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Intravitreal Aflibercept Versus Photodynamic Therapy in Chinese Patients with Neovascular Age-Related Macular Degeneration: Outcomes of the SIGHT Study

ABSTRACT: Abstract Purpose: SIGHT compared intravitreal aflibercept injections (IAI) with photodynamic therapy (PDT) in Chinese patients with predominantly classic choroidal neovascularization (CNV) secondary to neovascular age-related macular degeneration (nAMD). Methods: Patients were randomized 3:1 to IAI (2?mg every 8 weeks after 3 initial monthly injections)/sham PDT or active PDT/sham IAI (with switch to IAI at week 28). We report the primary outcome (mean change in best-corrected visual acuity [BCVA] at week 28) and final 52-week outcomes. Results: Patients were randomized to IAI (n?=?228) or PDT (n?=?76) (mean age: 65.1 years). Mean BCVA change was +14.0 (IAI) versus +3.9 letters (PDT?IAI) (week 28) and +15.2 versus +8.9 letters (between-group difference: 6.2 letters; P?=?0.0009) (week 52); mean reduction in central retinal thickness was ?189.6 versus ?170.0??m (week 52). The greatest improvements in BCVA with IAI were in youngest patients (<65 years), and in those with a smaller active component of the CNV lesion (<50% of lesion size). The most common ocular treatment-emergent adverse events (study eye; IAI vs. PDT?IAI) were macular fibrosis (11.8% vs. 6.6%) and visual acuity reduced (6.6% vs. 21.1%). Three treatment-emergent Antiplatelet Trialists' Collaboration-defined arterial thromboembolic events were observed but none was considered drug related. Conclusions: IAI demonstrated superiority over PDT in Chinese nAMD patients. The benefits of IAI were maintained through week 52 in all patients, including subgroups, and in patients who switched from PDT to IAI. The incidence of adverse events was consistent with the known safety profile of IAI. Trial registration number NCT01482910.

SUBMITTER: Li X

PROVIDER: S-EPMC5512466 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Project description:BackgroundAnti-vascular endothelial growth factor (anti-VEGF) agents have become the standard of care in neovascular age-related macular degeneration (nAMD). Despite generally excellent response rates to anti-VEGF therapy, some patients do not respond or may respond suboptimally. In the case of refractory or rapidly recurring fluid in nAMD, clinicians may switch to another anti-VEGF agent. TITAN was an observational study that assessed the effectiveness and safety of intravitreal aflibercept (IVT-AFL) in patients with nAMD refractory to ranibizumab who switched to IVT-AFL after less than 12?months of ranibizumab treatment in routine clinical practice in France.MethodsTITAN was an observational, retrospective and prospective 12-month study conducted at 28 centres in France. Patients with nAMD refractory to ranibizumab were enrolled. Patients who were switched from ranibizumab to IVT-AFL were followed for 12?months. Data were obtained from medical records for retrospectively included patients, and at routine follow-up visits for those included prospectively. The main outcome measure was percentage of patients who achieved treatment success (gain of ?1 Early Treatment Diabetic Retinopathy Study letters in best-corrected visual acuity [BCVA] and/or any reduction in central retinal thickness [CRT]) from baseline to 12?months after switching. A sample size of 225 patients was determined based on a 2-sided 95% confidence interval with a width equal to 0.12 when the sample proportion was 0.70.ResultsWe analysed safety data (N =?217) and clinical outcomes from patients in the per-protocol population (n =?125). The mean (standard deviation) number of IVT-AFL injections was 7.5 (2.6). Treatment success was achieved in 68.8% of patients. Mean BCVA change from baseline to Month 12 was +?1.5 letters (P =?0.105) and the mean CRT change was -?45.0??m (P <? 0.001). In a subgroup analysis, in patients who received three initial monthly IVT-AFL injections, mean BCVA gain was 3.3 letters at Month 12 (P =?0.015). Excluding lack of efficacy and inappropriate scheduling of drug administration, the most common adverse event was eye pain (2.3%).ConclusionsSwitching ranibizumab-refractory patients with nAMD to IVT-AFL may improve visual outcomes in some patients, particularly those who receive three initial monthly injections.Trial registrationClinicalTrials.gov , NCT02321241 . First posted: December 22, 2014; Last update posted: July 2, 2018.

