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Matching-adjusted indirect treatment comparison of onasemnogene abeparvovec and nusinersen for the treatment of symptomatic patients with spinal muscular atrophy type 1.
Bischof, M, Lorenzi, M, Lee, J, Druyts, E, Balijepalli, C, Dabbous, O
Current medical research and opinion. 2021;(10):1719-1730
Abstract
OBJECTIVE Onasemnogene abeparvovec, a one-time intravenous gene replacement therapy, and nusinersen, an antisense oligonucleotide that requires ongoing intrathecal administration, have been evaluated as treatments for spinal muscular atrophy (SMA) type 1 in separate Phase III trials, but no head-to-head comparison studies have been conducted. Onasemnogene abeparvovec was compared with nusinersen using a matching-adjusted indirect comparison (MAIC) to estimate the treatment effect of onasemnogene abeparvovec relative to nusinersen for the treatment of symptomatic patients with SMA type 1 for up to 24 months of follow-up. METHODS In the absence of studies for both onasemnogene abeparvovec and nusinersen with a common comparator, a Bayesian naïve indirect treatment comparison (ITC) and MAIC between onasemnogene abeparvovec and nusinersen were conducted to compare efficacy and safety of onasemnogene abeparvovec with nusinersen. Outcomes of interest were event-free survival (EFS), overall survival (OS), and motor milestone achievements (independent sitting and independent walking). Relative treatment effects were expressed as relative risk (RR) and risk difference. RESULTS Pooled and weighted patient-level data illustrated a favorable effect toward onasemnogene abeparvovec, suggesting longer EFS for patients compared with nusinersen (HR of onasemnogene abeparvovec vs. nusinersen: 0.19 [95% CI: 0.07-0.54; 99% CI: 0.05-0.74]). At 24 months of follow-up, patients receiving onasemnogene abeparvovec were statistically significantly more likely to achieve the motor milestone of sitting independently compared with patients treated with nusinersen. Although statistically significant differences were not observed at 6 to 18 months between treatment options, the likelihood of sitting independently at 12 and 18 months numerically favored onasemnogene abeparvovec. A numerically greater likelihood of walking by 18 and 24 months was also observed for patients treated with onasemnogene abeparvovec compared with nusinersen. Onasemnogene abeparvovec therapy was also associated with a favorable (but statistically nonsignificant) outcome for OS and may be associated with prolonged survival compared with nusinersen (HR of onasemnogene abeparvovec vs. nusinersen: 0.35 [95% CI: 0.09-1.32; 99% CI: 0.06-2.01]). Bayesian naïve ITC results were similar to the MAIC analysis for EFS, OS, and motor milestone achievements. Small sample size limited covariate matching to baseline CHOP INTEND and nutritional support requirement, leading to wider CIs and statistically inconclusive outcomes for some of the results. CONCLUSIONS Despite limitations of the current MAIC analysis (mainly a small sample size for statistical testing, even for the pooled onasemnogene abeparvovec trials, and potential differences in prognostic and predictive factors between studies), the relative treatment effects in EFS, OS, and motor milestone achievement indicate that onasemnogene abeparvovec may offer continued benefit compared with nusinersen through 24 months of follow-up.
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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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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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Association of Intravitreal Aflibercept With Optical Coherence Tomography Angiography Vessel Density in Patients With Proliferative Diabetic Retinopathy: A Secondary Analysis of a Randomized Clinical Trial.
