Incidence Of Ocular Adverse Events Research Articles

Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration (PULSAR): 48-week results from a randomised, double-masked, non-inferiority, phase 3 trial

Intravitreal aflibercept 8 mg could improve treatment outcomes and provide sustained disease control in patients with neovascular age-related macular degeneration (nAMD), with extended dosing compared with aflibercept 2 mg. PULSAR is a phase 3, randomised, three-group, double-masked, non-inferiority, 96-week trial conducted across 223 sites worldwide. Adults with nAMD were randomised 1:1:1 to aflibercept 8 mg every 12 weeks (8q12), aflibercept 8 mg every 16 weeks (8q16), or aflibercept 2 mg every 8 weeks (2q8), following three initial monthly doses in all groups. From week 16, patients in the aflibercept 8 mg groups had their dosing interval shortened if pre-specified dose regimen modification criteria denoting disease activity were met. The primary endpoint was change from baseline in best-corrected visual acuity (BCVA) at week 48. All patients with at least one dose of study treatment were included in the efficacy and safety analyses. This trial is registered with ClinicalTrials.gov (NCT04423718) and is ongoing. Of 1011 patients randomised to aflibercept 8q12 (n=336), 8q16 (n=338), or 2q8 (n=337) between Aug 11, 2020, and July 30, 2021, 1009 patients received study treatment (aflibercept 8q12 n=335; aflibercept 8q16 n=338; and aflibercept 2q8 n=336). Aflibercept 8q12 and 8q16 showed non-inferior BCVA gains versus aflibercept 2q8 (mean BCVA change from baseline +6·7 [SD 12·6] and +6·2 [11·7] vs +7·6 [12·2] letters). The least squares mean differences between aflibercept 8q12 versus 2q8 and 8q16 versus 2q8, respectively, were -0·97 (95% CI -2·87 to 0·92) and -1·14 (-2·97 to 0·69) letters (non-inferiority margin at 4 letters). The incidence of ocular adverse events in the study eye was similar across groups (aflibercept 8q12 n=129 [39%]; aflibercept 8q16 n=127 [38%]; and aflibercept 2q8 n=130 [39%]). Aflibercept 8 mg showed efficacy and safety with extended dosing intervals, which has the potential to improve the management of patients with nAMD. Bayer AG and Regeneron Pharmaceuticals.

Efficacy and Safety of Faricimab for Macular Edema due to Retinal Vein Occlusion: 24-Week Results from the BALATON and COMINO Trials

To evaluate the 24-week efficacy and safety of the dual angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF)-A inhibitor faricimab versus aflibercept in patients with vein occlusion. Phase 3, global, randomized, double-masked, active comparator-controlled trials: BALATON/COMINO (ClincalTrials.gov identifiers: NCT04740905/NCT04740931; sites: 149/192). Patients with treatment-naïve foveal center-involved macular edema resulting from branch (BALATON) or central or hemiretinal (COMINO) RVO. Patients were randomized 1:1 to faricimab 6.0 mg or aflibercept 2.0 mg every 4 weeks for 24weeks. Primary end point: change in best-corrected visual acuity (BCVA) from baseline to week 24. Efficacy analyses included patients in the intention-to-treat population. Safety analyses included patients who received ≥ 1 doses of study drug. Enrollment: BALATON, n = 553; COMINO, n = 729. The BCVA gains from the baseline to week 24 with faricimab were noninferior versus aflibercept in BALATON (adjusted mean change,+16.9 letters [95.03% confidence interval (CI), 15.7-18.1 letters] vs.+17.5 letters [95.03% CI, 16.3-18.6 letters]) and COMINO (+16.9 letters [95.03% CI, 15.4-18.3 letters] vs.+17.3 letters [95.03% CI, 15.9-18.8 letters]). Adjusted mean central subfield thickness reductions from the baseline were comparable for faricimab and aflibercept at week 24 in BALATON (-311.4 μm [95.03% CI,-316.4 to-306.4 μm] and-304.4 μm [95.03% CI,-309.3 to-299.4 μm]) and COMINO (-461.6 μm [95.03% CI,-471.4 to-451.9 μm] and-448.8 μm [95.03% CI,-458.6 to-439.0 μm]). A greater proportion of patients in the faricimab versus aflibercept arm achieved absence of fluorescein angiography-based macular leakage at week 24 in BALATON (33.6% vs. 21.0%; nominal P= 0.0023) and COMINO (44.4% vs. 30.0%; nominal P= 0.0002). Faricimab was well tolerated, with an acceptable safety profile comparable with aflibercept. The incidence of ocular adverse events was similar between patients receiving faricimab (16.3% [n= 45] and 23.0% [n= 84] in BALATON and COMINO, respectively) and aflibercept (20.4% [n= 56] and 27.7% [n= 100], respectively). These findings demonstrate the efficacy and safety of faricimab, a dual Ang-2/VEGF-A inhibitor, in patients with macular edema secondary to retinal vein occlusion. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Comparison of alcaftadine with olopatadine for allergic conjunctivitis: A meta-analysis study

