Roman G Rubio

University of California, San Francisco, San Francisco, CA, United States

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Publications (20)104.27 Total impact

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    ABSTRACT: To evaluate the incidence of collateral vessel formation and to determine their impact on best-corrected visual acuity and central foveal thickness in patients with branch or central retinal vein occlusion (BRVO, CRVO) receiving 0.3 mg or 0.5 mg of ranibizumab, or sham.
    Retina (Philadelphia, Pa.) 07/2014; · 2.93 Impact Factor
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    ABSTRACT: To describe the systemic pharmacokinetics of ranibizumab after intravitreal administration in patients with retinal vein occlusion (RVO) or diabetic macular edema (DME).
    Ophthalmology 07/2014; · 5.56 Impact Factor
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    ABSTRACT: To characterize preinjection intraocular pressure (IOP) in eyes receiving monthly ranibizumab versus sham or verteporfin photodynamic therapy (PDT) for age-related macular degeneration (AMD). Post hoc analysis of IOP data from 2 phase 3 clinical trials, the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA) and the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR) trial. All safety-evaluable patients who received 1 or more injections of sham or PDT or of ranibizumab and had 1 or more postbaseline IOP measurements recorded for the study eye. Preinjection IOP measurements for study eyes (n = 1125) and fellow eyes in MARINA and ANCHOR at baseline and at each monthly visit through month 24 were analyzed. End points evaluated were maximum preinjection IOP during the 24-month treatment period; any occurrence of absolute preinjection IOP of 21 mmHg or more, 25 mmHg or more, or 30 mmHg or more; any occurrence of IOP increase of 6 mmHg or more, 8 mmHg or more, or 10 mmHg or more from baseline; any combination of IOP increase of 6 mmHg or more or 8 mmHg or more from baseline with concurrent absolute preinjection IOP of 21 mmHg or more or 25 mmHg or more; glaucoma-related adverse events; new glaucoma medications used for 45 days or more; and glaucoma filtration or laser surgeries. Across treatment groups, 60.1% to 70.9% of study eyes had a maximum preinjection IOP of less than 21 mmHg. Comparing ranibizumab 0.5 mg versus sham or PTD treatment, respectively: 39.9% versus 29.1% and 10.9% versus 5.1% had maximum preinjection IOPs of 21 mmHg or more or 25 mmHg or more, respectively; 44.1% versus 29.9% and 24.2% versus 13.6% had IOP increases from baseline of 6 mmHg or more or 8 mmHg or more, respectively; 26.1% versus 13.6% and 16.8% versus 9.0% had 1 or more IOP increase from baseline of 6 mmHg or more or 8 mmHg or more, respectively, with a concurrent IOP of 21 mmHg or more; 9.6% versus 3.7% and 7.5% versus 2.4% had 1 or more IOP increase from baseline of 6 mmHg or more or 8 mmHg or more, respectively, with a concurrent IOP of 25 mmHg or more. No differences were observed in fellow eyes. Most ranibizumab-treated eyes did not experience sustained preinjection IOP of 21 mmHg or more (>2 consecutive visits) over 24 months. When evaluating the combined IOP end point, more ranibizumab-treated eyes had 1 or more IOP increase from baseline of 6 mmHg or more or 8 mmHg or more, with concurrent highest IOPs of 21 mmHg or more and 25 mmHg or more versus sham or PDT. Intraocular pressure should be monitored in eyes receiving ranibizumab.
