Sustained benefits from ranibizumab for macular edema following branch retinal vein occlusion: 12-month outcomes of a phase III study. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study. Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration: year 1 results of the FOCUS Study. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Comparison of registered and published primary outcomes in randomized controlled trials. One-year outcomes of the da Vinci Study of VEGF Trap-Eye in eyes with diabetic macular edema. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Randomized trial of supervised injectable versus oral methadone maintenance: report of feasibility and 6-month outcome. Intravitreal triamcinolone acetonide for diffuse diabetic macular oedema: 6-month results of a prospective controlled trial.
Assess 12-month efficacy and safety of intraocular injections of 0.3 mg or 0.5 mg ranibizumab in patients with macular edema after branch retinal vein occlusion (BRVO).
                Prospective, randomized, sham injection-controlled, double-masked, multicenter trial.
                A total of 397 patients with macular edema after BRVO.
                Eligible patients were randomized 1:1:1 to 6 monthly injections of 0.3 mg or 0.5 mg ranibizumab or sham injections. After 6 months, all patients with study eye best-corrected visual acuity (BCVA) ≤20/40 or central subfield thickness ≥250 μm were to receive ranibizumab. Patients could receive rescue laser treatment once during the treatment period and once during the observation period if criteria were met.
                The main efficacy outcome reported is mean change from baseline BCVA letter score at month 12. Additional visual and anatomic parameters were assessed.
                Mean (95% confidence interval) change from baseline BCVA letter score at month 12 was 16.4 (14.5-18.4) and 18.3 (15.8-20.9) in the 0.3 mg and 0.5 mg groups, respectively, and 12.1 (9.6-14.6) in the sham/0.5 mg group (P<0.01, each ranibizumab group vs. sham/0.5 mg). The percentage of patients who gained ≥15 letters from baseline BCVA at month 12 was 56.0% and 60.3% in the 0.3 mg and 0.5 mg groups, respectively, and 43.9% in the sham/0.5 mg group. On average, there was a marked reduction in central foveal thickness (CFT) after the first as-needed injection of 0.5 mg ranibizumab in the sham/0.5 mg group, which was sustained through month 12. No new ocular or nonocular safety events were identified.
                At month 12, treatment with ranibizumab as needed during months 6-11 maintained, on average, the benefits achieved by 6 monthly ranibizumab injections in patients with macular edema after BRVO, with low rates of ocular and nonocular safety events. In the sham/0.5 mg group, treatment with ranibizumab as needed for 6 months resulted in rapid reduction in CFT to a similar level as that in the 0.3 mg ranibizumab treatment group and an improvement in BCVA, but not to the extent of that in the 2 ranibizumab groups. Intraocular injections of ranibizumab provide an effective treatment for macular edema after BRVO.
                Proprietary or commercial disclosure may be found after the references.
                Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved. The expression of vascular endothelial growth factor (VEGF) is elevated in diabetic macular edema (DME). Ranibizumab binds to and inhibits multiple VEGF variants. We investigated the safety and efficacy of ranibizumab in DME involving the foveal center.
                This was a 12-month, multicenter, sham-controlled, double-masked study with eyes (age>18 years, type 1 or 2 diabetes, central retinal thickness [CRT]≥300 μm, and best corrected visual acuity [BCVA] of 73-39 ETDRS letters [Early Treatment Diabetic Retinopathy Study]) randomly assigned to intravitreal ranibizumab (0.3 or 0.5 mg; n=51 each) or sham (n=49). The treatment schedule comprised three monthly injections, after which treatment could be stopped/reinitiated with an opportunity for rescue laser photocoagulation (protocol-defined criteria). After month 1, dose-doubling was permitted (protocol-defined criteria, injection volume increased from 0.05 to 0.1 ml and remained at 0.1 ml thereafter). Efficacy (BCVA and CRT) and safety were compared between pooled ranibizumab and sham arms using the full analysis set (n=151, patients receiving≥1 injection).
