angiopoietin 2 (Ang2). Several pathological conditions including chronic hyperglycemia lead to Ang2 upregulation. Recent regulatory approval of the bi-specific antibody, faricimab, may improve long term outcomes in DME. It targets both the Ang/Tie and VEGF pathways. The YOSEMITE and RHINE were multicenter, double-masked, randomized non-inferiority phase 3 clinical trials that compared faricimab to aflibercept in eyes with center-involved DME. At 12 months of follow-up, faricimab demonstrated non-inferior vision gains, improved anatomic outcomes and a potential for extended dosing when compared to aflibercept. The 2-year results of the YOSEMITE and RHINE trials demonstrated that the anatomic and functional results obtained at the 1 year follow-up were maintained. Short term outcomes of previously treated and treatment-naive eyes with DME that were treated with faricimab during routine clinical practice suggest a beneficial effect of faricimab over other agents. Targeting of Ang2 has been reported by several other means including VE-PTP inhibitors, integrin binding peptide and surrobodies.

Diagnostic Utility of Swept-Source OCT-Based Biometry and Fundus Photographs Compared to Spectral Domain OCT in Center-Involving Diabetic Macular Edema

ABSTRACT Purpose This study was aimed to evaluate the agreement between the swept-source optical coherence tomography (SS-OCT)-based biometry, fundus photographs, and their combination, in comparison to the gold standard spectral-domain optical coherence tomography (SD-OCT) for the detection of center-involving diabetic macular edema (CI-DME). Methods We conducted a retrospective cross-sectional study involving 55 subjects (78 eyes) diagnosed with diabetic macular edema (DME) detected clinically and on SD-OCT (Carl Zeiss Meditec AG). Post-mydriatic 45-degree color fundus photograph (Crystal-Vue NFC-700), 1 mm macular scan obtained from SS-OCT-based biometry (IOL-Master 700), and macula cube scan obtained from SD-OCT was used to detect and grade DME into CI-DME and NCI-DME. Results Our findings revealed that SS-OCT-based biometry was noted to have a high sensitivity of 1 (0.94–1.00) and a specificity of 0.63 (0.31–0.89) in detecting CI-DME compared to the gold standard (SD-OCT). When combined with data from fundus photographs, specificity decreased to 0.32 (0.15–0.53). Fundus photographs alone exhibited a low sensitivity of 0.52 (0.38–0.64) and a specificity of 0.45 (0.16–0.76) in CI-DME detection. Conclusion In conclusion, SS-OCT-based biometry can be used as an effective tool for the detection of CI-DME in diabetic patients undergoing cataract surgery and can serve as a screening tool in centers without SD-OCT facilities.

Characterization of central-involved diabetic macular edema using OCT and OCTA.

To characterize the occurrence of diabetic macular edema and the presence of abnormal retinal fluid accumulation in nonproliferative diabetic retinopathy (NPDR). In this two-year prospective study, a total of 122 eyes with diabetes type 2 underwent optical coherence tomography (OCT) and OCT-Angiography in association with OCT-Fluid imaging, a novel algorithm of OCT analysis allowing quantification of abnormal accumulation of fluid in the retina through low optical reflectivity ratios (LOR). Early Treatment Diabetic Retinopathy Study (ETDRS) grading for diabetic retinopathy (DR) severity assessment was performed using 7-field color fundus photography. Best corrected visual acuity was also recorded. During the 2-year follow-up, 23 eyes (19%) developed central-involved diabetic macular edema (CI-DME) and 2 eyes (2%) developed clinically significant macular edema (CSME). In the two-year period of the study, eyes that developed CI-DME showed a progressive increase in central retinal thickness (CRT) (β = 7.7 ± 2.1 µm/year, p < 0.001) and in LOR values (β = 0.009 ± 0.004 ratio/year, p = 0.027). The increase in CRT and abnormal retinal fluid, represented by increased LOR ratios, are associated with increased retinal perfusion in the deep capillary plexus (DCP) (skeletonized vessel density, p = 0.039). In contrast, the eyes with CSME showed decreased retinal perfusion and abnormal fluid located in the outer layers of the retina. CI-DME and CSME appear to represent different entities. Eyes with CI-DME show increases in abnormal retinal fluid associated with increased retinal vascular perfusion in the DCP. Eyes with CSME are apparently associated with decreased retinal vascular perfusion in the DCP and abnormal fluid in the outer retina.

