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Archway Randomized Phase 3 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration.
Holekamp, NM, Campochiaro, PA, Chang, MA, Miller, D, Pieramici, D, Adamis, AP, Brittain, C, Evans, E, Kaufman, D, Maass, KF, et al
Ophthalmology. 2022;(3):295-307
Abstract
PURPOSE To evaluate the safety and efficacy of the Port Delivery System with ranibizumab (PDS) for the treatment of neovascular age-related macular degeneration (nAMD). DESIGN Phase 3, open-label, randomized, visual acuity assessor-masked noninferiority and equivalence trial. PARTICIPANTS Patients with nAMD diagnosed within 9 months of screening previously treated with and responsive to anti-vascular endothelial growth factor therapy. METHODS Patients were randomized 3:2 to treatment with the PDS with ranibizumab 100 mg/ml with fixed 24-week (Q24W) refill-exchanges (PDS Q24W) or intravitreal ranibizumab 0.5-mg injections every 4 weeks (monthly ranibizumab). MAIN OUTCOME MEASURES Primary end point was change in best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study letter (letters) score from baseline averaged over weeks 36 and 40 (noninferiority margin,-4.5 letters; equivalence margin, ±4.5 letters). RESULTS Archway enrolled 418 patients; 251 were randomized to and 248 received treatment with the PDS Q24W, and 167 were randomized to and received treatment with monthly ranibizumab. Baseline BCVA was 74.4 letters (PDS Q24W arm) and 75.5 letters (monthly ranibizumab arm; Snellen equivalent, 20/32). Adjusted mean change in BCVA score from baseline averaged over weeks 36 and 40 was +0.2 letters (standard error [SE], 0.5 letters) in the PDS Q24W arm and +0.5 letters (SE, 0.6 letters) in the monthly ranibizumab arm (difference, -0.3 letters; 95% confidence interval, -1.7 to 1.1 letters). PDS Q24W was both noninferior and equivalent to monthly ranibizumab. Of 246 PDS-treated patients assessed for supplemental ranibizumab treatment, 242 (98.4%) did not receive supplemental ranibizumab treatment before the first refill-exchange procedure, including 4 patients who discontinued treatment before the first refill-exchange procedure. Prespecified ocular adverse events of special interest were reported in 47 patients (19.0%) in the PDS Q24W arm and 10 patients (6.0%) in the monthly ranibizumab arm, which included, in the former arm, 4 (1.6%) endophthalmitis cases, 2 (0.8%) retinal detachments, 13 (5.2%) vitreous hemorrhages, 6 (2.4%) conjunctival erosions, and 5 (2.0%) conjunctival retractions. Most ocular adverse events in the PDS Q24W arm occurred within 1 month of implantation. CONCLUSIONS Archway met its primary objective and PDS Q24W demonstrated noninferior and equivalent efficacy to monthly ranibizumab, with 98.4% of PDS-treated patients not receiving supplemental treatment in the first 24-week interval.
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EFFECT OF RETINAL THICKNESS VARIABILITY ON VISUAL OUTCOMES AND FLUID PERSISTENCE IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Post Hoc Analysis of the HAWK and HARRIER Studies.
Dugel, PU, Jhaveri, CD, Chakravarthy, U, Wykoff, CC, Singh, RP, Hamilton, R, Weissgerber, G, Mulyukov, Z, Holz, FG
Retina (Philadelphia, Pa.). 2022;(3):511-518
Abstract
PURPOSE To determine the association between central subfield thickness (CST) variability and visual outcomes in eyes with neovascular age-related macular degeneration treated with anti-vascular endothelial growth factor therapies. METHODS In this post hoc, treatment-agnostic analysis, patients (N = 1,752) were grouped into quartiles of increasing CST variation. The association between CST variability and best-corrected visual acuity was measured from baseline, or from the end of the loading phase, until the end of the study using a multilevel modeling for repeated-measures model. The association between CST variability and the presence of retinal fluid was also assessed. RESULTS Increased CST variability was associated with worse best-corrected visual acuity outcomes at the end of study, with a least-square mean difference in best-corrected visual acuity of 8.9 Early Treatment Diabetic Retinopathy Study letters between the quartiles with the lowest and highest CST variability at the final visit. Increased variability was also associated with a higher mean fraction of visits with the presence of fluid. CONCLUSION More stable CST was associated with better visual outcomes at the end of treatment suggesting that CST variability may provide a more reliable prognostic marker of visual outcomes than the presence of fluid alone, with the potential to enhance the clinical care of neovascular age-related macular degeneration patients.