                At month 12, mean±SD BCVA improved from baseline by 10.3±9.1 letters with ranibizumab and declined by 1.4±14.2 letters with sham (P<0.0001). Mean CRT reduction was 194.2±135.1 μm with ranibizumab and 48.4±153.4 μm with sham (P<0.0001). Gain of ≥10 letters BCVA from baseline occurred in 60.8% of ranibizumab and 18.4% of sham eyes (P<0.0001). Safety data were consistent with previous studies of intravitreal ranibizumab.
                Ranibizumab is effective in improving BCVA and is well tolerated in DME. Future clinical trials are required to confirm its long-term efficacy and safety. To determine the long-term effects of ranibizumab (RBZ) in patients with diabetic macular edema (DME).
                Prospective, randomized, interventional, multicenter clinical trial.
                One hundred twenty-six patients with DME.
                Subjects were randomized 1:1:1 to receive 0.5 mg RBZ at baseline and months 1, 3, and 5 (group 1), focal or grid laser photocoagulation at baseline and month 3 if needed (group 2), or a combination of 0.5 mg RBZ and focal or grid laser at baseline and month 3 (group 3). Starting at month 6, if retreatment criteria were met, all subjects could be treated with RBZ.
                The mean change from baseline in best-corrected visual acuity (BCVA) at month 24.
                After the primary end point at month 6, most patients in all groups were treated only with RBZ, and the mean number of injections was 5.3, 4.4, and 2.9 during the 18-month follow-up period in groups 1, 2, and 3, respectively. For the 33 patients in group 1, 34 patients in group 2, and 34 patients in group 3 who remained in the study through 24 months, the mean improvement in BCVA was 7.4, 0.5, and 3.8 letters at the 6-month primary end point, compared with 7.7, 5.1, and 6.8 letters at month 24, and the percentage of patients who gained 3 lines or more of BCVA was 21, 0, and 6 at month 6, compared with 24, 18, and 26 at month 24. The percentage of patients with 20/40 or better Snellen equivalent at month 24 was 45% in group 1, 44% in group 2, and 35% in group 3. Mean foveal thickness (FTH), defined as center subfield thickness, at month 24 was 340 μm, 286 μm, and 258 μm for groups 1, 2, and 3, respectively, and the percentage of patients with center subfield thickness of 250 μm or less was 36%, 47%, and 68%, respectively.
                Intraocular injections of RBZ provided benefit for patients with DME for at least 2 years, and when combined with focal or grid laser treatments, the amount of residual edema was reduced, as were the frequency of injections needed to control edema.
                Proprietary or commercial disclosure may be found after the references.
                Copyright © 2010 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved. To demonstrate superiority of ranibizumab 0.5 mg monotherapy or combined with laser over laser alone based on mean average change in best-corrected visual acuity (BCVA) over 12 months in diabetic macular edema (DME).
                A 12-month, randomized, double-masked, multicenter, laser-controlled phase III study.
                We included 345 patients aged ≥18 years, with type 1 or 2 diabetes mellitus and visual impairment due to DME.
                Patients were randomized to ranibizumab + sham laser (n = 116), ranibizumab + laser (n = 118), or sham injections + laser (n = 111). Ranibizumab/sham was given for 3 months then pro re nata (PRN); laser/sham laser was given at baseline then PRN (patients had scheduled monthly visits).
                Mean average change in BCVA from baseline to month 1 through 12 and safety.