Severity of Disorganization of Retinal Layers and Visual Function Impairment in Diabetic Retinopathy

To evaluate best-corrected visual acuity (BCVA), retina sensitivity (RS), and fixation impairment by microperimetry (MP) due to the presence and severity of disorganization of retinal inner and outer layers (DRIL/DROL) and ischemia in OCT/OCT angiography (OCTA) in diabetic retinopathy (DR). Retrospective case-control study. Seventy-six eyes (65 patients) with DR were analyzed. Major exclusion criteria were: center-involving diabetic macular edema (DME), significant media opacity, nondiabetic macular pathology, and active proliferative DR. Patients with DRIL and DROL within central 3 mm were enrolled as cases. Patients with DR and no retina disorganization were considered as controls. A detailed grading of MP and OCT/OCTA images using Image J software, and specific Image Manipulation Program was applied to colocalize the presence of retina disorganization and RS. Best-corrected visual acuity and RS were correlated with the disorganization of retina layers' characteristics and grading (grade 1-DRIL; grade 2-DROL; grade 3-DROL plus, with involvement of the ellipsoid zone). The same procedure of colocalization was applied to the vascular layers on OCTA using MATLAB. Correlation between BCVA and MP parameters with disorganization of retina layers grading and OCTA parameters. Best-corrected visual acuity, mean RS within 1 mm and central 3 mm (overall RS [oRS]), perfusion density, vessel density, and geometric perfusion deficit in intermediate and deep capillary plexuses were lower in cases versus controls (P < 0.001). Mean RS within 1 mm (21.4 decibels [dB] ± 2.4 vs. 13.8 dB ± 5.4, P= 0.002), oRS (22.0 dB ± 2.1 vs. 14.4 dB ± 4.6, P < 0.001), and BCVA (76.1 ± 7.4 vs. 61.2 ± 20.4 ETDRS letters; P= 0.02), had a significant decrease from grade 1 to grade 3 retina disorganization. Choriocapillaris flow voids (CC-FVs) increased from grade 1 to grade 3 (DROL plus) (P= 0.004). Overall retina sensitivity and CC-FV were identified as significant predictors of retina disorganization grade with an adjusted coefficient of determination, R2= 0.45. Cases had more dense scotomas (P= 0.03) than controls with a positive correlation between the worsening of fixation stability and the severity of DRIL/DROL (P= 0.04). Microperimetry and BCVA documented a reduction in visual function in patients with DR and disorganization of retina layers at different grades, with greater functional impairment when outer retina layers and photoreceptors are involved. The severity of retina disorganization and the presence of ischemia could serve as a potential biomarker of functional impairment. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Short-Term Effects of Adding Topical Ketorolac to Intravitreal Bevacizumab in Diabetic Macular Edema: A Crossover Randomized Clinical Trial.

To evaluate the short-term additive effects of topical ketorolac to intravitreal bevacizumab (IVB) in the management of center-involved diabetic macular edema (CI-DME). In a randomized double-masked placebo-controlled crossover clinical trial, eyes with CI-DME and the best-corrected visual acuity (BCVA) between (20/40) and (20/400) were included. These eyes should have had at least one intravitreal anti-VEGF injection in the preceding two months. They were randomized into two groups; while both groups received two IVB injections with a six-week interval, one group received topical ketorolac every 6 hr in the first interval and artificial tears every 6 hr as a placebo in the second interval and the other group received the same medications using a crossover method. The main outcome measures were changes in BCVA and central macular thickness (CMT). Fifty-seven eyes of 35 patients with CI-DME were included in the study. The mean BCVA improvement was -0.09 0.47 logMAR in the periods of receiving ketorolac and -0.03 0.12 logMAR in the periods of placebo treatment, respectively (P = 0.99). Corresponding changes in CMT were -13.1 170.1 and +11.7 157.7 µm in the ketorolac and placebo periods, respectively (P = 0.322). The treatment effect was not statistically significant regarding both BCVA and CMT changes. Statistical analysis also disclosed that the carryover effect was insignificant for BCVA and CMT. Although the period effect was not significant for BCVA, it was at a meaningful level for CMT changes (P = 0.012). This crossover clinical trial demonstrated that in the course of DME treatment with IVB injections, topical ketorolac did not have any additive beneficial effect at least during a six-week period.