BackgroundThe efficacy of alcaftadine versus olopatadine remains elusive for the treatment of allergic conjunctivitis, and this meta-analysis aims to explore the impact of alcaftadine versus olopatadine on treatment efficacy for allergic conjunctivitis. MethodsPubMed, EMbase, Web of science, EBSCO and Cochrane library databases were systematically searched, and we included randomized controlled trials (RCTs) assessing the effect of alcaftadine versus olopatadine on efficacy in patients with allergic conjunctivitis. Ocular symptoms score and conjunctival hyperaemia score were included for this meta-analysis. ResultsTen RCTs were finally included in the meta-analysis. Overall, compared with olopatadine intervention for allergic conjunctivitis, alcaftadine intervention demonstrated no significant impact on ocular symptoms score on day 3 (SMD=–0.02; 95% CI=–0.20 to 0.16; P=0.82), day 7 (SMD=–0.02; 95% CI=–0.20 to 0.16; P=0.82), or conjunctival hyperaemia score on day 3 (SMD=0; 95% CI=–0.18 to 0.18; P=1.0), but was associated with substantially reduced ocular symptoms score on day 14 (SMD=–0.33; 95% CI=–0.51 to –0.15; P=0.0004) and conjunctival hyperaemia score on day 3 (SMD=0; 95% CI=–0.18 to 0.18; P=1.0). Additionally, there was similar incidence of ocular adverse events between alcaftadine intervention and olopatadine intervention (OR=1.37; 95% CI=0.12 to 16.12; P=0.80). ConclusionsAlcaftadine may be better to relieve ocular symptoms on day 14 and conjunctival hyperaemia on day 3 compared to olopatadine.

Brolucizumab Intravitreal Injections for Wet Age-Related Macular Degeneration: Real-Life Study on a Cohort of Italian Patients.

Background and Objectives: To report the real-life Brolucizumab therapeutical outcomes of treatment-naïve and non-treatment-naïve eyes with neovascular age-related macular degeneration (nAMD) and to analyze the incidence of therapy-related adverse events. Materials and Methods: A total of 56 eyes of 54 patients diagnosed with nAMD were retrospectively evaluated over a 3-month follow-up. Naïve eyes received a 3-month loading phase, whereas non-naïve eyes were treated with one intravitreal injection + ProReNata scheme. The main outcome measures were best-corrected visual acuity (BCVA) and central retinal thickness (CRT) change. In addition, patients were stratified on the basis of fluid accumulation site, whether intra-retinal (IRF), sub-retinal (SRF), or sub-retinal pigmented epithelium (SRPE), to separately assess the eventual BCVA change in each subgroup. Finally, the incidence of ocular adverse events was evaluated. Results: In naïve eyes, a significant improvement of BCVA (LogMar) was observed at all timepoints from baseline (1 month-Mean Difference (MD): -0.13; 2 months MD: -0.17; 3 months MD: -0.24). In non-naïve eyes, a significant mean change was observed at all timepoints, with the exception of 1-month follow-up (2 months MD: -0.08; 3 months MD: -0.05). CRT significantly changed in both groups at all timepoints at a similar pace within the first two months, with naïve eyes displaying a larger overall thickness decrease at the end of the follow-up (Group 1 = MD: -123.91 µm; Group 2 = MD: -110.33 µm). With respect to the location of the edema, a significant BCVA change was observed in naïve patients with fluid in all three sites at the end of the follow-up (SRPE = MD: -0.13 (p = 0.043); SR = MD: -0.15 (p = 0.019); IR = MD: -0.19 (p = 0.041). Non-naïve patients exhibited significant mean BCVA changes only with respect to SR and IR fluid presence (SRPE = MD: -0.13 (p = 0.152); SR = MD: -0.15 (p = 0.007); IR = MD: -0.06 (p = 0.011). One naïve patient experienced acute-onset anterior and intermediate uveitis which completely resolved after therapy. Conclusions: Brolucizumab was demonstrated to be a safe and efficient alternative in improving both the anatomical and functional parameters of eyes with nAMD in this small, uncontrolled, series of patients.