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Retinal Fluid Volatility Associated With Interval Tolerance and Visual Outcomes in Diabetic Macular Edema in the VISTA Phase III Trial.
Ehlers, JP, Uchida, A, Sevgi, DD, Hu, M, Reed, K, Berliner, A, Vitti, R, Chu, K, Srivastava, SK
American journal of ophthalmology. 2021;:217-227
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Abstract
PURPOSE To describe longitudinal retinal fluid dynamics on spectral domain OCT and to identify imaging biomarkers that predict the worsening of DME with interval extension during anti-vascular endothelial growth factor (VEGF) therapy. DESIGN A post hoc sub-analysis of phase III, VISTA-DME study. METHODS Eyes received either intravitreal aflibercept injection 2 mg every 4 weeks (2q4) or every 8 weeks after 5 initial monthly injections (2q8), and eyes imaged with the Cirrus HD-OCT system were included. The macular cube was analyzed for 10 time-points from baseline through week 100. Retinal OCT images were evaluated using a novel software platform to extract retinal fluid features for calculation of volumetric fluid parameters, including the retinal fluid index (RFI): the percentage of retinal volume that was occupied by intraretinal fluid. RESULTS Fifty-five eyes were included in the 2q4 group, and 58 eyes were included in the 2q8 group. Early RFI volatility with a central macular RFI increase by ≥5 points from week 4 to 8 (P = .004, odds ratio [OR] 31.3, 95% confidence interval [CI] 3.0 to 329) and cumulative RFI volatility with an aggregate increase in macular RFI by ≥10 points from those timepoints with increased RFI between baseline to week 20, P = .005, OR 10.2, 95% CI 2.1 to 51.3) were both significant predictors for the worsening of DME and visual acuity when the treatment interval was extended to 8 weeks in the 2q8 group. CONCLUSIONS Early fluid dynamics as measured by (1) early RFI volatility and (2) cumulative RFI instability with aggregate increased RFI were associated with intolerance of interval extension.
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Real-Time Photographic- and Fluorescein Angiographic-Guided Management of Diabetic Retinopathy: Randomized PRIME Trial Outcomes.
Yu, HJ, Ehlers, JP, Sevgi, DD, Hach, J, O'Connell, M, Reese, JL, Srivastava, SK, Wykoff, CC
American journal of ophthalmology. 2021;:126-136
Abstract
PURPOSE To assess the safety and efficacy of as-needed (PRN) intravitreal aflibercept injections (IAI) in managing diabetic retinopathy (DR) guided by the real-time DR severity scale (DRSS) level or panretinal leakage index (PLI) assessment among eyes without diabetic macular edema (DME). DESIGN Prospective, randomized phase 2 trial (PRIME). METHODS A total of 40 eyes with nonproliferative (NPDR) or proliferative DR (PDR) received monthly IAIs until a DRSS improvement of ≥2 steps was achieved and eyes were randomized (1:1) to DRSS-guided or PLI-guided management strategies graded by a central reading center. Main outcome measurements included safety and changes in DRSS and PLI. RESULTS Through week 52, 95% of eyes achieved a DRSS improvement of ≥2 steps. Following DRSS improvement, 97% of eyes required at least 1 PRN IAI. In eyes requiring PRN IAI and completing week 52, 100% and 59% experienced DRSS worsening (P = .01) in the DRSS- and PLI-guided arms, respectively. Through week 52, mean PLI decreased 18.2% (P = .49) and 54.6% (P <.0001), respectively, in the DRSS- and PLI-guided arms. NPDR versus PDR eyes at baseline achieved a DRSS improvement of ≥2 steps after a mean 4.9 and 3.6 IAIs (P = .03). Two eyes developed a PDR event at week 52 following 5 months of quiescence. CONCLUSIONS The randomized PRIME study analyzed 2 imaging-based biomarkers to guide PRN management with IAI of DR without DME: DRSS level and PLI. Within the context of this study with limitations, most patients required IAI re-treatment every 3-4 months, and deterioration of PLI appeared to precede DRSS level worsening. Finally, these findings reaffirm the fact that close clinical follow-up is important even among eyes that achieve substantial DRSS improvements with apparently quiescent disease.