    Ophthalmology 01/2014; · 5.56 Impact Factor
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    ABSTRACT: Objective To determine the effect of suppression of vascular endothelial growth factor (VEGF) by monthly injection of ranibizumab on posterior retinal nonperfusion (RNP) in patients with diabetic macular edema (DME). Design Unplanned retrospective analysis of prospectively collected data from 2 randomized, sham injection-controlled, double-masked, multicenter clinical trials. Participants Six hundred sixty-six patients with DME. Methods An independent reading center measured the area of RNP on fluorescein angiograms obtained in the phase 3 RISE and RIDE trials. Main Outcome Measures The percentage of patients with no posterior RNP. Results The percentage of patients with no posterior RNP decreased in the sham group between baseline and month 24, but remained relatively stable in the 2 ranibizumab groups. After month 24, the sham group crossed over to receive monthly injections of ranibizumab 0.5 mg, and the differences between the sham and ranibizumab groups were reduced. The percentage of patients who showed an increase in posterior RNP from baseline increased over time in all 3 groups, but at a faster rate in the sham group, resulting in statistically significant differences at every time point between months 3 (9.6% vs. 18.5%; P = 0.016) and 24 (16.1% vs. 37.6%; P<0.0001) for ranibizumab 0.5 mg versus sham and from months 6 (12.3% vs. 23.0%; P = 0.013) through 24 (15.0% vs. 37.6%; P<0.0001) for ranibizumab 0.3 mg. Initiation of ranibizumab in the sham group at month 24 was followed by reduction in the percentage of patients with an increase in posterior RNP from baseline at months 30 and 36, whereas the 2 ranibizumab groups continued their gradual rise. Conclusions Just as high VEGF levels contribute to progression of retinal nonperfusion in retinal vein occlusion, the same is true in patients with DME, suggesting that regardless of the underlying disease process, high levels of VEGF can cause closure of retinal vessels. However, our data also suggest that VEGF-induced worsening of retinal perfusion in DME is superimposed on another cause of more gradually worsening perfusion, possibly glucotoxicity. Thus, monthly injections of ranibizumab can slow, but not completely prevent, retinal capillary closure in patients with DME.
    Ophthalmology 01/2014; · 5.56 Impact Factor
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    ABSTRACT: PURPOSE: To report 36-month outcomes of RIDE (NCT00473382) and RISE (NCT00473330), trials of ranibizumab in diabetic macular edema (DME). DESIGN: Phase III, randomized, multicenter, double-masked, 3-year trials, sham injection-controlled for 2 years. PARTICIPANTS: Adults with DME (n=759), baseline best-corrected visual acuity (BCVA) 20/40 to 20/320 Snellen equivalent, and central foveal thickness (CFT) ≥275 μm on optical coherence tomography. METHODS: Patients were randomized equally (1 eye per patient) to monthly 0.5 mg or 0.3 mg ranibizumab or sham injection. In the third year, sham patients, while still masked, were eligible to cross over to monthly 0.5 mg ranibizumab. Macular laser was available to all patients starting at month 3; panretinal laser was available as necessary. MAIN OUTCOME MEASURES: The proportion of patients gaining ≥15 Early Treatment Diabetic Retinopathy Study letters in BCVA from baseline at month 24. RESULTS: Visual acuity (VA) outcomes seen at month 24 in ranibizumab groups were consistent through month 36; the proportions of patients who gained ≥15 letters from baseline at month 36 in the sham/0.5 mg, 0.3 mg, and 0.5 mg ranibizumab groups were 19.2%, 36.8%, and 40.2%, respectively, in RIDE and 22.0%, 51.2%, and 41.6%, respectively, in RISE. In the ranibizumab arms, reductions in CFT seen at 24 months were, on average, sustained through month 36. After crossover to 1 year of treatment with ranibizumab, average VA gains in the sham/0.5 mg group were lower compared with gains seen in the ranibizumab patients after 1 year of treatment (2.8 vs. 10.6 and 11.1 letters). Per-injection rates of endophthalmitis remained low over time (∼0.06% per injection). The incidence of serious adverse events potentially related to systemic vascular endothelial growth factor inhibition was 19.7% in patients who received 0.5 mg ranibizumab compared with 16.8% in the 0.3 mg group. CONCLUSIONS: The strong VA gains and improvement in retinal anatomy achieved with ranibizumab at month 24 were sustained through month 36. Delayed treatment in patients receiving sham treatment did not seem to result in the same extent of VA improvement observed in patients originally randomized to ranibizumab. Ocular and systemic safety was generally consistent with the results seen at month 24. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.