NOV03 for Signs and Symptoms of Dry Eye Disease Associated With Meibomian Gland Dysfunction: The Randomized Phase 3 MOJAVE Study

To evaluate the efficacy and safety of NOV03 (perfluorohexyloctane) ophthalmic drop for the treatment of signs and symptoms of dry eye disease (DED) associated with meibomian gland dysfunction (MGD). Randomized, double-masked, controlled trial. Patients ≥18 years of age with a history of DED and signs of MGD were randomly assigned 1:1 to treatment with NOV03 or hypotonic saline (0.6%) 4 times daily for 8 weeks. The primary sign and symptom endpoints were change from baseline to week 8 in total corneal fluorescein staining (tCFS; National Eye Institute scale) and eye dryness score (0-100 visual analog scale), respectively. A total of 620 patients (NOV03, n = 311; saline, n = 309) were randomized and treated. Least-squares (LS) mean change from baseline to week 8 was statistically significantly greater for NOV03 compared with saline for both tCFS (-2.3 vs -1.1; LS mean treatment difference, -1.2 [95% confidence interval -1.7 to -0.8]; P < .001) and visual analog scale dryness score (-29.4 vs -19.2; LS mean treatment difference, -10.2 [95% CI -14.4 to -6.1]; P < .001), with statistically significant between-group differences observed as early as week 2. The incidence of ocular adverse events was similar for NOV03 (12.9%) and saline (12.3%). There were no serious adverse events and no adverse events leading to treatment discontinuation. In this randomized controlled trial of patients with DED associated with MGD, NOV03 significantly reduced both signs and symptoms of DED compared with hypotonic saline control. NOV03 was well tolerated, with an adverse event profile similar to that of saline.

Ocular Adverse Events after Coronavirus Disease 2019 mRNA Vaccination: Matched Cohort and Self-Controlled Case Series Studies Using a Large Database

PurposeTo investigate the risk of ocular adverse events after COVID-19 mRNA vaccination.DesignMatched cohort and self-controlled case series (SCCS) studies.Subjects/ControlsWe used a population-based database of medical claims and vaccination records in a large city of Japan. In the matched cohort study, we identified individuals who received COVID-19 vaccination (BNT162b2) from February 2021 to September 2021. One control was selected from non-vaccinated individuals by matching time, date of birth, sex, Charlson comorbidity index, and the enrollment period for health insurance. In the SCCS study, we analyzed individuals who developed ocular adverse events from February 2021 to the end of follow-up.MethodsIn the matched cohort study, we applied the Kaplan–Meier estimator to estimate the cumulative incidence of ocular adverse events over 21 days after the first dose and 84 days after the second dose. In the SCCS method, we used conditional Poisson regression to estimate the incidence rate ratio of ocular adverse events during the risk periods (0–21 days after the first dose and 0–84 days after the second dose) compared to the remaining periods.Main Outcome MeasuresComposite outcome of uveitis, scleritis, retinal vein occlusion, and optic neuritis.ResultsThere were 99,718 pairs eligible for the matched cohort study after the first dose (mean age, 69.3 years; male, 44%). The vaccinated and control groups developed 29 and 21 events, respectively, over 21 days after the first dose, and 79 and 28 events, respectively, over 84 days after the second dose. The differences in cumulative incidence (reference, the control group) were 2.9 (95% confidence interval, -14.5 to 19.1) events/100,000 persons and 51.3 (16.2 to 84.3) events/100,000 persons, respectively, for the first and second dose. The SCCS study showed the incidence rate ratios of 0.89 (0.62 to 1.28) and 0.89 (0.71 to 1.11) for the first and second doses, respectively.ConclusionsThe matched cohort analysis found an increased risk for the composite outcome after the second dose; however, the SCCS analysis showed no increased risk. Considering that the SCCS can cancel out time-invariant confounders, the current results suggest that COVID-19 vaccination is unlikely to causally increase the risk of ocular adverse events.

Incidence of adverse events after loading phase of the brolucizumab therapy of neovascular AMD: Real-life evidence in the Czech Republic.

To evaluate the incidence of ocular adverse events after loading phase of the brolucizumab therapy in patients with neovascular age-related macular degeneration (nAMD) in real-life clinical practice - in treatment-naive patients and in patients after switching from another anti-VEGF agent. Another aim was to evaluate treatment outcomes in patients with adverse events. This is a multicentre, retrospective, observational study from 16 application centres in the Czech Republic. Patients diagnosed with nAMD were treated with brolucizumab in a fixed regimen of loading phase (3 injections administered at one-month intervals) and the mean follow-up period was 120 ± 10 days after the first injection. The incidence of adverse events and the development of best corrected visual acuity (BCVA) and central retinal thickness (CRT) in patients with complications were evaluated. A total of 1,098 eyes were followed up, of which 783 were treatment-naive and 315 eyes were after switching from another anti-VEGF agent. Adverse events were recorded in 42 eyes (3.83%), of which 30 eyes were treatment-naive (2.7%) and 12 eyes were post-switch (1.09%). The mean baseline BCVA ± SD was 56.7 ± 10.7 ETDRS chart letters in the group of patients with adverse events, 58.8 ± 10.1 letters in treatment-naive patients, and 51.4 ± 10.2 letters in patients after switch from another anti-VEGF agent. The mean baseline CRT ± SD was 432.2 ± 154.7 μm, being 435.8 ± 137.3 μm in treatment-naive patients and 424.5 ± 186.6 μm in patients after switch from another anti-VEGF agent. At the end of the follow-up, the mean BCVA ± SD was 53.4 ± 9.5 ETDRS charts letters in patients with adverse events, 55.6 ± 10 letters in treatment-naive patients, and 47.6 ± 10 letters in patients after switching from another anti-VEGF agent. The mean CRT ± SD at the end of the follow-up was 300.7 ± 115.7 μm in the total patient cohort, 285.2 ± 78.8 μm in treatment-naive patients and 334.5 ± 165.4 μm in patients after switching from another anti-VEGF agent. We observed the development of adverse events in the form of intraocular inflammation or vasculitis with subsequent decrease in BCVA in 3.83% of cases after loading phase of the brolucizumab therapy. The decrease in BCVA was reversible in most cases after initiation of anti-inflammatory steroid treatment. From a functional and morphological point of view, we did not demonstrate any statistically significant difference between the groups of treatment-naive patients and patients after switching from another anti-VEGF agent.