Intravitreal aflibercept 8 mg in diabetic macular oedema (PHOTON): 48-week results from a randomised, double-masked, non-inferiority, phase 2/3 trial

A high-dose formulation of intravitreal aflibercept (8 mg) could improve treatment outcomes in diabetic macular oedema (DMO) by requiring fewer injections than the standard comparator, aflibercept 2 mg. We report efficacy and safety results of aflibercept 8 mg versus 2 mg in patients with DMO. PHOTON was a randomised, double-masked, non-inferiority, phase 2/3 trial performed at 138 hospitals and specialty retina clinics in seven countries. Eligible patients were adults aged 18 years or older with type 1 or 2 diabetes and centre-involved DMO. Patients were randomly assigned (1:2:1) to intravitreal aflibercept 2 mg every 8 weeks (2q8), aflibercept 8 mg every 12 weeks (8q12), or aflibercept 8 mg every 16 weeks (8q16), following initial monthly dosing. From week 16, dosing intervals for the aflibercept 8 mg groups were shortened if patients met prespecified dose regimen modification criteria denoting disease activity. The primary endpoint was change from baseline in best-corrected visual acuity (BCVA) at week 48 (non-inferiority margin of 4 letters). Efficacy and safety analyses included all randomly assigned patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov (NCT04429503). Between June 29, 2020, and June 28, 2021, 970 patients were screened for eligibility. After exclusions, 660 patients were enrolled and randomly assigned to receive aflibercept 8q12 (n=329), 8q16 (n=164), or 2q8 (n=167); two patients were randomly assigned in error and did not receive treatment. 658 (99·7%) patients were treated and included in the full analysis set and safety analysis set (8q12 n=328, 8q16 n=163, and 2q8 n=167). Mean patient age was 62·3 years (SD 10·4). 401 (61%) patients were male. 471 (72%) patients were White. Aflibercept 8q12 and 8q16 demonstrated non-inferior BCVA gains to aflibercept 2q8 (BCVA mean change from baseline 8·8 letters [SD 9·0] in the 8q12 group, 7·9 letters [8·4] in the 8q16 group, and 9·2 letters [9·0] in the 2q8 group). The difference in least squares means was -0·57 letters (95% CI -2·26 to 1·13, p value for non-inferiority <0·0001) between 8q12 and 2q8 and -1·44 letters (-3·27 to 0·39, p value for non-inferiority 0·0031) between aflibercept 8q16 and 2q8. Proportions of patients with ocular adverse events in the study eye were similar across groups (8q12 n=104 [32%], 8q16 n=48 [29%], and 2q8 n=46 [28%]). Aflibercept 8 mg demonstrated efficacy and safety with extended dosing intervals and could decrease treatment burden in patients with DMO. Regeneron Pharmaceuticals and Bayer.

Topical Dorzolamide as Adjunctive Treatment With Intravitreal Bevacizumab in Bilateral Diabetic Macular Edema.

Intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents is accepted as the gold standard treatment for center-involving diabetic macular edema (CI-DME). Adjunctive administration of topical dorzolamide may enhance the therapeutic effects of anti-VEGF agents. In this study, we compared the efficacy of topical dorzolamide plus intravitreal injection of bevacizumab (IVB) versus IVB alone in patients with bilateral DME. This prospective, randomized contralateral eye study was carried out in a tertiary referral ophthalmology center, Al-Zahra Eye Hospital, Zahedan, Iran, between April 2021 and April 2022. Thisstudy included 50 eyes of 25 patients with bilateral DME. All eyes received three consecutive monthly injections of IVB. For each patient, one eye was randomized to instill dorzolamide eye drops three times a day as an intervention, and the other received artificial tear drops as a placebo. Best-corrected visual acuity (BCVA), central macular thickness (CMT), and intraocular pressure (IOP) were evaluated before starting treatment and then monthly for the first three months. Among 25 included patients, the average age was 56.64 ± 7.97 years, and 48% were female. BCVA did not improve significantly in any groups (P > 0.05). No significant difference was observed in terms of BCVA between the intervention and control groups (P > 0.05). The present study showed a decrease in CMT in both study groups (P < 0.05). At month 3, the decrease in mean CMT from baseline was significantly higher in eyes receiving topical dorzolamide compared to the control group (-88.92 ± 82.90 vs. -37.64 ± 86.16 µM, respectively; P = 0.037). IOP decreased significantly only in eyes receiving dorzolamide (P < 0.001). The results of the present study indicate that adjunctive administration of topical dorzolamide has a beneficial effect on CMT reduction from baseline, but it did not have an additive effect on BCVA improvement compared to IVB monotherapy.