                Ranibizumab alone and combined with laser were superior to laser monotherapy in improving mean average change in BCVA letter score from baseline to month 1 through 12 (+6.1 and +5.9 vs +0.8; both P<0.0001). At month 12, a significantly greater proportion of patients had a BCVA letter score ≥15 and BCVA letter score level >73 (20/40 Snellen equivalent) with ranibizumab (22.6% and 53%, respectively) and ranibizumab + laser (22.9% and 44.9%) versus laser (8.2% and 23.6%). The mean central retinal thickness was significantly reduced from baseline with ranibizumab (-118.7 μm) and ranibizumab + laser (-128.3 μm) versus laser (-61.3 μm; both P<0.001). Health-related quality of life, assessed through National Eye Institute Visual Function Questionnaire (NEI VFQ-25), improved significantly from baseline with ranibizumab alone and combined with laser (P<0.05 for composite score and vision-related subscales) versus laser. Patients received ∼7 (mean) ranibizumab/sham injections over 12 months. No endophthalmitis cases occurred. Increased intraocular pressure was reported for 1 patient each in the ranibizumab arms. Ranibizumab monotherapy or combined with laser was not associated with an increased risk of cardiovascular or cerebrovascular events in this study.
                Ranibizumab monotherapy and combined with laser provided superior visual acuity gain over standard laser in patients with visual impairment due to DME. Visual acuity gains were associated with significant gains in VFQ-25 scores. At 1 year, no differences were detected between the ranibizumab and ranibizumab + laser arms. Ranibizumab monotherapy and combined with laser had a safety profile in DME similar to that in age-related macular degeneration.
                Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved. To investigate the safety and efficacy of intravitreal ranibizumab treatment combined with verteporfin photodynamic therapy (PDT) in patients with predominantly classic choroidal neovascularization secondary to age-related macular degeneration.
                In this 2-year, phase I/II, multicenter, randomized, single-masked, controlled study, patients received monthly ranibizumab (0.5 mg) (n = 106) or sham (n = 56) injections. The PDT was performed 7 days before initial ranibizumab or sham treatment and then quarterly as needed.
                Proportion of patients losing fewer than 15 letters from baseline visual acuity at 12 months (primary efficacy outcome) and the incidence and severity of adverse events.
                At 12 months, 90.5% of the ranibizumab-treated patients and 67.9% of the control patients had lost fewer than 15 letters (P<.001). The most frequent ranibizumab-associated serious ocular adverse events were intraocular inflammation (11.4%) and endophthalmitis (1.9%; 4.8% if including presumed cases). On average, patients with serious inflammation had better visual acuity outcomes at 12 months than did controls. Key serious nonocular adverse events included myocardial infarctions in the PDT-alone group (3.6%) and cerebrovascular accidents in the ranibizumab-treated group (3.8%). CONCLUSION/APPLICATION TO CLINICAL PRACTICE: Ranibizumab + PDT was more efficacious than PDT alone for treating neovascular age-related macular degeneration. Although ranibizumab treatment increased the risk of serious intraocular inflammation, affected patients, on average, still experienced visual acuity benefit. To assess the efficacy and safety of intraocular injections of 0.3 mg or 0.5 mg ranibizumab in patients with macular edema after central retinal vein occlusion (CRVO).
                Prospective, randomized, sham injection-controlled, double-masked, multicenter clinical trial.
                A total of 392 patients with macular edema after CRVO.
                Eligible patients were randomized 1:1:1 to receive monthly intraocular injections of 0.3 or 0.5 mg of ranibizumab or sham injections.
                The primary efficacy outcome measure was mean change from baseline best-corrected visual acuity (BCVA) letter score at month 6. Secondary outcomes included other parameters of visual function and central foveal thickness (CFT).
                Mean (95% confidence interval [CI]) change from baseline BCVA letter score at month 6 was 12.7 (9.9-15.4) and 14.9 (12.6-17.2) in the 0.3 mg and 0.5 mg ranibizumab groups, respectively, and 0.8 (-2.0 to 3.6) in the sham group (P<0.0001 for each ranibizumab group vs. sham). The percentage of patients who gained > or =15 letters in BCVA at month 6 was 46.2% (0.3 mg) and 47.7% (0.5 mg) in the ranibizumab groups and 16.9% in the sham group (P<0.0001 for each ranibizumab group vs. sham). At month 6, significantly more ranibizumab-treated patients (0.3 mg = 43.9%; 0.5 mg = 46.9%) had BCVA of > or = 20/40 compared with sham patients (20.8%; P<0.0001 for each ranibizumab group vs. sham), and CFT had decreased by a mean of 434 microm (0.3 mg) and 452 microm (0.5 mg) in the ranibizumab groups and 168 microm in the sham group (P<0.0001 for each ranibizumab group vs. sham). The median percent reduction in excess foveal thickness at month 6 was 94.0% and 97.3% in the 0.3 mg and 0.5 mg groups, respectively, and 23.9% in the sham group. The safety profile was consistent with previous phase III ranibizumab trials, and no new safety events were identified in patients with CRVO.
