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Neovascular, or wet, age-related macular degeneration causes central vision loss and represents a major health problem in elderly people, and is currently treated with frequent intraocular injections of anti-VEGF protein. Gene therapy might enable long-term anti-VEGF therapy from a single treatment. We tested the safety of rAAV.sFLT-1 in treatment of wet age-related macular degeneration with a single subretinal injection. In this single-centre, phase 1, randomised controlled trial, we enrolled patients with wet age-related macular degeneration at the Lions Eye Institute and the Sir Charles Gairdner Hospital (Nedlands, WA, Australia). Eligible patients had to be aged 65 years or older, have age-related macular degeneration secondary to active subfoveal choroidal neovascularisation, with best corrected visual acuity (BCVA) of 3/60–6/24 and 6/60 or better in the other eye. Patients were randomly assigned (3:1) to receive either 1 × 1010 vector genomes (vg; low-dose rAAV.sFLT-1 group) or 1 × 1011 vg (high-dose rAAV.sFLT-1 group), or no gene-therapy treatment (control group). Randomisation was done by sequential group assignment. All patients and investigators were unmasked. Staff doing the assessments were masked to the study group at study visits. All patients received ranibizumab at baseline and week 4, and rescue treatment during follow-up based on prespecified criteria including BCVA measured on the Early Treatment Diabetic Retinopathy Study (EDTRS) scale, optical coherence tomography, and fluorescein angiography. The primary endpoint was ocular and systemic safety. This trial is registered with ClinicalTrials.gov, number NCT01494805. From Dec 16, 2011, to April 5, 2012, we enrolled nine patients of whom eight were randomly assigned to receive either intervention (three patients in the low-dose rAAV.sFLT-1 group and three patients in the high-dose rAAV.sFLT-1 group) or no treatment (two patients in the control group). Subretinal injection of rAAV.sFLT-1 was highly reproducible. No drug-related adverse events were noted; procedure-related adverse events (subconjunctival or subretinal haemorrhage and mild cell debris in the anterior vitreous) were generally mild and self-resolving. There was no evidence of chorioretinal atrophy. Clinical laboratory assessments generally remained unchanged from baseline. Four (67%) of six patients in the treatment group required zero rescue injections, and the other two (33%) required only one rescue injection each. rAAV.sFLT-1 was safe and well tolerated. These results support ocular gene therapy as a potential long-term treatment option for wet age-related macular degeneration. National Health and Medical Research Council of Australia, Richard Pearce Bequest, Lions Save Sight Foundation, Brian King Fellowship, and Avalanche Biotechnologies, Inc.

Background and aimThere is still no established treatment regimen for eyes with inflammatory choroidal neovascularisation (iCNV) treated with intravitreal anti-vascular endothelial growth factor (VEGF) injections. This study compared the 24-month outcomes of two treatment regimens of anti-VEGF injections in eyes with iCNV.MethodsEyes with iCNV treated with anti-VEGF injections were divided into two groups: eyes treated with a loading phase of 3 monthly injections and then re-treated as needed (LOADING group) and eyes treated as needed from the beginning (PRN group). Visual acuity (VA), number of injections and iCNV recurrences at 24 months were compared between the groups.ResultsEighty-two eyes were included, 42 in the LOADING and 40 in the PRN group. Baseline VA (mean(SD)) was 57.3 (15.8) letters in the LOADING vs 60.7 (15.6) letters in the PRN group (p=0.32). The VA (mean (95% CI)) increased at 3 months (+14.8 (10.6 to 18.9) and +11.2 (6.4 to 16) letters in the LOADING and PRN group, respectively) and remained significantly higher than baseline over the entire follow-up in both groups (all p<0.001). At 24 months, there was no difference in VA between the LOADING and PRN group (72.3 (14.0) vs 74.7 (11.3) letters, p=0.36) but the LOADING group received significantly more injections (median (Q1–Q3)) than the PRN (4.5 (3–7) vs 2.5 (2–3.2), p<0.0001). The iCNV recurrences were similar in both groups.ConclusionsiCNV responded well to anti-VEGF with significant and sustained VA improvement. The loading phase did not confer any advantage in terms of outcomes. PRN regimen from the beginning was as effective as more intensive treatment.