Risk Factors for Meeting Criteria for Switching from Bevacizumab to Aflibercept When Treating Eyes with Diabetic Macular Edema and Visual Acuity of < 20/40

ObjectiveTo identify factors for meeting prespecified criteria for switching from bevacizumab to aflibercept in eyes with center-involved diabetic macular edema (CI-DME) and moderate vision loss initially treated with bevacizumab in DRCR Retina Network Protocol AC. DesignPost hoc analysis of data from a randomized clinical trial Participants270 participants with one or both eyes with CI-DME and visual acuity (VA) letter score of 69 to 24 (Snellen equivalent 20/50-20/320) MethodsEligible eyes were assigned to receive intravitreal aflibercept monotherapy (N=158) or bevacizumab followed by aflibercept if prespecified criteria for switching were met between 12 weeks and 2 years (N=154). Main Outcome MeasuresMeeting switching criteria: 1) at any time, 2) at 12 weeks, and 3) after 12 weeks. Associations between meeting the criteria for switching and factors measured at baseline and 12 weeks were evaluated in univariable analyses. Stepwise procedures were used to select variables for multivariable models. ResultsIn the bevacizumab first group, older participants had higher risk of meeting the switching criteria at any time, with a hazard ratio (HR) for a 10-year increase in age (95% confidence interval) of 1.32 (1.11 – 1.58). Male participants or eyes with worse baseline VA were more likely to switch at 12 weeks (HR for male vs. female = 4.84 [1.32 – 17.81]; HR for 5-letter lower baseline VA: 1.30 [1.03 – 1.63]). Worse 12-week CST (HR for 10-μm greater = 1.06 [1.04 – 1.07]) was associated with increased risk for switching after 12 weeks. The mean (SD) improvement after completing the switch to aflibercept was 3.7 (4.9) letters. ConclusionsThe identified factors can be used to refine expectations regarding the likelihood that an eye will meet protocol criteria to switch to aflibercept when treatment is initiated with bevacizumab. Older patients are more likely to be switched. At twelve weeks, thicker central subfield thickness was predictive of eyes most likely to be switched in the future.

Consensus on managing center-involving diabetic macular edema in Hong Kong: perspective

Consensus on managing center-involving diabetic macular edema in Hong Kong: perspective

Long-lasting, Pathogeneses-related Drying of Diabetic Macular Edema

Center-involved diabetic macular edema (DME) is the major cause of vision loss in the working-age population. Enduring DME might progressively injure the foveal layers with subsequent visual acuity loss. Therefore, the primary aim of DME therapy is to achieve an early, long-lasting dry macula to improve or sustain visual acuity. Current drug treatment has not achieved this aim. Diffuse DME (DDME), the most challenging DME type, is characterized by a compromised diffuse vasculature. Its pathogeneses include vitreofoveal traction and tractional epimacular membrane, as well as two newly-recognized pathogeneses: a) extrafoveal traction, the most common one, which is primarily detectable by 3D optical coherence tomography, and b) transitional-phase type, which represents the early tractional process and is detectable only ultra-structurally. Hence, all DDME eyes are apparently tractional. Consequently, treatment of naïve-treated DDME eyes by early pars plana vitrectomy has achieved long-lasting dry maculae in 92%–100% of eyes, typically in one step, and habitually associated with improved visual acuity. The surgery also naturally included the elimination of leaking microaneurysms (the "focal DME" component) when they were present. The transitional-phase type presents circumstances for attaining efficacious outcome by grid laser photocoagulation as well. Hence, DME seems to approach a curative situation. Accordingly, a revised pathogenesis-related DME classification is presented.