                Intraocular injections of 0.3 mg or 0.5 mg ranibizumab provided rapid improvement in 6-month visual acuity and macular edema following CRVO, with low rates of ocular and nonocular safety events.
                Copyright 2010 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved. As of 2005, the International Committee of Medical Journal Editors required investigators to register their trials prior to participant enrollment as a precondition for publishing the trial's findings in member journals.
                To assess the proportion of registered trials with results recently published in journals with high impact factors; to compare the primary outcomes specified in trial registries with those reported in the published articles; and to determine whether primary outcome reporting bias favored significant outcomes.
                MEDLINE via PubMed was searched for reports of randomized controlled trials (RCTs) in 3 medical areas (cardiology, rheumatology, and gastroenterology) indexed in 2008 in the 10 general medical journals and specialty journals with the highest impact factors.
                For each included article, we obtained the trial registration information using a standardized data extraction form.
                Of the 323 included trials, 147 (45.5%) were adequately registered (ie, registered before the end of the trial, with the primary outcome clearly specified). Trial registration was lacking for 89 published reports (27.6%), 45 trials (13.9%) were registered after the completion of the study, 39 (12%) were registered with no or an unclear description of the primary outcome, and 3 (0.9%) were registered after the completion of the study and had an unclear description of the primary outcome. Among articles with trials adequately registered, 31% (46 of 147) showed some evidence of discrepancies between the outcomes registered and the outcomes published. The influence of these discrepancies could be assessed in only half of them and in these statistically significant results were favored in 82.6% (19 of 23).
                Comparison of the primary outcomes of RCTs registered with their subsequent publication indicated that selective outcome reporting is prevalent. To compare different doses and dosing regimens of Vascular Endothelial Growth Factor (VEGF) Trap-Eye with laser photocoagulation in eyes with diabetic macular edema (DME).
                Randomized, double-masked, multicenter, phase 2 clinical trial.
                Diabetic patients (n = 221) with center-involved DME.
                Participants were assigned randomly to 1 of 5 treatment regimens: VEGF Trap-Eye 0.5 mg every 4 weeks (0.5q4); 2 mg every 4 weeks (2q4); 2 mg every 8 weeks after 3 initial monthly doses (2q8); or 2 mg dosing as needed after 3 initial monthly doses (2PRN), or macular laser photocoagulation.
                The change in best-corrected visual acuity (BCVA) at 24 weeks (the primary end point) and at 52 weeks, proportion of eyes that gained 15 letters or more in Early Treatment of Diabetic Retinopathy Study (ETDRS) BCVA, and mean changes in central retinal thickness (CRT) from baseline.