Infigratinib Reduces Fibroblast Growth Factor 23 (FGF23) and Increases Blood Phosphate in Tumor‐Induced Osteomalacia

ABSTRACTTumor‐induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by ectopic production of fibroblast growth factor 23 (FGF23) by phosphaturic mesenchymal tumors (PMTs). Acting on renal tubule cells, excess FGF23 decreases phosphate reabsorption and 1,25‐dihydroxy‐vitamin D (1,25D) production, leading to hypophosphatemia, impaired bone mineralization, pain, and fractures. Fibronectin 1‐fibroblast growth factor receptor 1 (FN1‐FGFR1) gene fusions have been identified as possible drivers in up to 40% of resected PMTs. Based on the presumptive role of FGFR1 signaling by chimeric FN1‐FGFR1 proteins, the effectiveness of infigratinib, a FGFR1‐3 tyrosine kinase inhibitor, was studied in an open‐label, single‐center, phase 2 trial. The primary endpoint was persistent normalization of blood phosphate and FGF23 after discontinuation. Four adults with TIO (two nonlocalized, two nonresectable PMTs) were treated with daily infigratinib for up to 24 weeks. All patients had a favorable biochemical response that included reduction in intact FGF23, and normalization of blood phosphate and 1,25D. However, these effects disappeared after drug discontinuation with biochemistries returning to baseline; no patients entered biochemical remission. In the two patients with identifiable tumors, 68Gallium (68Ga)‐DOTATATE and 18Fluoride (18F)‐Fluorodeoxyglucose (FDG) PET/CT scans showed a decrease in PMT activity without change in tumor size. Patients experienced mild to moderate, treatment‐related, dose‐limiting adverse events (AEs), but no serious AEs. Three patients had dose interruptions due to AEs; one patient continued on a low dose for the entire 24 weeks and one patient stopped therapy at 17 weeks due to an AE. The study closed early due to a failure to meet the primary endpoint and a higher‐than‐expected incidence of ocular AEs. Infigratinib treatment lowered FGF23, increased blood phosphate, and suppressed PMT activity, confirming the role of FGFR signaling in PMT pathogenesis. However, treatment‐related AEs at efficacy doses and disease persistence on discontinuation support restricting the use of infigratinib to patients with life‐limiting metastatic PMTs. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials

To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody. YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593). 3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference -0·2 ETDRS letters [-2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [-0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [-1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [-1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%]). Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema. F Hoffmann-La Roche.

Safety of soft contact lenses in children: retrospective review of six randomized controlled trials of myopia control.

To examine the rate and types of ocular adverse events among children wearing soft contact lenses. This study is a retrospective review of ocular adverse event data from six randomized controlled trials among a total of 581 myopic children (aged 7-15years at baseline) administered daily disposable hydrogel contact lenses (etafilcon A). During 816 patient years of contact lens wear, no significant or serious ocular adverse events were reported. A total of 86 non-significant ocular adverse events occurred in 53 children. The crude rate of ocular adverse events was 10.6 per 100 patient years with the estimated pooled incidence being 8.9 per 100 patient years (95% CI: 4.5-17.4). Two asymptomatic corneal infiltrative events were reported (both non-significant), which is an incidence of 0.3 (95% CI: 0.1-0.9) per 100 patient years. The most common ocular adverse events (n) were slit-lamp findings of Grade 2 or less requiring treatment (26), unspecified conjunctivitis (14), and allergic conjunctivitis (13). No cases of microbial keratitis were observed. Of the 86 adverse events, 37 were classified as highly likely or possibly lens-related, giving a crude incidence of 4.5 per 100 patient years for contact lens-related events. The crude incidence of ocular adverse events among spectacle wearers was 1.8 per 100 patient years. These data suggest that daily disposable soft contact lenses can be safely worn by children. Additional studies will be needed to precisely quantify the adverse event rate of soft contact lenses in normal clinical practice.