Faricimab Treat-and-Extend for Diabetic Macular Edema: Two-Year Results from the Randomized Phase 3 YOSEMITE and RHINE Trials

PurposeTo evaluate the 2-year efficacy, durability, and safety of dual angiopoietin-2/vascular endothelial growth factor (VEGF)-A pathway inhibition with intravitreal faricimab according to a personalized treat-and-extend–based regimen (T&E) with up to every-16-week (Q16W) dosing in the YOSEMITE/RHINE (NCT03622580/NCT03622593) phase 3 trials of diabetic macular edema (DME). DesignRandomized, double-masked, noninferiority phase 3 trials. ParticipantsAdults with visual acuity loss due to center-involving DME. MethodsPatients were randomized 1:1:1 to faricimab 6.0 mg Q8W, faricimab 6.0 mg T&E (previously referred to as personalized treatment interval), or aflibercept 2.0 mg Q8W. The T&E up to Q16W dosing regimen was based on central subfield thickness (CST) and best-corrected visual acuity (BCVA) change. Main Outcome MeasuresIncluded changes from baseline in BCVA and CST, number of injections, durability, absence of fluid, and safety through week 100. ResultsIn YOSEMITE/RHINE (N=940/951), noninferior year 1 visual acuity gains were maintained through year 2; mean BCVA change from baseline at 2 years (weeks 92/96/100 average) with faricimab Q8W (YOSEMITE/RHINE, +10.7/+10.9 letters) or T&E (+10.7/+10.1 letters) were comparable with aflibercept Q8W (+11.4/+9.4 letters). The median number of study drug injections was lower with faricimab T&E (YOSEMITE/RHINE, 10/11 injections) versus faricimab Q8W (15 injections) and aflibercept Q8W (14 injections) across both trials during the entire study. In the faricimab T&E arms, durability was further improved during year 2, with >60% of patients on Q16W dosing and ∼80% on ≥Q12W dosing at week 96. Almost 80% of patients who achieved Q16W dosing at week 52 maintained Q16W dosing without an interval reduction through week 96. Mean CST reductions were greater, and more patients achieved absence of DME (CST <325μm) and absence of intraretinal fluid with faricimab Q8W or T&E versus aflibercept Q8W through year 2. Overall, faricimab was well tolerated, with a safety profile comparable to aflibercept. ConclusionsClinically meaningful visual acuity gains from baseline, anatomic improvements, and extended durability with intravitreal faricimab up to Q16W were maintained through year 2. Faricimab given as a personalized T&E–based dosing regimen supports the role of dual angiopoietin-2/VEGF-A inhibition to promote vascular stability and provide durable efficacy for patients with DME.

Optical coherence tomography angiography in diabetic retinopathy.

There remain many unanswered questions on how to assess and treat the pathology and complications that arise from diabetic retinopathy (DR). Optical coherence tomography angiography (OCTA) is a novel and non-invasive three-dimensional imaging method that can visualize capillaries in all retinal layers. Numerous studies have confirmed that OCTA can identify early evidence of microvascular changes and provide quantitative assessment of the extent of diseases such as DR and its complications. A number of informative OCTA metrics could be used to assess DR in clinical trials, including measurements of the foveal avascular zone (FAZ; area, acircularity, 3D para-FAZ vessel density), vessel density, extrafoveal avascular zones, and neovascularization. Assessing patients with DR using a full-retinal slab OCTA image can limit segmentation errors and confounding factors such as those related to center-involved diabetic macular edema. Given emerging data suggesting the importance of the peripheral retinal vasculature in assessing and predicting DR progression, wide-field OCTA imaging should also be used. Finally, the use of automated methods and algorithms for OCTA image analysis, such as those that can distinguish between areas of true and false signals, reconstruct images, and produce quantitative metrics, such as FAZ area, will greatly improve the efficiency and standardization of results between studies. Most importantly, clinical trial protocols should account for the relatively high frequency of poor-quality data related to sub-optimal imaging conditions in DR and should incorporate time for assessing OCTA image quality and re-imaging patients where necessary.