Project description:IntroductionThe aim of this post hoc analysis of the ARIES study is to explore the requirement for intravitreal aflibercept (IVT-AFL) treatment intervals of < 8 weeks (w) in patients with neovascular age-related macular degeneration (nAMD), and to assess vision and anatomic outcomes in such patients who require more intensive treatment.MethodsARIES was a multicenter, randomized, phase 3b/4 study that investigated the efficacy of two IVT-AFL proactive, individualized, treat-and-extend regimens over 2 years in treatment-naïve patients with nAMD. Patients were determined as injection-intensive if the study investigator identified that a treatment interval of < 8 w was needed and if they had ≥ 1 interval of < 8 w after three initial monthly doses. Treatment intervals could be extended subsequently if extension criteria were met. This is a post hoc analysis of patients enrolled in ARIES and statistical analysis is descriptive.ResultsOf 269 patients in the combined treatment arms, 23.0% (n = 62) were injection-intensive (Year 1: 13.8% [n = 37]; Year 2: 9.3% [n = 25]). Time from IVT-AFL initiation to injection-intensive determination varied (range, 16-100 w; median: 43.2 w). Mean treatment interval was 8.4 w before and 6.1 w after injection-intensive determination. Overall, 59.7% achieved treatment intervals of ≥ 8 w following injection-intensive determination. Vision improvements from baseline to Week 104 were smaller for injection-intensive patients than non-injection-intensive patients (mean [SD] best-corrected visual acuity change: + 2.3 [15.6] vs. + 5.9 [12.3] letters). Anatomic outcomes were similar between injection-intensive and non-injection-intensive patients (central retinal thickness change from baseline to Week 104: - 160 [154] vs. - 167 [136] µm).ConclusionsIn ARIES, 23% of treatment-naïve patients with nAMD experienced at least one treatment interval of < 8 w. Injection-intensive patients showed improved vision and anatomic outcomes. For most, treatment intervals could be extended to ≥ 8 w following injection-intensive determination.Clinicaltrialsgov Identifier: NCT02581891.

Project description:BackgroundTo determine the safety and efficacy of intravitreal sirolimus and adjunct aflibercept in subjects with persistent, exudative age-related macular degeneration despite previous intravitreal anti-vascular endothelial growth factor (VEGF) treatment.MethodsThis institutional review board approved, registered (NCT02732899), prospective, subject-masked, single center, randomized controlled trial in subjects with persistent, exudative age-related macular degeneration compared alternating monthly intravitreal sirolimus and aflibercept (combination) versus aflibercept monotherapy (control) every 2 months over the course of 36 weeks. The primary measure of efficacy in the study was the mean change in central subfield thickness.Results20 subjects were enrolled in the study, with 10 subjects assigned to each treatment group. Subjects had an average of 38 previous anti-VEGF injections. Mean central subfield thickness decreased in the combination group by 54.0 μm compared to 0.1 μm in the control group (p = 0.28). Mean visual acuity improved in the combination group by 2.5 ETDRS letters versus 0.8 ETDRS letters in the control group (p = 0.42). There were no serious ocular adverse events in either group; however, there were three serious systemic events in the combination group, including hospitalizations due to pancreatitis, pneumonia, and worsening hypertension.ConclusionThere was no statistically significant difference in the mean central subfield thickness change between the combination and control groups. However, intravitreal sirolimus with adjunct aflibercept did appear to have potential anatomical benefits as a treatment for persistent, exudative age-related macular degeneration and requires further investigation with a larger cohort to better understand the potential risks and benefits.Trial registrationClinicalTrials.gov, NCT02732899. Registered 11 March 2016, https://clinicaltrials.gov/ct2/show/NCT02732899 . This trial was approved by the institutional review board at Advarra. Funding was provided by an investigator-initiated grant from Santen. Santen played no role in the design or implementation of this study.