                As previously reported, mean improvements in BCVA in the VEGF Trap-Eye groups at week 24 were 8.6, 11.4, 8.5, and 10.3 letters for 0.5q4, 2q4, 2q8, and 2PRN regimens, respectively, versus 2.5 letters for the laser group (P ≤ 0.0085 versus laser). Mean improvements in BCVA in the VEGF Trap-Eye groups at week 52 were 11.0, 13.1, 9.7, and 12.0 letters for 0.5q4, 2q4, 2q8, and 2PRN regimens, respectively, versus -1.3 letters for the laser group (P ≤ 0.0001 versus laser). Proportions of eyes with gains in BCVA of 15 or more ETDRS letters at week 52 in the VEGF Trap-Eye groups were 40.9%, 45.5%, 23.8%, and 42.2% versus 11.4% for laser (P = 0.0031, P = 0.0007, P = 0.1608, and P = 0.0016, respectively, versus laser). Mean reductions in CRT in the VEGF Trap-Eye groups at week 52 were -165.4 μm, -227.4 μm, -187.8 μm, and -180.3 μm versus -58.4 μm for laser (P < 0.0001 versus laser). Vascular Endothelial Growth Factor Trap-Eye generally was well tolerated. The most frequent ocular adverse events with VEGF Trap-Eye were conjunctival hemorrhage, eye pain, ocular hyperemia, and increased intraocular pressure, whereas common systemic adverse events included hypertension, nausea, and congestive heart failure.
                Significant gains in BCVA from baseline achieved at week 24 were maintained or improved at week 52 in all VEGF Trap-Eye groups. Vascular Endothelial Growth Factor Trap-Eye warrants further investigation for the treatment of DME.
                Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved. To evaluate the efficacy and safety of intravitreal ranibizumab in diabetic macular edema (DME) patients.
                Two parallel, methodologically identical, phase III, multicenter, double-masked, sham injection-controlled, randomized studies.
                Adults with vision loss from DME (best-corrected visual acuity [BCVA], 20/40-20/320 Snellen equivalent) and central subfield thickness ≥275 μm on time-domain optical coherence tomography (OCT).
                Monthly intravitreal ranibizumab (0.5 or 0.3 mg) or sham injections. Macular laser was available per-protocol-specified criteria.
                Proportion of patients gaining ≥15 letters in BCVA from baseline at 24 months.
                In RISE (NCT00473330), 377 patients were randomized (127 to sham, 125 to 0.3 mg, 125 to 0.5 mg). At 24 months, 18.1% of sham patients gained ≥15 letters versus 44.8% of 0.3-mg (P<0.0001; difference vs sham adjusted for randomization stratification factors, 24.3%; 95% confidence interval [CI], 13.8-34.8) and 39.2% of 0.5-mg ranibizumab patients (P<0.001; adjusted difference, 20.9%; 95% CI, 10.7-31.1). In RIDE (NCT00473382), 382 patients were randomized (130 to sham, 125 to 0.3 mg, 127 to 0.5 mg). Significantly more ranibizumab-treated patients gained ≥15 letters: 12.3% of sham patients versus 33.6% of 0.3-mg patients (P<0.0001; adjusted difference, 20.8%; 95% CI, 11.4-30.2) and 45.7% of 0.5-mg ranibizumab patients (P<0.0001; adjusted difference, 33.3%; 95% CI, 23.8-42.8). Significant improvements in macular edema were noted on OCT, and retinopathy was less likely to worsen and more likely to improve in ranibizumab-treated patients. Ranibizumab-treated patients underwent significantly fewer macular laser procedures (mean of 1.8 and 1.6 laser procedures over 24 months in the sham groups vs 0.3-0.8 in ranibizumab groups). Ocular safety was consistent with prior ranibizumab studies; endophthalmitis occurred in 4 ranibizumab patients. The total incidence of deaths from vascular or unknown causes, nonfatal myocardial infarctions, and nonfatal cerebrovascular accidents, which are possible effects from systemic vascular endothelial growth factor inhibition, was 4.9% to 5.5% of sham patients and 2.4% to 8.8% of ranibizumab patients.
                Ranibizumab rapidly and sustainably improved vision, reduced the risk of further vision loss, and improved macular edema in patients with DME, with low rates of ocular and nonocular harm.
                Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved. To assess the feasibility of a randomized clinical trial of supervised injectable versus oral methadone maintenance and to assess medium-term treatment outcomes.
                Randomized clinical trial of supervised injectable versus supervised oral methadone maintenance treatment (MMT). Trial participants were dependent illicit opiate injectors allocated at intake to supervised injectable or oral methadone maintenance treatment.