Alagorie, AR, Nittala, MG, Velaga, S, Zhou, B, Rusakevich, AM, Wykoff, CC, Sadda, SR
JAMA ophthalmology. 2020;(8):851-857
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IMPORTANCE Although previous studies have evaluated the association between anti-vascular endothelial growth factor therapy and macular vessel density, they were confounded by the presence of macular edema, which may be associated with artifacts and segmentation errors in optical coherence tomography angiography (OCTA). OBJECTIVE To evaluate the association of intravitreal aflibercept with changes in macular vascular density using OCTA in patients with proliferative diabetic retinopathy without diabetic macular edema. DESIGN, SETTING, AND PARTICIPANTS This post hoc analysis of a randomized clinical trial used data on 40 eyes of 40 patients with proliferative diabetic retinopathy without diabetic macular edema who were enrolled in the Intravitreal Aflibercept for Retinal Nonperfusion in Proliferative Diabetic Retinopathy (RECOVERY) clinical trial from August 1, 2016, to June 31, 2017. Three patients were lost to follow-up at month 12, and 5 patients were excluded from analysis because of poor OCTA image quality, leaving 16 patients in each cohort in the final analysis. Data analysis was performed from March 1, 2018, to January 15, 2019. INTERVENTION In the RECOVERY trial, patients were randomized into cohorts receiving 2 mg of aflibercept injections monthly (n = 20) or quarterly (n = 20) and treated for 12 months. MAIN OUTCOMES AND MEASURES The percentage of vascular density (in total scan and foveal and parafoveal regions) was compared before and after 12 months of therapy. RESULTS The sample for this OCTA analysis included 32 eyes from 32 patients (mean [SD] age, 48.37 [12.30] years; 17 [53.1%] male). The mean (SD) total scan vascular density for the superficial vascular complex was 42.28% (4.03%; 95% CI, 40.63%-43.93%) at baseline and 39.64% (4.01%; 95% CI, 37.91%-41.37%) at month 12 (P = .69). For the deep vascular complex, the mean (SD) vascular density was 48.42% (4.99%; 95% CI, 46.36%-50.47%) at baseline and 45.69% (4.63%; 95% CI, 43.69%-47.70%) at month 12 (P = .40). For the choriocapillaris, the mean (SD) vascular density was 64.42% (3.36%; 95% CI, 63.04%-65.81%) at baseline and 62.55% (4.79%; 95% CI, 60.48%-64.62%) at month 12 (P = .16). There was no difference in vascular density parameters between monthly and quarterly injection arms at month 12. CONCLUSIONS AND RELEVANCE In this study, macular vascular density did not change after 12 months of intravitreal aflibercept therapy. Because nonperfusion is expected to progress in diabetic retinopathy, this finding may represent a beneficial association between anti-vascular endothelial growth factor therapy and macular vascular density. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02863354.
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Efficacy and Treatment Burden of Intravitreal Aflibercept Versus Intravitreal Ranibizumab Treat-and-Extend Regimens at 2 Years: Network Meta-Analysis Incorporating Individual Patient Data Meta-Regression and Matching-Adjusted Indirect Comparison.
Ohji, M, Lanzetta, P, Korobelnik, JF, Wojciechowski, P, Taieb, V, Deschaseaux, C, Janer, D, Tuckmantel, C
Advances in therapy. 2020;(5):2184-2198
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PURPOSE To compare visual outcomes and treatment burden between intravitreally administered aflibercept (IVT-AFL) and ranibizumab (RBZ) treat-and-extend (T&E) regimens in patients with wet age-related macular degeneration (wAMD) at 2 years. METHODS A systematic literature review was carried out in Medline, EMBASE, and CENTRAL in October 2018. Matching-adjusted indirect comparison (MAIC) and/or individual patient data meta-regression was used to connect ALTAIR (assessing IVT-AFL T&E) with other studies, adjusting for between-trial differences in baseline visual acuity and age or baseline visual acuity, age, and polypoidal choroidal vasculopathy (PCV) status. Sensitivity analyses were conducted to test the robustness of the results, including direct MAIC between IVT-AFL T&E (ALTAIR) and RBZ T&E (CANTREAT and TREX-AMD trials). RESULTS Six randomized controlled trials (RCTs) (ALTAIR, VIEW 1 and 2, CATT, CANTREAT, and TREX) were included in the analysis. IVT-AFL T&E was assessed in one study, ALTAIR (n = 255), while RBZ T&E was assessed in two trials (n = 327). At 2 years, the median difference (95% credibility interval) between IVT-AFL T&E and RBZ T&E regarding the numbers of Early Treatment Diabetic Retinopathy Study (ETDRS) letters gained was not significant (M1: - 2.29 [- 8.10, 3.58]; M2: - 0.55 [- 6.34, 5.29]). IVT-AFL T&E was associated with significantly fewer injections than RBZ-T&E (M1: - 6.12 [- 7.60, - 4.65]; M2: - 5.93 [- 7.42, - 4.45]). Results of the sensitivity analyses were consistent with the main scenarios. CONCLUSION Patients with wAMD receiving an IVT-AFL T&E regimen achieved and maintained improvement in visual acuity with fewer injections over 2 years compared with RBZ T&E. IVT-AFL T&E may therefore serve as the optimal therapy for wAMD, as it was associated with clinical efficacy and minimized treatment burden.
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Five-Year Outcomes after Initial Aflibercept, Bevacizumab, or Ranibizumab Treatment for Diabetic Macular Edema (Protocol T Extension Study).