    Ophthalmology 05/2013; · 5.56 Impact Factor
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    ABSTRACT: IMPORTANCE Treatment of macular edema secondary to retinal vein occlusion with ranibizumab has been shown to improve visual acuity compared with macular laser or observation. It is important to determine whether these visual acuity improvements translate into measurable improvements in visual function. OBJECTIVE To examine the benefit of ranibizumab (Lucentis) on measured reading speed, a direct performance assessment, through 6 months in eyes of patients with macular edema after retinal vein occlusion (RVO). DESIGN Two multicenter, double-masked, phase 3 trials in which participants with macular edema after branch RVO or central RVO were randomized 1:1:1 to monthly sham, ranibizumab, 0.3 mg, or ranibizumab, 0.5 mg, for 6 months. SETTING Community- and academic-based ophthalmology practices specializing in retinal diseases. PARTICIPANTS Seven hundred eighty-nine eyes of 789 participants who were at least aged 18 years with macular edema secondary to retinal vein occlusion in the branch vein occlusion (BRAVO) and central vein occlusion (CRUISE) trials. INTERVENTIONS Eyes were randomized 1:1:1 to 1 of 3 groups for monthly injections for 6 months: sham (132 in BRAVO and 130 in CRUISE), intravitreal ranibizumab, 0.3 mg (134 in BRAVO and 132 in CRUISE), and intravitreal ranibizumab, 0.5 mg (131 in BRAVO and 130 in CRUISE). Patients were able to receive macular laser after 3 months if they met prespecified criteria. MAIN OUTCOMES AND MEASURES Reading speed in the study eye was measured with enlarged text (letter size equivalent to approximately 20/1500 at the test distance) at baseline and 1, 3, and 6 months. The number of correctly read words per minute (wpm) was reported. The reading speed test requires a sixth-grade reading level and does not account for literacy or cognitive state. RESULTS In patients with branch RVO, the mean gain for the 0.5-mg group was 31.3 wpm compared with 15.0 wpm in sham-treated eyes (difference, 16.3 wpm; P = .007) at 6 months. In patients with central RVO, the mean gain for the 0.5-mg group was 20.5 wpm compared with 8.1 wpm in sham-treated eyes (difference, 12.4 wpm; P = .01) at 6 months. A gain of 15 or more letters of best-corrected visual acuity letter score corresponded to an increase in reading speed of 12.3 wpm and 15.8 wpm in patients with branch and central RVO, respectively. CONCLUSIONS AND RELEVANCE These results suggest that patients with macular edema after RVO treated monthly with ranibizumab are more likely to have improvements in reading speed of the affected eyes through 6 months compared with sham treatment. These results demonstrate the relevance of the treatment benefit to functional visual gain. TRIAL REGISTRATION clinicaltrials.gov Identifier:NCT00486018 and NCT00485836.
    Jama Ophthalmology 05/2013; · 3.83 Impact Factor
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    ABSTRACT: PURPOSE: To determine if optical coherence tomography (OCT) at baseline or month 3 in the Treatment of Macular Edema following Branch Retinal Vein Occlusion: Evaluation of Efficacy and Safety (BRAVO) and Treatment of Macular Edema following Central Retinal Vein Occlusion: Evaluation of Efficacy and Safety (CRUISE) studies provides information that predicts visual outcome. DESIGN: Post hoc analysis from 2 prospective, randomized, controlled clinical trials. PARTICIPANTS: Three hundred ninety-seven patients from the BRAVO study and 392 patients from the CRUISE study. METHODS: Time-domain OCT imaging data were analyzed. MAIN OUTCOME MEASURES: Mean change from baseline best-corrected visual acuity (BCVA) letter score at month 6 and month 12. RESULTS: Among ranibizumab-treated patients, 71.2% (0.3 mg) and 78.5% (0.5 mg) in the CRUISE study and 79.1% (0.3 mg) and 84.7% (0.5 mg) in the BRAVO study had central foveal thickness (CFT) of 250 μm or less at month 3 and therefore were categorized as early ranibizumab responders. Early ranibizumab responders had excellent visual outcomes regardless of ranibizumab dose; mean improvement in BCVA letter score at 6 and 12 months was 