Low‐dose brimonidine for relief of ocular redness: integrated analysis of four clinical trials

BackgroundThe aim of this study was to provide an integrated analysis of safety and efficacy data for brimonidine tartrate ophthalmic solution 0.025 per cent (low‐dose; Bausch & Lomb Incorporated), a topical vasoconstrictor for relief of ocular redness.MethodsIntegrated efficacy data from two randomised, double‐masked, vehicle‐controlled studies in subjects with ocular redness as well as safety data from the two efficacy studies, a vehicle‐controlled safety study, and a pharmacokinetic study were analysed. Efficacy outcomes analysed included investigator‐assessed ocular redness (scale, 0–4) before treatment instillation and at five to 240-minutes post‐instillation on Day 1, at five-minutes post‐instillation on Days 15 and 29, and one-week after treatment discontinuation (Day 36), and redness self‐assessed by subjects recorded daily in diaries. Safety assessments included adverse events, ophthalmic examinations, and rebound redness upon treatment discontinuation. Drop comfort (scale, 0–10) was a tolerability measure.ResultsThe efficacy population included 117 subjects (brimonidine, n = 78; vehicle, n = 39). The safety population included 635 subjects (brimonidine, n = 426; vehicle, n = 209). Investigator‐assessed ocular redness was significantly lower with brimonidine versus vehicle at all post‐instillation time points on Day 1 (mean change from pre‐instillation of −1.4-units for brimonidine and −0.2-units for vehicle; p < 0.0001). Subject‐assessed ocular redness was also significantly lower with brimonidine versus vehicle (mean treatment difference in average daily ratings of −0.9; p < 0.0001). There was no evidence of tachyphylaxis through Day 29 and rebound redness was rare. Incidence of ocular adverse events was low, the most common being reduced visual acuity (brimonidine, 4.0-per cent; vehicle, 4.3-per cent) and conjunctival hyperaemia (2.6 and 2.9-per cent, respectively). Both brimonidine and vehicle were rated as very comfortable (mean post‐instillation scores, 0.4–0.5).ConclusionIn this integrated analysis, low‐dose brimonidine significantly reduced ocular redness with no tachyphylaxis, and minimal rebound redness, and was generally safe and well tolerated.

Nurse-administered intravitreal injections of anti-VEGF: study protocol for noninferiority randomized controlled trial of safety, cost and patient satisfaction.

BackgroundIntravitreal injections (IVI) of anti-vascular endothelial growth factor (anti-VEGF) now improve or stabilize visual acuity in a number of previously untreatable eye diseases, of which the main are age-related macular degeneration, retinal vein occlusion and diabetic macular edema. Most patients require multiple injections over lengthy periods of time and the prevalence of treatable conditions is increasing. Anti-VEGF IVI normally administered by physicians, therefore represent a considerable workload on ophthalmologic clinics and will continue to do so in the near future. Nurse-administered IVI may relieve this workload, but the safety, cost and patient satisfaction of such an extended role for nurses in ophthalmologic clinics has not earlier been investigated. To investigate these outcomes following independent anti-VEGF IVI by trained nurses, a noninferiority randomized controlled trial is being conducted.Methods/DesignPatients eligible for anti-VEGF treatment, minimum 304, are recruited and randomized to IVI administration by either trained nurses or physicians. The primary outcome is safety, measured by difference in mean change in visual acuity between the two groups during an observation period of 12 months. Secondary outcomes are incidence of ocular adverse events, cost per patient and patient satisfaction.DiscussionThis study protocol describes the design of the first randomized controlled trial of nurse-administered IVI of anti-VEGF. The study is designed to examine safety, cost and patient satisfaction during 12 months follow-up.Trial registrationClinicalTrials.gov NCT02359149. Registered February 4, 2015.Electronic supplementary materialThe online version of this article (doi:10.1186/s12886-016-0348-4) contains supplementary material, which is available to authorized users.

Long‐Term Safety of Intravitreal Sirolimus for the Treatment of Non‐infectious Uveitis (NIU) of the Posterior Segment: 12‐Month SAKURA Study 1 Results

PurposeIntravitreal sirolimus significantly reduced inflammation in subjects with NIU of the posterior segment and provided clinically relevant visual benefit, with an acceptable incidence of ocular adverse events (AEs), in the double‐masked period of SAKURA Study 1, the first of 2 phase 3 randomized trials. Here, we report the long‐term (12 month) safety findings from the combined double‐masked and open‐label treatment periods.MethodsSubjects with active NIU of the posterior segment (N = 347) were randomized to 44 μg (active control), 440 μg, or 880 μg injections of intravitreal sirolimus, administered every 2 months. At M6, all subjects transitioned to 880 µg injections every 2 months.Results287 subjects entered the open‐label treatment period and completed the M12 Vitreous Haze assessment. Of these, 211 received ≥1 intravitreal sirolimus injections. Through M12, the most common serious ocular AEs (study eye) occurring in ≥2% of subjects were ocular inflammation (2.9–5.8%), cataract (3.8%), and medication residue (transient drug depot in the visual axis; 2.3%). The mean change in intraocular pressure was &lt;2 mm Hg. The incidence of confirmed endophthalmitis was 0.06%/injection.ConclusionsThere was a low incidence of serious ocular AEs over 12 months with intravitreal sirolimus in this heterogeneous group of subjects with NIU of the posterior segment.