Glassman, AR, Wells, JA, Josic, K, Maguire, MG, Antoszyk, AN, Baker, C, Beaulieu, WT, Elman, MJ, Jampol, LM, Sun, JK
Ophthalmology. 2020;(9):1201-1210
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PURPOSE Assess follow-up treatment and clinical outcomes at 5 years in eyes initially treated with anti-VEGF therapy for center-involved diabetic macular edema (CI-DME) in a 2-year randomized clinical trial. DESIGN Multicenter cohort study. PARTICIPANTS Participants with diabetic macular edema (DME) and visual acuity (VA) 20/32 to 20/320 enrolled in DRCR.net Protocol T with visits 5 years after randomization (3 years after Protocol T completion). METHODS Participants were assigned randomly to aflibercept, bevacizumab, or ranibizumab with protocol-defined follow-up and re-treatment for 2 years. Thereafter, participants were managed at clinician discretion and recalled for a 5-year visit. MAIN OUTCOME MEASURES Anti-vascular endothelial growth factor (VEGF) treatment, VA letter score, and central subfield thickness (CST). RESULTS Sixty-eight percent (317/463) of eligible participants completed the 5-year visit. Between years 2 and 5, 68% (217/317) of study eyes received at least 1 anti-VEGF treatment (median, 4; interquartile range [IQR], 0-12). At 5 years, mean VA improved from baseline by 7.4 letters (95% confidence interval [CI], 5.9-9.0) but decreased by 4.7 letters (95% CI, 3.3-6.0) between 2 and 5 years. When baseline VA was 20/50 to 20/320, mean 5-year VA was 11.9 letters (95% CI, 9.3-14.5) better than baseline but 4.8 letters (95% CI, 2.5-7.0) worse than 2 years. When baseline VA was 20/32 to 20/40, mean 5-year VA was 3.2 letters (95% CI, 1.4-5.0) better than baseline but 4.6 letters (95% CI, 3.1-6.1) worse than 2 years. Mean CST decreased from baseline to 5 years by 154 μm (95% CI, 142-166) and was stable between 2 and 5 years (-1 μm; 95% CI, -12 to 9). CONCLUSIONS Among the two-thirds of eligible Protocol T participants who completed a 5-year visit, mean VA improved from baseline to 5 years without protocol-defined treatment after follow-up ended at 2 years. Although mean retinal thickness was similar at 2 and 5 years, mean VA worsened during this period. Additional investigation into strategies to improve long-term outcomes in eyes with DME seems warranted to determine if VA can be better maintained with different management approaches.
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Intravitreal Aflibercept injection with Panretinal photocoagulation versus early Vitrectomy for diabetic vitreous hemorrhage: randomized clinical trial.
Abd Elhamid, AH, Mohamed, AAEA, Khattab, AM
BMC ophthalmology. 2020;(1):130
Abstract
BACKGROUND To compare efficacy and safety of intravitreal aflibercept (IVA) injection with panretinal photocoagulation (PRP) versus early vitrectomy for diabetic vitreous hemorrhage (VH). METHODS Prospective, randomized study that included 34 eyes with diabetic VH. They were divided into two groups, Group Ι (17 eyes) received three successive IVA injections followed by PRP and group ΙΙ (17 eyes) for whom early vitrectomy was done. Follow up was carried out after one, two, three, six and nine months. The primary outcome measure was change in the mean best corrected visual acuity (BCVA) after nine months, secondary outcome measures were mean duration of clearance of VH and rate of recurrent hemorrhage with any additional treatment in both groups. Complications were reported. RESULTS There was no statistically significant difference regarding initial demographic criteria between both groups. The mean final log MAR BCVA was statistically better than the initial BCVA in both groups (0.51 ± 0.20, 1.17 ± 0.48 for group I and 0.48 ± 0.18, 1.44 ± 0.44 for group II, P < 0.001). There was no statistically significant difference between both groups regarding the mean final Log Mar BCVA (0.51 ± 0.20 for group I, 0.48 ± 0.18 for group II, p ≥ 0.05), the mean duration of clearance of VH was 7.8 ± 1.8 weeks, 5 days for group I and II respectively. PRP was completely done for all eyes in group I after three months. The difference in the recurrence rate between group I (29.4%) and group II (11.8%) was statistically significant (p < 0.05). Vitrectomy was done for three eyes (17.6%) due to recurrent non-resolving VH in group I. late recurrent VH occurred in two eyes (11.8%) in group II, IVA was given with complete clearance of the hemorrhage. No vision threatening complications were reported in both groups. CONCLUSION Both intravitreal injection of aflibercept followed by PRP and early vitrectomy are effective and safe modalities for treatment of diabetic vitreous hemorrhage. Early vitrectomy leads to faster vision gain with less incidence of recurrence than intravitreal injection. TRIAL REGISTRATION Randomized clinical trial under the number of NCT04153253 on November 6, 2019 "Retrospectively registered".