15.0 to 16.5 (central retinal vein occlusion [CRVO]) and 17.4 to 19.1 (branch retinal vein occlusion [BRVO]). Late or incomplete ranibizumab responders with CRVO (CFT >250 μm at month 3) did not fare as well as early responders if they were treated with 0.3 mg ranibizumab (month 6, P = 0.012). At month 6, compared with ranibizumab-treated CRVO patients with resolved cystoid macular edema (CME) at month 3, those with persistent CME did worse, on average, and significantly so for 0.5 mg (13.1 vs. 18.6; P = 0.027). At baseline, subretinal fluid (SRF) was present in 57% of patients with CRVO and in 45% of patients with BRVO; its presence did not portend a poor outcome in patients treated with ranibizumab for whom SRF was eliminated in almost all by month 3. CONCLUSIONS: At month 3 of ranibizumab treatment, OCT images provide predictive information for patients with CRVO, but not for those with BRVO. Visual outcome at months 6 and 12 was reduced in 0.5 mg ranibizumab-treated patients with CRVO who had persistent CME at month 3. It also was reduced in CRVO for those with CFT of more than 250 μm at month 3 who were treated with 0.3 mg ranibizumab. The findings suggest that late or incomplete responders may need careful follow-up. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.
    Ophthalmology 02/2013; · 5.56 Impact Factor
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    ABSTRACT: OBJECTIVE: To evaluate the 12-month efficacy and safety of intravitreal ranibizumab 0.5 mg and 2.0 mg administered monthly and on an as-needed (PRN) basis in treatment-naïve patients with subfoveal neovascular age-related macular degeneration (wet AMD). DESIGN: A 24-month, phase III, randomized, multicenter, double-masked, dose-response study. PARTICIPANTS: Patients aged ≥50 years with subfoveal wet AMD. METHODS: Patients (n = 1098) were randomized to receive ranibizumab 0.5 mg or 2.0 mg intravitreal injections administered monthly or on a PRN basis after 3 monthly loading doses. MAIN OUTCOME MEASURES: The primary efficacy end point was the mean change from baseline in best-corrected visual acuity (BCVA) at month 12. Key secondary end points included the mean number of ranibizumab injections, the mean change from baseline in central foveal thickness (CFT) over time, and the proportion of patients who gained ≥15 letters of BCVA. Unless otherwise specified, end point analyses were performed using the last-observation-carried-forward method to impute missing data. RESULTS: At month 12, the mean change from baseline in BCVA for the 4 groups was +10.1 letters (0.5 mg monthly), +8.2 letters (0.5 mg PRN), +9.2 letters (2.0 mg monthly), and +8.6 letters (2.0 mg PRN). The proportion of patients who gained ≥15 letters from baseline at month 12 in the 4 groups was 34.5%, 30.2%, 36.1%, and 33.0%, respectively. The mean change from baseline in CFT at month 12 in the 4 groups was -172.0 μm, -161.2 μm, -163.3 μm, and -172.4 μm, respectively. The mean number of injections was 7.7 and 6.9 for the 0.5-mg PRN and 2.0-mg PRN groups, respectively. Ocular and systemic safety profiles were consistent with previous ranibizumab trials in AMD and comparable between groups. CONCLUSIONS: At month 12, the ranibizumab 2.0-mg monthly group did not meet the prespecified superiority comparison and the ranibizumab 0.5-mg and 2.0-mg PRN groups did not meet the prespecified noninferiority (NI) comparison. However, all treatment groups demonstrated clinically meaningful visual improvement (+8.2 to +10.1 letters) and improved anatomic outcomes, with the PRN groups requiring approximately 4 fewer injections (6.9-7.7) than the monthly groups (11.2-11.3). No new safety events were observed despite a 4-fold dose escalation in the study. The pHase III, double-masked, multicenter, randomized, Active treatment-controlled study of the efficacy and safety of 0.5 mg and 2.0 mg Ranibizumab administered monthly or on an as-needed Basis (PRN) in patients with subfoveal neOvasculaR age-related macular degeneration (HARBOR) study confirmed that ranibizumab 0.5 mg dosed monthly provides optimum results in patients with wet AMD. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.