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Randomized Trial of Monthly Versus As-Needed Intravitreal Ranibizumab for Radiation Retinopathy-Related Macular Edema: 1-Year Outcomes.
Schefler, AC, Fuller, D, Anand, R, Fuller, T, Moore, C, Munoz, J, Kim, RS, ,
American journal of ophthalmology. 2020;:165-173
Abstract
PURPOSE To assess efficacy of intravitreal ranibizumab injections and targeted panretinal photocoagulation (TRP) for radiation retinopathy-related macular edema. DESIGN Phase IIb, prospective, randomized clinical trial. METHODS Setting: Multicenter. SUBJECTS Forty eyes in 40 treatment-naïve patients with radiation-induced macular edema and a resulting decrease in visual acuity ranging between 20/25 and 20/400 (Snellen equivalent). INTERVENTION Patients either received intravitreal 0.5 mg ranibizumab monthly, monthly ranibizumab with TRP, or 3 monthly ranibizumab (loading doses) followed by as-needed (PRN) injections and TRP. After week 52, all subjects entered a treat-and-extend protocol for ranibizumab. MainOutcomeMeasures: Mean Early Treatment Diabetic Maculopathy Study (ETDRS) BCVA change from baseline. RESULTS Mean patient age was 57 years (range, 22-80 years), ETDRS BCVA was 56.7 letters (20/74 Snellen equivalent), and central macular thickness (CMT) was 423 μm (range, 183-826 μm). Thirty-seven patients completed the month 12 visit (92.5%), at which time the change in mean BCVA was +4.0 letters, -1.9 letters, and +0.9 letters in the monthly, monthly plus laser, and PRN plus laser cohorts, respectively. There was a significant difference in mean BCVA at 1 year among all 3 cohorts (P < .001), as well as between cohorts in pairwise comparisons, with the most significant gains in the monthly group. A total of 82.5% of the patients retained visual acuity of 20/200 or better, and 20.0% improved 10 or more ETDRS letters. CONCLUSIONS Ranibizumab may improve vision and anatomy in patients with radiation retinopathy-related macular edema and prevent vision loss through 48 weeks of therapy. Monthly injections were more effective than as-needed approach, and the addition of TRP yielded no therapeutic benefits.
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Neoadjuvant intravitreal ranibizumab treatment in high-risk ocular melanoma patients: a two-stage single-centre phase II single-arm study.
Hussain, RN, Heimann, H, Damato, B
Melanoma research. 2020;(1):102-106
Abstract
Despite an established history of intraocular antivascular endothelial growth factor (anti-VEGF) agents therapy in a variety of ocular pathologies as well as other cancer forms, use in the primary treatment of uveal melanoma has not been well assessed. This was a two-stage therapeutic and exploratory phase II, non-randomised, single centre trial involving intraocular treatment with 0.5 mg in 0.05 ml of ranibizumab via six intravitreous injections over 6 months in patients with primary ocular melanoma that otherwise required radical surgery because of tumour size. Seven patients were recruited with a median age of 66 years. At baseline, the longest basal diameter was 15.1 mm (mean, range 10-20.4 mm) with a height measured by ultrasonography of 9.2 mm (mean, range 6.6-12.7 mm). No patients achieved complete or partial response at any visit. All required enucleation. Histopathological analysis revealed mixed cell melanoma in 5/7 (71%) and spindle cell morphology in 2/7 (29%) with ciliary body involvement in 4/7 (57%) and the presence of closed loops also in 4/7 (57%). Genetic analysis demonstrated loss of chromosome 3 in 5/7 (71%) but abnormalities in chromosome 1,6 or 8 in all cases. Our study was terminated early as alternative treatments were clearly superior for local tumour control. There continues to be a role of intravitreal anti-VEGF for the treatment of the sequelae of local radiotherapy in the form of radiation retinopathy and so these agents may be used as adjuncts in the treatment of uveal melanoma rather than as a primary treatment.
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Effects of Food on the Pharmacokinetic Properties of Surufatinib: A Phase I, Single-dose, Randomized, Open-label Crossover Study in Healthy Subjects.