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Can subthreshold micropulse yellow laser treatment change the anti-vascular endothelial growth factor algorithm in diabetic macular edema? A randomized clinical trial.
Kanar, HS, Arsan, A, Altun, A, Akı, SF, Hacısalihoglu, A
Indian journal of ophthalmology. 2020;(1):145-151
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PURPOSE To compare the efficacy of subthreshold micropulse yellow laser (SMYL) and intravitreal aflibercept injection (IAI) combination therapy with IAI monotherapy in the treatment of diabetic macular edema (DME) and to evaluate the number of injections and SMYL sessions required. METHODS This prospective study compared a group of 28 patients treated with a combination of SMYL and IAI with a group of 28 patients treated only with IAI. All patients initially received 3 monthly IAIs, and the monotherapy group was given additional injections as needed. The combination therapy patients additionally received SMYL after the loading phase. The primary outcome measures were the change in the best-corrected visual acuity (BCVA) and central macular thickness (CMT) from baseline to month 12; the secondary outcomes were the mean number of required injections and SMYL sessions. RESULTS In the monotherapy group, the BCVA improved from 0.38 ± 0.10 to 0.20 ± 0.10 logMAR; in the combination group, BCVA improved from 0.40 ± 0.09 to 0.17 ± 0.06 logMAR at the end of the 12th month. The CMT was reduced from 451.28 ± 44.85 to 328.8 ± 49.69 μm in the monotherapy group and from 466.07 ± 71.79 to 312.0 ± 39.29 μm in the combination group. Improvement of the mean BCVA and reduction of the mean CMT were similar in each group. The combination group required significantly fewer injections (3.21 ± 0.41 vs 5.39 ± 1.54; P < 0.001). By month 12, 75% of patients in the monotherapy group had required additional IAIs when compared with 16% in the combination group (P < 0.001). CONCLUSION SMYL combination therapy demonstrated significant visual improvements in patients with DME. In the combination group, the retreatment rate and number of required injections were significantly lower compared with the IAI monotherapy group.
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Ziv-aflibercept versus bevacizumab administration prior to diabetic vitrectomy: a randomised and controlled trial.
Aleman, I, Castillo Velazquez, J, Rush, SW, Rush, RB
The British journal of ophthalmology. 2019;(12):1740-1746
Abstract
PURPOSE To compare the effectiveness of intravitreal ziv-aflibercept (IVZ) to intravitreal bevacizumab (IVB) administered preoperatively to patients undergoing pars plana vitrectomy (PPV) for severe manifestations of proliferative diabetic retinopathy (PDR). DESIGN Randomised clinical trial (RCT). METHODS Two hundred and six patients with PDR-related complications requiring PPV were randomised into one of two treatment groups: Group A received IVZ (1.25 mg/0.05 mL) 1-10 days before PPV, while Group B received IVB (1.25 mg/0.05 mL) 1-10 days before PPV. The primary outcome was best-corrected visual acuity (BCVA) at 6 months follow-up. Secondary outcome measures were perioperative tractional retinal detachment (TRD) rates, surgical times, intraoperative and postoperative complications and incidence of unplanned PPV during the 6 month study interval. RESULTS One hundred and seventy three subjects underwent PPV and completed the 6-month follow-up interval. Group A subjects had better BCVA at 6 months (p=0.0035), shorter surgical times (p=0.0013) and were less likely to have a recurrence of vitreous haemorrhaging in the postoperative period (p=0.0101) when compared with subjects in Group B. There were no significant differences among the treatment groups with regards to baseline characteristics, perioperative TRD development, intraoperative complications and incidence of unplanned PPV during the 6 month study interval. CONCLUSIONS This RCT demonstrated better final visual outcomes, shorter operating times and less vitreous haemorrhage recurrences in the postoperative period when subjects received IVZ compared to IVB prior to PPV for the treatment of PDR-related complications.