PurposeTo compare the efficacy and safety of conbercept and ranibizumab when administered according to a treat-and-extend (TREX) protocol for the treatment of neovascular age-related macular degeneration (AMD) in China.Patients and methodsBetween May 2014 and May 2015, 180 patients were treated in a 1 : 1 ratio using conbercept or ranibizumab from four hospitals. Patients received either conbercept 0.5 mg or ranibizumab 0.5 mg intravitreal injections. Follow-up time was 1 year and treated based on a TREX approach. Main outcomes and measures include best-corrected visual acuity (BCVA), using Early Treatment Diabetic Retinopathy Study (ETDRS); number of injections; central retinal thickness (CRT); and leakage of choroidal neovascularization before and after the treatment was analyzed by fluorescein fundus angiography and indocyanine green angiography.ResultsThe 1-year visit was completed by 168 (93.3%) of patients. Mean BCVA was equivalent between two cohorts, and were improved by 12.7±7.770 and 12.3±7.269 letters in the conbercept and ranibizumab cohorts, respectively (P=0.624). There was no significant difference in measured CRT, with a mean decrease of 191.5 μm for conbercept and 187.8 μm for ranibizumab (P=0.773). There was a statistically significant difference (P=0.001) between the drugs regarding the number of treatments: 7.4 for conbercept and 8.7 for ranibizumab. The difference in the distribution of injection intervals was statistically significant between two groups (P=0.011). During the study, there were no cases of endophthalmitis or intraocular inflammation.ConclusionBoth drugs had equivalent effects in visual and anatomic gains at 1 year when administered. In the conbercept group, longer treatment intervals were achieved with more patients.

AimsTo investigate the impact of posterior vitreous detachment (PVD) on the efficacy of treat-and-extend (T&E) ranibizumab in neovascular age-related macular degeneration.MethodsIn a post hoc analysis of a randomised controlled clinical trial, spectral-domain optical coherence tomography images of treatment-naïve patients randomised to receive T&E (n=265) or monthly (n=264) ranibizumab for 12 months were included. Certified, masked graders diagnosed the presence or the absence of complete PVD. The main outcome measures were the mean change in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) at month 12, the number of administered ranibizumab injections and the proportion of patients extended to more than 8 weeks.ResultsAt baseline, complete PVD was present in 51% and 56% of patients in the monthly and T&E arms, respectively. Mean change in BCVA at month 12 was +9.0 (PVD) vs +9.5 letters (no PVD, p=0.78) in monthly treated eyes, and +6.0 (PVD) vs +7.5 letters (no PVD, p=0.42) in T&E treated eyes. Conversely, mean change in CRT at month 12 was −174 (PVD) vs −173 µm (no PVD, p=0.98) in the monthly arm, and −175 (PVD) vs −164 µm (no PVD, p=0.58) in the T&E arm. In T&E treated patients, the median number of injections was eight vs nine (p=0.035). 71% of PVD eyes were extended successfully, compared with 55% of eyes without PVD (p=0.005).ConclusionPVD was not found to impact functional and anatomical outcomes of T&E ranibizumab therapy. However, patients without a complete PVD required more retreatments and were significantly less likely to be successfully extended.Trial registration number NCT01948830

Background/aimsTo understand changes in disease activity as assessed by leakage and retinal fluid status in patients with neovascular age-related macular degeneration (nAMD) receiving fixed dosing with an anti-vascular endothelial growth factor (anti-VEGF) agent.MethodsIn the phase III VIEW 1 (NCT00509795) and VIEW 2 (NCT00637377) studies, eyes with nAMD were treated with intravitreal aflibercept or ranibizumab. Independent, masked reading centres determined the presence/absence of leakage (fluorescein angiography) and retinal fluid (optical coherence tomography) at baseline, week 24 and week 52. In this integrated, post hoc analysis of the VIEW studies, the relationship between leakage/fluid status and best-corrected visual acuity (BCVA) was assessed. The impact of baseline lesion type (predominantly classic (PC), minimally classic (MC), occult) was also evaluated. Data from all treatment groups were pooled.Results2373 eyes were included in this analysis. At baseline, 95.4% of eyes presented with both leakage and fluid. By week 52, leakage and fluid were present in 16.0% of eyes. Mean BCVA gains at week 52 were numerically greater in eyes without leakage and fluid versus eyes with both leakage and fluid (10.3 vs 9.2 letters). At week 52, 11.6%, 15.3% and 20.1% of eyes with PC, MC and occult lesions, respectively, had both leakage and fluid present.ConclusionIn this post hoc analysis, fixed dosing with an anti-VEGF agent over 52 weeks eliminated disease activity (absence of both leakage and fluid) in most eyes. The effect of anti-VEGF treatment on leakage/fluid status favoured PC versus occult lesions.