Qian, H, Wu, X, Chen, Q, Li, T, Wang, W, Jia, J, Yu, C, Li, K, Sai, Y, Su, W, et al
Clinical therapeutics. 2020;(9):1778-1786
Abstract
PURPOSE Surufatinib is a potent and orally active small-molecule tyrosine kinase inhibitor targeting VEGFRs 1 to 3, FGFR-1, and CSF-1R, and thus may exert antitumor and antiangiogenic effects. The objective of this study was to determine the tolerability and effects of food intake on the pharmacokinetic properties of surufatinib in healthy Chinese subjects. METHODS A total of 24 healthy Chinese male subjects aged between 18 and 55 years were enrolled. Subjects were administered a single dose of surufatinib 250-mg capsules in the fasted and fed states in succession. Pharmacokinetic analysis was performed through the collection of blood samples at predose and at several time points after surufatinib administration. Tolerability assessments comprised physical examination including vital sign measurements, laboratory testing, and ECG to determine adverse events (AEs). FINDINGS The 90% CIs of the geometric mean ratios of AUC0-t and AUC0-∞ in the fasted and fed states was within 0.80 to 1.25; and for Cmax, within 0.70 to 1.43, indicating that food had no effect on the bioavailability of surufatinib in these healthy Chinese male subjects. Food intake delayed the time to peak absorption of surufatinib, as the median Tmax in the fed state was longer than that in the fasted state (4.0 vs 2.0 h). Surufatinib was marginally excreted from urine (mean [SD] cumulative excretion fraction, 1.2% [0.4%]). AEs occurred in 7 of the 24 subjects (29.2%) and included upper respiratory tract infection, dizziness, merycism, intervertebral disc protrusion, influenza-like disease, hematuria, prostatitis, and elevated blood urea nitrogen. All AEs were grade 1 or 2. IMPLICATIONS The bioavailability of surufatinib was not affected by food intake prior to dosing. However, food intake led to delated Tmax of surufatinib. The tolerability of a single oral dose of surufatinib 250 mg in the fasted and fed states was favorable in these healthy Chinese male subjects. These results indicate that surufatinib capsules could be administered before or after meals. ClinicalTrials.gov identifier: NCT02320409.
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Randomized Safety and Feasibility Trial of Ultra-Rapid Cooling Anesthesia for Intravitreal Injections.
Besirli, CG, Smith, SJ, Zacks, DN, Gardner, TW, Pipe, KP, Musch, DC, Shah, AR
Ophthalmology. Retina. 2020;(10):979-986
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PURPOSE To test the safety and preliminary efficacy of rapid, nonpharmacologic anesthesia via cooling for intravitreal injections. DESIGN Single-center, randomized phase 1 dose-ranging safety study (ClinicalTrials.gov identifier, NCT02872012). PARTICIPANTS Adults 18 years of age or older with a diagnosis of exudative macular degeneration or diabetic macular edema requiring bilateral anti-vascular endothelial growth factor therapy were included. METHODS A handheld device was developed to provide anesthesia via cooling to a focal area on the surface of the eye before intravitreal treatment (IVT). In 22 patients undergoing bilateral IVT, 1 eye was randomized to receive standard of care (SOC) lidocaine-based anesthesia and the other eye received cooling-anesthesia at 1 of 5 different temperatures and cooling times. Subjective pain was assessed via the visual analog scale (VAS; range, 1-10) at 2 time points: (1) immediately after IVT and (2) 4 hours after IVT. Treated eyes were assessed for ocular safety 24 hours after IVT. MAIN OUTCOME MEASURES We determined the occurrence of adverse events in eyes treated with cooling anesthesia. Mean VAS pain scores immediately after IVT and 4 hours after IVT in eyes receiving cooling anesthesia were compared with eyes receiving SOC. RESULTS A total of 44 eyes were treated, 22 with cooling anesthesia and 22 with SOC. No dose-related toxicity was found with cooling anesthesia. Mild, transient adverse events were recorded in 32% of patients treated with cooling anesthesia versus 44% of patients receiving SOC. The mean±standard error of the mean (SEM) VAS pain scores immediately after intravitreal injection were 2.3 ± 0.4 for patients receiving SOC and 2.2 ± 0.6 in patients receiving -10° C cooling anesthesia (P = 0.8). Mean±SEM pain scores 4 hours after injection were 1.6 ± 0.4 for SOC and 1.2 ± 0.5 in the combined -10° C arms (P = 0.56). Total mean±SEM procedure time was 124 ± 5 seconds for patients treated with cooling anesthesia versus 395 ± 40 seconds for SOC (P < 0.0001). CONCLUSIONS Ultra-rapid cooling of the eye for anesthesia was well tolerated, with -10° C treatment resulting in comparable levels of anesthesia to SOC with a reduction in procedure time.