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OCT angiography-based monitoring of neovascular regression on fibrovascular membrane after preoperative intravitreal conbercept injection.
Hu, Z, Su, Y, Xie, P, Chen, L, Ji, J, Feng, T, Wu, S, Liang, K, Liu, Q
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2019;(8):1611-1619
Abstract
PURPOSE To quantify the preoperative neovascular change pattern on the fibrovascular membrane (FVM) within 7 days after intravitreal injection of conbercept (IVC) using optical coherence tomography angiography (OCTA) in proliferative diabetic retinopathy (PDR). METHODS Prospective, observational study of PDR patients with visible FVM receiving or not receiving IVC. Neovascular changes were assessed by OCTA pre-IVC and 1, 3, 5, and 7 days post-IVC. Vessel skeleton density (SD) and vessel density (VD) were quantified by an intensity-based optical microangiography algorithm. The interclass correlation coefficient (ICC) was calculated to assess the agreement between measurements. The SD and VD were compared between follow-ups using repeated-measures analysis in the IVC group. RESULTS The ICC was 0.992 (95% confidence interval [CI]: 0.982-0.996) for SD and 0.926 (95% CI: 0.838-0.912) for VD of neovascularization. The neovascularization on FVM significantly regressed in the IVC group (n = 16) compared with no IVC (n = 8) (p = 0.001 for SD and p < 0.001 for VD). The comparisons between consecutive follow-ups showed a statistically significant reduction in SD and VD at 1 and 3 days post-IVC. However, from day 3 onward, the SD and VD remained unchanged. There was no development or progression of tractional retinal detachment within the 7-day period after IVC. CONCLUSION OCTA-based quantification of the neovascularization on FVM in PDR is feasible, with high inter-reader agreement. The regression of neovascularization reaches a plateau 3 days after IVC. CLINICAL TRIAL REGISTRATION This trial is registered with the Chinese Clinical Trial Registry ( http://www.chictr.org.cn , registration number ChiCTR-IPR-17014160).
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Aflibercept for Radiation Maculopathy Study: A Prospective, Randomized Clinical Study.
Murray, TG, Latiff, A, Villegas, VM, Gold, AS
Ophthalmology. Retina. 2019;(7):561-566
Abstract
PURPOSE To evaluate 2 treatment approaches to intravitreal vascular endothelial growth factor antagonist therapy in radiation maculopathy comparing aflibercept delivered by either a 6-week treatment interval or treat-and-adjust interval. DESIGN Randomized, prospective clinical trial. METHODS Forty consecutive patients were enrolled in an institutional review board-approved clinical trial and randomized to aflibercept treatment via 1 of 2 regimens: (1) fixed, every-6-weeks treatment or (2) variable, treat-and-adjust treatment centered around 6 weeks. All patients had a diagnosis of treated uveal melanoma with documented tumor control. All patients showed visually compromising radiation maculopathy confirmed by a decline in best-corrected visual acuity (BCVA) and spectral-domain (SD) OCT documentation of radiation maculopathy. MAIN OUTCOME MEASURES Best-corrected visual acuity and SD OCT central retinal thickness at 1 year. RESULTS Thirty-nine of 40 patients completed the trial (97.5%) with 1 year of follow-up. Baseline study entry BCVA was 20/63 and was maintained at 20/62 at study conclusion at 60 weeks (1 year). At baseline, SD OCT mean central retinal thickness was 432 μm and improved to 294 μm at 60 weeks (P < 0.02). At the study conclusion, 42.5% of eyes (17/40) showed better than 20/50 BCVA, and only 5% of eyes (2/40) showed a BCVA worse than 20/200. In the every-6-weeks interval treatment arm, patients received 9 injections, whereas in the treat-and-adjust study arm, patients received 8.4 injections (P = 0.88, not significant). One patient experienced an inflammatory response after aflibercept injection, but this did not occur again for this patient, nor for any other study injections (1/400 injections [0.0025%]). No patients demonstrated endophthalmitis or metastatic disease or died during the study window. CONCLUSIONS Aflibercept seems to limit vision loss associated with radiation maculopathy. In this randomized, prospective clinical study, no difference was found between a fixed 6-week treatment interval and a variable treat-and-adjust interval because virtually all patients required treatment every 6 weeks and were not able to extend. Remarkably, almost half of all treated patients maintained BCVA of 20/50 or better throughout 1 year of treatment. Aflibercept is effective in treating radiation maculopathy, but requires an ongoing treatment approach.