Project description:IntroductionSTELLAR was a Belgian, multicentre, retrospective, observational chart review that described the utilization (number of injections and treatment regimen) and effectiveness of intravitreal aflibercept (IVT-AFL) in patients with anti-vascular endothelial growth factor (VEGF) treatment-naïve neovascular age-related macular degeneration (nAMD) during the first 12 months of IVT-AFL treatment.MethodsPatients initiating IVT-AFL between July 2013 and July 2017 were included in STELLAR. Primary endpoints were number of visits and IVT-AFL injections, and number of patients who received ≥ 7 versus < 7 IVT-AFL injections during the first 12 months of treatment.ResultsA total of 337 patients completed ≥ 12 months of IVT-AFL treatment. The mean number of visits and mean number of injections during the first 12 months was 9.8 and 7.1 injections, respectively (64% received ≥ 7 injections). Overall, 96% of patients received ≥ 3 initial monthly injections. Of the 337 patients, 180 received VT-AFL as needed (pro re nata), 141 received it as treat-and-extend dosing and 16 received it as fixed dosing. The proportion of patients who received treat-and-extend dosing increased year-on-year. Mean best-corrected visual acuity (BCVA) (± standard deviation) was 61.6 (± 14.9) Early Treatment Diabetic Retinopathy Study (ETDRS) letters at baseline and improved by + 3.9 and + 5.7 ETDRS letters at 3 and 12 months, respectively. Mean BCVA improvement was numerically greater in patients who received ≥ 7 versus < 7 injections during the first 12 months 7 (+ 6.5 vs. + 4.4 ETDRS letters) and in patients who received ≥ 3 versus < 3 initial monthly injections (+ 5.2 vs. - 0.25 ETDRS letters [3 at months]; + 5.9 vs + 1.2 ETDRS letters [at 12 months]). No specific adverse events were reported.ConclusionMost patients in this Belgian study received ≥ 7 IVT-AFL injections during a mean of 9.8 visits over the 12 months assessed. IVT-AFL was an effective treatment for nAMD in clinical practice, with numerically higher BCVA gains in patients receiving ≥ 7 versus < 7 injections over the first 12 months and ≥ 3 versus < 3 injections in the first 3 months.

Project description:BackgroundTo review treatment outcomes from real-world data of patients with neovascular age-related macular degeneration (nAMD) treated with intravitreal aflibercept (IVT-AFL) injection.MethodsRAINBOW (ClinicalTrials.gov, NCT02279537) is an ongoing, observational, 4-year study to monitor the effectiveness and safety of IVT-AFL in patients with nAMD in clinical practice in France. Treatment-naïve patients diagnosed with nAMD who had been prescribed IVT-AFL by their treating physician were eligible. The regimens of interest were regular treatment interval cohort (patients who received three initial monthly IVT-AFL injections followed by regular injections every 2 months) and two irregular treatment interval cohorts (with and without three initial monthly injections). Here we describe results at 24 months in patients according to IVT-AFL treatment regimen.ResultsThe mean change in best-corrected visual acuity (BCVA) with IVT-AFL from baseline to 24 months was + 3.0 letters in the overall population (P < 0.05 vs baseline). The mean change was positive for the regular and irregular treatment interval cohorts with initial doses (+ 4.9 and + 4.0 letters, respectively; P < 0.05 vs baseline) and negative for the irregular treatment interval cohort without initial doses (- 2.5 letters; P = 0.365 vs baseline) at 24 months. The mean overall number of IVT-AFL injections over 12 and 24 months was 6.0 and 8.8, respectively. The most common ocular adverse events were lack of efficacy (6.3%), vitreous floaters (2.7%), and increased lacrimation (1.7%).ConclusionsIn the real-world RAINBOW study, visual outcomes observed at 24 months were consistent with results from the primary endpoint at 12 months. In this study, treatment-naïve patients who received three initial IVT-AFL doses and regular IVT-AFL treatment over the first 24 months experienced better visual outcomes than patients who received no initial doses and an irregular treatment regimen.Trial registrationwww.ClinicalTrials.gov (NCT02279537). Registered 29 October 2014.