Purpose To report the long-term results of anti-vascular endothelial growth factor (VEGF) therapy for choroidal neovascularization (CNV) secondary to pathological myopia (PM). Methods Prospective interventional study with extension phase. Eyes affected by CNV due to PM included. All patients received an intravitreal bevacizumab injection (1.25 mg/0.05 ml) at baseline. Re-treatment was considered at each follow-up visit. Results The study included 101 consecutive eyes of 86 patients. All patients reached 24 months of follow-up. After 24 months, mean best-corrected visual acuity (BCVA) improvement was −0.13 (95 % CI: −0.2; −0.05) logMAR (p < 0.001) and central retinal thickness (CRT) decreased on average by 67 (95 % CI: 27; 102) μm (p < 0.01). The chorioretinal atrophy (CRA) area increased significantly after 2 years of follow-up (+7.82 mm 2 , p < 0.0001). Patients received 4.1 treatments, on average. Thirty-two eyes were included in the extension phase (from 24 to 60 months of follow-up). Visual acuity improved on average by −0.05 (95 % CI: −0.2; 0.1) logMAR (p > 0.05) compared to baseline. Mean reduction in CRT was 102 (95 % CI: 64;141) μm (p < 0.01). The CRA area enlarged significantly after 5 years of follow-up (+14.15 mm 2 , p < 0.0001). Patients received a mean of 6.7 treatments in 60 months. Conclusions An individualized regimen with intravitreal bevacizumab to treat CNV secondary to PM resulted in BCVA improvement and CRT decrease at 2 and 5 years. The main visual benefit was obtained between month 3 and month 24. A gradual loss of the initial BCVA gain was observed starting from month 30 to month 60 due to progression of CRA.

Background To review treatment outcomes from real-world data of patients with neovascular age-related macular degeneration (nAMD) treated with intravitreal aflibercept (IVT-AFL) injection. Methods RAINBOW ( 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. Results The 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%). Conclusions In 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 registration www.ClinicalTrials.gov ( NCT02279537 ). Registered 29 October 2014.

PurposeTo evaluate criteria driving retreatment with ranibizumab in Italian patients with myopic choroidal neovascularization (mCNV).MethodsOLIMPIC was a 12-month, phase IIIb, open-label study. Patients with active mCNV were treated with ranibizumab 0.5 mg according to the European label. The study assessed local criteria in Italy driving retreatment decisions with ranibizumab; and the efficacy, safety, and tolerability of ranibizumab.ResultsThe mean (standard deviation [SD]) age of treated patients (N = 200) was 61.8 (12.7) years; range 22–85 years. The multivariate regression model indicated that presence of active leakage (odds ratio [OR] 95% confidence interval [CI]: 11.30 [1.03–124.14]), presence of intraretinal fluid (OR [95%CI]: 28.21 [1.55–513.73]), and an improvement in best-corrected visual acuity (BCVA) from baseline < 10 letters (OR [95%CI]: 17.60 [1.39–222.75]) were the factors with the greatest effect on retreatment with ranibizumab. The mean (SD) BCVA gain from baseline to month 12 was 8.4 (12.8) letters (P < 0.0001). The mean (SD) number of injections was 2.41 (1.53); range 1–9. Ocular and non-ocular adverse events were reported in 41 (20.5%) and 30 (15.0%) patients, respectively.ConclusionsIndividualized treatment with ranibizumab was effective in improving BCVA in patients with mCNV over 12 months. Both anatomical and functional variables had significant effects on causing retreatment. There were no new safety findings.Trial registrationwww.ClinicalTrials.Gov (NCT No: NCT02034006)