    Ophthalmology 01/2013; · 5.56 Impact Factor
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    ABSTRACT: OBJECTIVE: Central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO) causes hypoperfusion, high levels of vascular endothelial growth factor (VEGF), macular edema, and loss of vision. Many patients also show areas of complete closure of retinal vessels (retinal nonperfusion [RNP]) that increase over time. The objective was to assess the effect of blocking VEGF on progression of RNP. DESIGN: Retrospective analysis of prospectively collected data from 2 randomized, sham injection-controlled, double-masked, multicenter clinical trials. PARTICIPANTS: A total of 392 and 397 patients with macular edema due to CRVO or BRVO. METHODS: An independent reading center measured the area of RNP on fluorescein angiograms (FAs) in 2 phase III trials investigating the effect of ranibizumab (RBZ; Lucentis; Genentech, Inc, South San Francisco, CA) in patients with CRVO or BRVO. MAIN OUTCOME MEASURES: The percentage of patients with no posterior RNP at months 0, 3, 6, 9, and 12. RESULTS: There was no difference among treatment groups at baseline, but at the month 6 primary end point the percentage of patients with CRVO and no RNP was significantly greater in the RBZ groups (0.3 mg, 82.0%, P = 0.0092; 0.5 mg, 84.0%, P = 0.0067) versus the sham group (67.0%). Reperfusion of nonperfused retina was rare (1%) in sham-treated patients with CRVO, but occurred in 6% to 8% of patients with CRVO treated with RBZ (30% of those who had RNP and could improve). Results in patients with BRVO mirrored those in patients with CRVO. Crossover to 0.5 mg RBZ from sham at month 6 halted the progression of RNP and resulted in improvement in both CRVO and BRVO. CONCLUSIONS: Treatment with RBZ did not worsen RNP in patients with RVO, but rather reduced its occurrence compared with sham. These data provide an important new insight regarding the pathogenesis of RVO; the initial vein occlusion is a precipitating event that causes baseline ischemia and release of VEGF, which then contributes to progression of RNP and thus worsening of ischemia. Timely, aggressive blockade of VEGF prevents the worsening of RNP, promotes reperfusion, and eliminates a positive feedback loop. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.
    Ophthalmology 12/2012; · 5.56 Impact Factor
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    ABSTRACT: : To analyze cerebrovascular accidents (CVAs) pooled from large, randomized, controlled clinical trials of ranibizumab treatment for neovascular age-related macular degeneration. : Events in five trials (FOCUS, MARINA, ANCHOR, PIER, and SAILOR) were analyzed using a standard safety monitoring process. Exact methods, stratified by study, were used to test for treatment differences based on odds ratios. A stepwise logistic regression model was fit to classify subjects' risk for CVA based on medical history. Treatment differences in CVA rates at 1 year or 2 years were evaluated within risk groups using stratified exact methods. : Pooled 2-year CVA rates were <3%; odds ratios (95% confidence intervals) for CVA risk were 1.2 (0.4-4.4) for ranibizumab 0.3-mg versus control, 2.2 (0.8-7.1) for 0.5 mg versus control, and 1.5 (0.8-3.0) for 0.5-mg versus 0.3-mg ranibizumab. No substantial increased risk of CVA for 0.5 mg versus 0.3 mg was identified in pooled analyses or any of the individual trials. In pooled analyses, the difference between 0.5-mg ranibizumab and control was larger (7.7 [1.2-177]) among high-risk CVA patients. : This analysis provided some evidence, although not definitive, of a potential increased risk of CVA with ranibizumab versus control or with 0.5-mg versus 0.3-mg ranibizumab. Continued monitoring for CVA within clinical trials seems warrented.