                Specialist addictions treatment centre in South London.
                Forty dependent illicit opiate injectors seeking methadone maintenance treatment.
                Daily supervised injectable and oral methadone maintenance, delivered at the treatment centre.
                Frequency of illicit heroin use and frequency of illicit drug injecting during 30 days before intake to treatment and prior to 6-month follow-up. Secondary outcome measures: frequency of use of illicit methadone, crack cocaine, benzodiazepines and alcohol, physical and psychological health symptoms and acquisitive crime.
                Injectable and oral MMT were both generally acceptable to the study participants: there was a high level of agreement to enter the randomized trial, and subsequent retention in treatment was good. The average number of days of illicit heroin use reduced from 22.2 to 7.6 for the injectable MMT group and from 22.4 to 8.7 for the oral MMT group. The average number of days of illicit injecting reduced from 25.7 to 10.8 days for the injectable group and from 20.1 to 11.9 days for the oral group. Patients' physical and psychological health symptoms and involvement in acquisitive crime also reduced in both groups. Treatment satisfaction ratings at follow-up were higher among patients in the injectable MMT group. The ratio for the actual medication costs between injectable and oral MMT was 6.8:1, and for the direct operational costs was 4.7:1. There was some evidence of a differential patient response with greater reductions in heroin use occurring among patients who were daily illicit injectors and had poorer psychological and physical health (at entry) who were allocated to injectable MMT.
                Conduct of the trial has demonstrated that it is feasible to implement supervised injectable methadone maintenance treatment in the context of (although separate from) a specialist oral methadone maintenance service. Patients assigned to receive either supervised injectable or oral MMT had broadly equivalent, positive during-treatment outcomes at 6-month follow-up. Future studies should seek to identify patient characteristics which are linked to good outcome in injectable MMT. Practical evidence-based guidance to physicians about determining which patients are more suitable for injectable MMT is urgently needed. To evaluate prospectively the efficacy and safety of one intravitreal injection of 4 mg triamcinolone acetonide for refractory diffuse diabetic macular edema.
                Seventeen patients with bilateral diabetic macular edema unresponsive to laser photocoagulation. In all patients, one eye was injected, and the other served as a control. The intervention consisted in intravitreal injection of 4 mg triamcinolone acetonide. The main outcome measure was central macular thickness (CMT) at 4, 12 and 24 weeks, measured by Optical Coherence Tomography. Secondary outcomes were Early Treatment Diabetic Rentinopathy Study (ETDRS) scores, intraocular pressure and cataract PROGRESSION.
                Before injection, mean +/- SD CMT was 566.4 +/- 182.4 mum in injected eyes. Four, 12, and 24 weeks after injection, it was 228.4 +/- 47.5 mum, 210.9 +/- 87.2 mum and 358.5 +/- 160.5 mum respectively. CMT was significantly lower in injected eyes vs. control eyes except 24 weeks after injection because of a recurrence of macular edema in 9/17 injected eyes. Mean +/- SD gain in ETDRS score was significantly better in injected eyes vs. control eyes 4, 12 and 24 weeks after TA injection. In 9 of the 17 injected eyes, intraocular pressure exceeded 24 mmHg and was controlled by topical medication.
                In the short-term, intravitreal injection of triamcinolone effectively reduces macular thickening due to diffuse diabetic macular edema and improves visual acuity in most cases. The long-term effect of this treatment and predictive factors of visual recovery remain to be elucidated.
The available RCT evidence suggests that repeated treatment of non-ischaemic MO secondary to BRVO with the anti-VEGF agent ranibizumab may improve clinical and visual outcomes at six and 12 months. However, the frequency of re-treatment has not yet been determined and the impact of prior or combined treatment with laser photocoagulation on the primary outcome is unclear. Results from ongoing studies should assess not only treatment efficacy but also, the number of injections needed for maintenance and long-term safety and the effect of any prior treatment.