Project description:IntroductionXTEND (NCT03939767) is a multicenter, observational, prospective study of patients with treatment-naïve neovascular age-related macular degeneration (nAMD) in routine clinical practice. The study aims to examine treatment outcomes of proactive intravitreal aflibercept (IVT-AFL) treatment regimens (fixed dosing or treat-and-extend) according to local marketing labels.MethodsStudy eyes received IVT-AFL injections as per the local label. The mean changes in best-corrected visual acuity (BCVA) and central subfield thickness (CST) from baseline to month (M) 12 and M24 were measured and stratified by baseline factors. Treatment exposure and safety data were evaluated. Statistical analysis was descriptive.ResultsOverall, 1466 patients from 17 countries were treated. For the overall population, the mean ± standard deviation (SD) age was 78.7 ± 8.5 (range 50-100) years, and 891 patients (60.8%) were female. The mean ± SD baseline BCVA was 54.3 ± 20.3 letters and CST was 374 ± 126 µm. At M12 and M24, mean (95% confidence interval [CI]) BCVA change was + 4.3 (3.4, 5.3) and + 2.3 (1.3, 3.3) letters, respectively. Mean (95% CI) CST was - 106 (- 114, - 99) μm and - 109 (- 117, - 102) μm at M12 and M24, respectively. At M24, 41.5% of patients had a BCVA ≥ 70 letters. Patients received a mean ± SD of 7.7 ± 2.7 injections by M12 and 10.8 ± 5.0 injections by M24 (3.1 injections between M12 and M24). Adverse events were consistent with the known safety profile of IVT-AFL.ConclusionThe 24-month results indicate that, in routine clinical practice, a proactive IVT-AFL regimen achieves functional improvements in patients with treatment-naïve nAMD. The proportion of patients achieving ≥ 70 letters at M24 increased, and patients with baseline BCVA ≥ 70 letters maintained vision regardless of the followed IVT-AFL label.Trial registrationClinicalTrials.gov identifier: NCT03939767. A video abstract is available for this article. Supplementary file2 (MP4 364624 KB).

Project description:BackgroundNeovascular age-related macular degeneration (nAMD) is a leading cause of blindness in older people. Low-grade inflammation is well-known as one of the pathogenic mechanisms in nAMD. Anti-vascular endothelial growth factor (VEGF) therapy is the first-line treatment for nAMD, although macula atrophy (MA) developed under anti-VEGF therapy causes irreversible visual function impairment and is recognized as a serious disorder. Here, we show specific expression patterns of aqueous humor (AH) cytokines in nAMD eyes developing MA under intravitreal injection of aflibercept (IVA) as an anti-VEGF antibody and present predictive cytokines as biomarkers for the incidence of MA in nAMD eyes under IVA treatment.MethodsTwenty-eight nAMD patients received three consecutive monthly IVA, followed by a pro re nata regimen for 2 years. AH specimens were collected before first IVA (pre-IVA) and before third IVA (post-IVA). AH cytokine levels, visual acuity (VA), and central retinal thickness (CRT) were measured.ResultsTwo-year incidence of MA was 21.4%. In nAMD eyes developing MA [MA (+) group], pre-IVA levels of monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1β, VEGF and post-IVA level of MCP-1 were higher than those in nAMD eyes without MA [MA (-) group]. In hierarchical cluster analysis, pre-IVA MCP-1 and VEGF were grouped into the same subcluster, as were post-IVA MCP-1 and CRT. In principal component analysis, principal component loading (PCL) of pre-IVA interferon-γ-inducible protein 10 (IP-10) was 0.61, but PCL of post-IVA IP-10 decreased to -0.09. In receiver operating characteristic analysis and Kaplan-Meier curves, pre-IVA MCP-1, MIP-1β, and VEGF and post-IVA interleukin-6, MCP-1, and MIP-1β were detected as predictive factors for MA incidence. In 2-year clinical course, changes of VA in groups with high levels of pre-IVA MIP-1β (over 39.9 pg/ml) and VEGF (over 150.4 pg/ml) were comparable to those in MA (+) group.ConclusionSubstantial loss of IP-10 effects and persistent inflammation contribute to incidence of MA, and screening of AH cytokine levels could be a useful method to predict MA incidence in nAMD eyes under anti-VEGF therapy.

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Intravitreal Aflibercept Versus Photodynamic Therapy in Chinese Patients with Neovascular Age-Related Macular Degeneration: Outcomes of the SIGHT Study

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