Objectives To evaluate the efficacy and safety of intravitreous bevacizumab injections for the treatment of neovascular age related macular degeneration.Design Prospective, double masked, multicentre, randomised controlled trial.Setting Three ophthalmology centres in the United Kingdom.Participants 131 patients (mean age 81) with wet age related macular degeneration randomised 1:1 to intervention or control.Interventions Intravitreous bevacizumab (1.25 mg, three loading injections at six week intervals followed by further treatment if required at six week intervals) or standard treatment available at the start of the trial (photodynamic treatment with verteporfin for predominantly classic type neovascular age related macular degeneration, or intravitreal pegaptanib or sham treatment for occult or minimally classic type neovascular age related macular degeneration).Main outcome measures Primary outcome: proportion of patients gaining ≥15 letters of visual acuity at one year (54 weeks). Secondary outcomes: proportion of patients with stable vision and mean change in visual acuity.Results Of the 131 patients enrolled in the trial, five patients did not complete the study because of adverse events, loss to follow-up, or death. In the bevacizumab group, 21 (32%) patients gained 15 or more letters from baseline visual acuity compared with two (3%) in the standard care group (P<0.001); the estimated adjusted odds ratio was 18.1 (95% confidence interval 3.6 to 91.2) and the number needed to treat was 4 (3 to 6). In addition, the proportion of patients who lost fewer than 15 letters of visual acuity from baseline was significantly greater among those receiving bevacizumab treatment (91% (59) v 67% (44) in standard care group; P<0.001). Mean visual acuity increased by 7.0 letters in the bevacizumab group with a median of seven injections compared with a decrease of 9.4 letters in the standard care group (P<0.001), and the initial improvement at week 18 (plus 6.6 letters) was sustained to week 54. Among 65 patients treated with bevacizumab, there were no cases of endophthalmitis or serious uveitis related to the intervention. All end points with respect to visual acuity in the study eye at 54 weeks favoured bevacizumab treatment over standard care.Conclusions Bevacizumab 1.25 mg intavitreous injections given as part of a six weekly variable retreatment regimen is superior to standard care (pegaptanib sodium, verteporfin, sham), with low rates of serious ocular adverse events. Treatment improved visual acuity on average at 54 weeks.Trial registration number Current controlled trials ISRCTN83325075

Aims: To compare functional and anatomical outcomes of intravitreal bevacizumab (Avastin) and verteporfin (photodynamic) therapy (PDT) combined with intravitreal triamcinolone (IVTA) in patients with neovascular age-related macular degeneration (AMD).Methods: Twenty-eight patients with neovascular AMD were enrolled in a prospective, randomised, controlled clinical trial. All patients randomly assigned to 1 mg intravitreal bevacizumab (0.04 ml) received three initial treatments at 4-week intervals. In further follow-up retreatment was based on optical coherence tomography (OCT). Patients randomly assigned to standard PDT received a same-day intravitreal injection of 4 mg triamcinolone (Kenalog). Retreatment was based on fluorescein angiography at 3-month intervals. Functional and anatomical results were evaluated using the Early Treatment Diabetic Retinopathy Study protocol vision charts, fluorescein angiography and OCT.Results: In the bevacizumab-treated group mean visual acuity (VA) improved to a 2.2 line gain at 6 months follow-up. Eyes treated in the PDT plus IVTA group had a stable mean VA at month 6 compared with baseline. There was a statistically significant difference (p = 0.03, analysis of variance (ANOVA)) between both groups as early as one day after initial treatment. The reduction in central retinal thickness (CRT) showed no significant difference between both groups (p = 0.3, ANOVA). Mean CRT was reduced from 357 μm at baseline to 239 μm at month 6 in bevacizumab-treated patients and from 326 μm to 222 μm, respectively, in PDT plus IVTA-treated patients. No significant local or systemic safety concerns were detected up to month 6.Conclusion: Intravitreal bevacizumab showed promising 6-month results in patients with neovascular AMD. Functional outcomes appear not only to be dependent on a reduction in CRT but also on the treatment modality used.