Intravitreal Aflibercept Injection in Patients with Myopic Choroidal Neovascularization: The MYRROR Study

To evaluate intravitreal aflibercept 2 mg in patients with myopic choroidal neovascularization (CNV). An international, phase III, multicenter, randomized, double-masked, sham-controlled study. Patients aged ≥ 18 years with high myopia (≤-6.0 diopters or axial length of ≥ 26.5 mm), active myopic CNV, and best-corrected visual acuity (BCVA) of 73-35 Early Treatment Diabetic Retinopathy Study letters in the study eye were included. Patients were randomized 3:1 to intravitreal aflibercept or sham. In the intravitreal aflibercept arm, patients received 1 injection at baseline. Additional injections were performed in case of CNV persistence or recurrence at monthly visits through week 44. In the sham arm, patients received sham injections through week 20. At week 24, after assessment of the primary efficacy end point, sham patients received a mandatory intravitreal aflibercept injection followed by intravitreal aflibercept (if disease persisted/recurred) or sham injection every 4 weeks. Mean change in BCVA from baseline to week 24. A total of 122 patients were randomized to intravitreal aflibercept (n = 91) or sham (n = 31). Baseline demographics were similar across groups. At week 24, patients in the intravitreal aflibercept and sham groups gained 12.1 and lost 2 letters, respectively (P < 0.0001). By week 48, patients in the intravitreal aflibercept and sham/intravitreal aflibercept groups gained 13.5 and 3.9 letters. Patients in the intravitreal aflibercept group received 2 injections (median) in the first study quarter (week 0-8). Median number of injections in quarters 2 to 4 was 0. Patients in the "sham/intravitreal aflibercept" group received 2 and 1 (median) intravitreal aflibercept injections in quarters 3 and 4. Central retinal thickness improved in parallel with visual gains. Incidence of ocular adverse events was similar in both groups through week 48 (37.4% vs. 38.7); most were assessed by investigators as mild. No deaths occurred. Intravitreal aflibercept 2 mg was effective for treatment of myopic CNV with clinically important visual and anatomic benefits achieved with a limited number of injections given in the first 8 weeks of treatment. No new safety concerns occurred with treatment. Intravitreal aflibercept should be considered as a treatment option for myopic CNV.

Prospective Study of Ocular Adverse Events Induced By S-1

ABSTRACT Aim: S-1 is an oral fluoropyrimidine agent and widely used for patients with various solid tumors in Asian countries. Few case reports and studies have documented common ocular adverse events including lacrimal canaliculus stenosis (LCS) and cornea epithelium disorder (CED) induced by S-1 administration. LCS causes watery eyes, blurred vision and photophobia, and CED causes vision disorder, as well as corneal ulcers which lead to blindness. Although these symptoms severely affect Quality of Life of cancer patients, the risk has not been clearly recognized by clinicians. We conducted a prospective study to investigate the incidence and severity of ocular adverse events induced by S-1. Methods: Patients who were candidates for S-1 were prospectively examined by 3 ophthalmologists to check their lacrimal canalicules and cornea epithelium before and every 4 weeks during administration of S-1 until cessation of the treatments. The patients underwent slit lamp biomicroscopic examinations to evaluate the incidence and severity of LCS and CED. Results: From December 2012 to December 2013, 40 patients were enrolled in this study (gastric cancer 23 patients, colorectal 8, pancreatic 4, lung 2, and other cancers 3). The ocular adverse events were detected in 17 patients (42.5%) in ophthalmic surveillance. LCS was seen in 13 cases (32.5%) and the median onset time of LCS was 99.6 days (21 to 274 days) after the initiation of S-1. Eight patients (20%) were diagnosed as grade 3 (CTCAE v4.0) and required needle dilatation of lacrimal canaliculus and 5 patients with severe symptoms of LCS needed insertion of drainage tubes in the lacrimal canaliculus. Seven cases (17.5%) were diagnosed as CED, of which 3 cases with grade 3 severe vision disorder required cessation of S-1 treatment. Corneal ulcers were detected in one patient. The mean onset time of CED was 112.7 days (42 to 331 days) after initiation of S-1. After cessation of S-1, recovery from all adverse effects was observed in all patients. Conclusions: This study showed a high incidence of ocular adverse events induced by S-1 treatment, with some patients suffering severe effects requiring ophthalmologic treatment. Oncologists should cooperate with ophthalmologists during S-1 treatment to prevent severe ocular adverse events by detecting disorders at an early stage. Disclosure: All authors have declared no conflicts of interest.