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Anatomical and functional outcomes following switching from aflibercept to ranibizumab in neovascular age-related macular degeneration in Europe: SAFARI study.
Gale, RP, Pearce, I, Eter, N, Ghanchi, F, Holz, FG, Schmitz-Valckenberg, S, Balaskas, K, Burton, BJL, Downes, SM, Eleftheriadis, H, et al
The British journal of ophthalmology. 2020;(4):493-499
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BACKGROUND/AIMS: Prospective data on switching anti-vascular endothelial growth factors in patients with neovascular age-related macular degeneration (nAMD) who have previously shown no/partial response are limited. This prospective study assessed the effect of switching from aflibercept to ranibizumab on anatomical and functional outcomes in patients with persistent/recurrent disease activity. METHODS SAFARI (NCT02161575) was a 6-month, prospective, single-arm study conducted in the UK and Germany. Patients, meeting strict eligibility criteria for one of two subgroups (primary treatment failure or suboptimal treatment response), received 3 monthly intravitreal ranibizumab injections (0.5 mg). Thereafter, ranibizumab was administered pro re nata at monthly visits. The primary endpoint was change from baseline (CfB) to day 90 in central subfield retinal thickness (CSRT). Best-corrected visual acuity (BCVA) and retinal morphology parameters were assessed. RESULTS One hundred patients were enrolled (primary treatment failure, 1; suboptimal treatment response, 99). In the overall population, there was a significant CfB in median CSRT of -30.75 µm (95% CI -59.50,-20.50; p<0.0001) to day 90. Improvements were also observed in other quantitative and qualitative optical coherence tomography parameters. In Early Treatment Diabetic Retinopathy Study letters assessed by category, 55% and 59% of patients gained 0-≥15 letters versus baseline at day 90 and day 180, respectively. However, mean improvements in BCVA (CfB) to each time point were small (≤2 letters). No new safety signals were identified. CONCLUSION Switching from aflibercept to ranibizumab led to a significant improvement in CSRT, with ~60% experiencing stabilised/improved BCVA. Therefore, patients with nAMD who have shown a suboptimal response to aflibercept may benefit from switching to ranibizumab.
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Comparison of the Efficacy of Brolucizumab with Natural Disease Progression in Wet AMD Using Clinical Data from the Phase III HAWK and HARRIER Trials and Modelled Placebo Data.
Agostini, H, Mulyukov, Z, Tsilimbaris, M, Calvo, P, Bucher, F, Gaucher, D, Pigeolet, E, Colafrancesco, V, Clemens, A
Current eye research. 2020;(10):1298-1301
Abstract
Aim: To compare the treatment effect of brolucizumab, a novel anti-vascular endothelial growth factor therapeutic, with a putative placebo in patients with wet age-related macular degeneration. Materials and Methods: Clinical treatment-effect data from patients receiving brolucizumab 6 mg in the HAWK and HARRIER studies were compared with modelled placebo data using a previously developed and validated indirect response, non-linear, mixed effects model describing the natural visual acuity decline in wet age-related macular degeneration. The placebo model incorporated patient-level data from the sham injection arms of the MARINA and PIER studies, corrected for baseline best corrected visual acuity and age difference between these studies and the HAWK and HARRIER studies. Results: Compared with a modelled placebo, brolucizumab treatment was associated with an overall best corrected visual acuity gain of approximately 22 Early Treatment Diabetic Retinopathy Study letters at Week 48 and 28 letters at Week 96. Conclusions: As anti-vascular endothelial growth factor therapy is now a standard of care for wet age-related macular degeneration, it is not feasible to conduct placebo-controlled trials for new wet age-related macular degeneration treatments. By allowing comparison with the natural decline in visual acuity without treatment, this analysis conveys the clinical importance of brolucizumab for the treatment of wet age-related macular degeneration.