Enzymatic Vitreolysis with Ocriplasmin for Vitreomacular Traction and Macular Holes

BackgroundVitreomacular adhesion can lead to pathologic traction and macular hole. The standard treatment for severe, symptomatic vitreomacular adhesion is vitrectomy. Ocriplasmin is a recombinant protease with activity against fibronectin and laminin, components of the vitreoretinal interface.MethodsWe conducted two multicenter, randomized, double-blind, phase 3 clinical trials to compare a single intravitreal injection of ocriplasmin (125 μg) with a placebo injection in patients with symptomatic vitreomacular adhesion. The primary end point was resolution of vitreomacular adhesion at day 28. Secondary end points were total posterior vitreous detachment and nonsurgical closure of a macular hole at 28 days, avoidance of vitrectomy, and change in best-corrected visual acuity.ResultsOverall, 652 eyes were treated: 464 with ocriplasmin and 188 with placebo. Vitreomacular adhesion resolved in 26.5% of ocriplasmin-injected eyes and in 10.1% of placebo-injected eyes (P<0.001). Total posterior vitreous detachment was more prevalent among the eyes treated with ocriplasmin than among those injected with placebo (13.4% vs. 3.7%, P<0.001). Nonsurgical closure of macular holes was achieved in 40.6% of ocriplasmin-injected eyes, as compared with 10.6% of placebo-injected eyes (P<0.001). The best-corrected visual acuity was more likely to improve by a gain of at least three lines on the eye chart with ocriplasmin than with placebo. Ocular adverse events (e.g., vitreous floaters, photopsia, or injection-related eye pain — all self-reported — or conjunctival hemorrhage) occurred in 68.4% of ocriplasmin-injected eyes and in 53.5% of placebo-injected eyes (P<0.001), and the incidence of serious ocular adverse events was similar in the two groups (P=0.26).ConclusionsIntravitreal injection of the vitreolytic agent ocriplasmin resolved vitreomacular traction and closed macular holes in significantly more patients than did injection of placebo and was associated with a higher incidence of ocular adverse events, which were mainly transient. (Funded by ThromboGenics; ClinicalTrials.gov numbers, NCT00781859 and NCT00798317.)

Role of anti‐VEGF

AbstractPurpose To assess safety and efficacy of intraocular injections of anti‐VEGF in patients with diabetic macular edema (DME)Methods The gold standard for treatment has been laser coagulation. Limitations of this therapy are refractive DME, ischemic diabetic maculopathy and complications after laser application. The need for a non‐destructive and effective strategy has led to investigations regarding VEGF inhibitors for reduction of vessel leakage and edema formation. Critical analysis of the most recent trials on the use of intravitreal anti‐VEGF will be discussed for the treatment of DME.Results For DME, intravitreal pegaptanib and bevacizumab have shown beneficial short‐term effects on both visual acuity and retinal thickness. Most recent datas concern the use of ranibizumab and will be detailled. Incidence of ocular adverse events are consistent with prior clinical trials of ranibizumab across multiple retinal diseases. VEGF‐trap study will be reported.Conclusion New therapeutic approaches based on intravitreal injections of anti‐VEGF molecules offer new hope for the management of diabetic macular edema. However, randomized studies are needed in order to attest longterm safety and efficacy profiles.

Ocular safety of sildenafil citrate when administered chronically for pulmonary arterial hypertension: results from phase III, randomised, double masked, placebo controlled trial and open label extension

Objective To assess the ocular effects and safety profile of chronic sildenafil oral dosing in patients with pulmonary arterial hypertension.Design 12 week, double masked, randomised, placebo controlled, phase III trial...

Dexamethasone Intravitreal Implant in Patients with Macular Edema Related to Branch or Central Retinal Vein Occlusion: Twelve-Month Study Results

To evaluate the safety and efficacy of 1 or 2 treatments with dexamethasone intravitreal implant (DEX implant) over 12 months in eyes with macular edema owing to branch or central retinal vein occlusion (BRVO or CRVO). Two identical, multicenter, prospective studies included a randomized, 6-month, double-masked, sham-controlled phase followed by a 6-month open-label extension. We included 1256 patients with vision loss owing to macular edema associated with BRVO or CRVO. At baseline, patients received DEX implant 0.7 mg (n = 421), DEX implant 0.35 mg (n = 412), or sham (n = 423) in the study eye. At day 180, patients could receive DEX implant 0.7 mg if best-corrected visual acuity (BCVA) was <84 letters or retinal thickness was >250 μm. The primary outcome for the open-label extension was safety; BCVA was also evaluated. At day 180, 997 patients received open-label DEX implant. Except for cataract, the incidence of ocular adverse events was similar in patients who received their first or second DEX implant. Over 12 months, cataract progression occurred in 90 of 302 phakic eyes (29.8%) that received 2 DEX implant 0.7 mg injections versus 5 of 88 sham-treated phakic eyes (5.7%); cataract surgery was performed in 4 of 302 (1.3%) and 1 of 88 (1.1%) eyes, respectively. In the group receiving two 0.7-mg DEX implants (n = 341), a ≥ 10-mmHg intraocular pressure (IOP) increase from baseline was observed in (12.6% after the first treatment, and 15.4% after the second). The IOP increases were usually transient and controlled with medication or observation; an additional 10.3% of patients initiated IOP-lowering medications after the second treatment. A ≥ 15-letter improvement in BCVA from baseline was achieved by 30% and 32% of patients 60 days after the first and second DEX implant, respectively. Among patients with macular edema owing to BRVO or CRVO, single and repeated treatment with DEX implant had a favorable safety profile over 12 months. In patients who qualified for and received 2 DEX implant injections, the efficacy and safety of the 2 implants were similar with the exception of cataract progression. Proprietary or commercial disclosure may be found after the references.

Efficacy and Tolerability of Besifloxacin Ophthalmic Suspension 0.6% Administered Twice Daily for 3 Days in the Treatment of Bacterial Conjunctivitis: A Multicenter, Randomized, Double-Masked, Vehicle-Controlled, Parallel-Group Study in Adults and Children

BackgroundBesifloxacin is a topical fluoroquinolone with potent in vitro activity against a broad spectrum of ocular pathogens, including drug-resistant strains. Besifloxacin ophthalmic suspension 0.6% given 3 times daily for 5 days has been reported to be more effective than its vehicle in the treatment of bacterial conjunctivitis. Pharmacokinetic/pharmacodynamic modeling suggests that besifloxacin might also be effective given twice daily. ObjectiveThis study evaluated the efficacy and tolerability of besifloxacin ophthalmic suspension 0.6% administered twice daily for 3 days compared with vehicle (formulation without besifloxacin) in the treatment of adults and children with bacterial conjunctivitis. MethodsThis was a multicenter, prospective, randomized, double-masked, vehicle-controlled, parallel-group study. Patients aged ≥1 year with bacterial conjunctivitis were randomized to receive besifloxacin ophthalmic suspension or vehicle administered twice daily for 3 days. There were 3 study visits: the baseline visit, visit 2 (day 4 or 5), and visit 3 (day 7±1). Participants recorded the times of medication instillation in a patient diary. The primary end points were clinical resolution and bacterial eradication of the baseline bacterial infection at visit 2 in patients with culture-confirmed bacterial conjunctivitis. Secondary end points were clinical resolution and bacterial eradication of the baseline bacterial infection at visit 3, individual clinical outcomes (ocular conjunctival discharge and bulbar conjunctival injection) at the follow-up visits, and microbial and clinical outcomes for overall bacterial species and individual gram-positive and gram-negative bacterial species. Tolerability assessments included ocular adverse events (AEs), changes in visual acuity, biomicroscopy and ophthalmoscopy findings, and nonocular AEs. ResultsOf 202 patients randomized to treatment (mean [SD] age, 25.2 [24.3] years; 56.9% female; 76.7% white), 109 had culture-confirmed bacterial conjunctivitis (53 besifloxacin ophthalmic suspension, 56 vehicle). At visit 2, the besifloxacin ophthalmic suspension group had significantly greater rates of clinical resolution compared with the vehicle group (37/53 [69.8%] vs 21/56 [37.5%], respectively; P < 0.001), as well as significantly greater rates of bacterial eradication (46/53 [86.8%] vs 32/56 [57.1%]; P < 0.001). At visit 3, rates of bacterial eradication were also significantly greater in the besifloxacin ophthalmic suspension group compared with the vehicle group (46/53 [86.8%] vs 39/56 [69.6%]; P = 0.038). Results for the individual clinical outcomes and microbial and clinical outcomes by gram-positive and gram-negative species were consistent with the primary efficacy outcomes. The incidence of ocular AEs did not differ significantly between treatment groups (4/94 [4.3%] vs 8/98 [8.2%]). Ocular AEs in all treated eyes in the respective groups included bacterial conjunctivitis (3/157 [1.9%] and 5/154 [3.2%]), conjunctivitis (3/157 [1.9%] and 4/154 [2.6%]), and allergic conjunctivitis (2/157 [1.3%] and 1/154 [0.6%]). These events were of mild or moderate severity. Changes in visual acuity and biomicroscopy and ophthalmoscopy findings were comparable between groups. There were few nonocular AEs (2/94 [2.1%] vs 3/98 [3.1%]; P = NS), none of them considered treatment related. ConclusionIn these adults and children with bacterial conjunctivitis, treatment with besifloxacin ophthalmic suspension 0.6% administered twice daily for 3 days was effective and well tolerated. ClinicalTrials.gov identifier: NCT00972777.