    Retina (Philadelphia, Pa.) 10/2012; 32(9):1821-8. · 2.93 Impact Factor
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    ABSTRACT: To examine the impact of intravitreal ranibizumab on patient-reported visual function using the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) through 6 months in patients with macular edema (ME) secondary to branch or central retinal vein occlusion (RVO). Two multicenter, double-masked trials, which enrolled participants with ME secondary to branch or central RVO: the RanibizumaB for the Treatment of Macular Edema following BRAnch Retinal Vein Occlusion: Evaluation of Efficacy and Safety (BRAVO) trial or the Central Retinal Vein OcclUsIon Study: Evaluation of Efficacy and Safety (CRUISE) trial. Three hundred ninety-seven BRAVO and 392 CRUISE patients. Patients were randomized 1:1:1 to monthly sham, 0.3-mg, or 0.5-mg injections of ranibizumab for 6 months. Although visual acuity was the main outcome measure for the trials, mean change from baseline in NEI VFQ-25 scores at month 6 was a secondary outcome measure. In BRAVO, among the 132, 134, and 131 patients randomized, respectively, to sham, 0.3 mg ranibizumab, or 0.5 mg ranibizumab, the study eye was the worse-seeing eye in 121 (91.7%), 118 (88.1%), and 125 (95.4%) patients and 123 (93.2%), 128 (95.5%), and 125 (95.4%), respectively, had a 6-month follow-up visit. In CRUISE, among the 130, 132, and 130 patients randomized, respectively, to sham, 0.3 mg ranibizumab, and 0.5 mg ranibizumab, the study eye was the worse-seeing eye in 117 (90.0%), 123 (93.2%), and 120 (92.3%) patients and 115 (88.5%), 129 (97.7%), and 119 (91.5%), respectively, had a 6-month follow-up visit. In both trials, patients treated with ranibizumab reported greater mean improvements in visual function, with substantial differences observed as early as month 1, including the NEI VFQ-25 composite score and near and distance activities subscales, compared with sham patients. P values for comparisons with sham for the composite score and these 2 subscales were <0.05. These results from the BRAVO and CRUISE trials indicate that patients with ME from RVOs treated with monthly ranibizumab report greater improvements in vision-related function compared with sham-treated patients through 6 months, even when a majority of patients present with RVOs in the worse-seeing eye. Proprietary or commercial disclosure may be found after the references.
    Ophthalmology 07/2012; 119(10):2108-18. · 5.56 Impact Factor
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    ABSTRACT: 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.
    Ophthalmology 02/2012; 119(4):789-801. · 5.56 Impact Factor
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    ABSTRACT: To assess long-term safety and efficacy of intraocular ranibizumab injections in patients with macular edema after retinal vein occlusion (RVO). Open-label extension trial of the 12-month Ranibizumab for the Treatment of Macular Edema following Branch Retinal Vein Occlusion: Evaluation of Efficacy and Safety (BRAVO) and Central Retinal Vein Occlusion Study: Evaluation of Efficacy and Safety (CRUISE) trials. We included 304 patients who completed BRAVO and 304 patients who completed CRUISE. Patients were seen at least every 3 months and given an intraocular injection of 0.5 mg ranibizumab if they met prespecified retreatment criteria. Primary outcomes were incidence and severity of ocular and nonocular adverse events (AEs). Key efficacy outcomes included mean change from baseline best-corrected visual acuity (BCVA) letter score by Early Treatment Diabetic Retinopathy Study protocol and central foveal thickness. In patients who completed month 12, the mean number of injections (excluding month 12 injection) in the sham/0.5-, 0.3/0.5-, and 0.5-mg groups was 2.0, 2.4, and 2.1 (branch RVO) and 2.9, 3.8, and 3.5 (central RVO), respectively. The incidence of study eye ocular serious AEs (SAEs) and SAEs potentially related to systemic vascular endothelial growth factor inhibition across treatment arms was 2% to 9% and 1% to 6%, respectively. The mean change from baseline BCVA letter score at month 12 in branch RVO patients was 0.9 (sham/0.5 mg), -2.3 (0.3/0.5 mg), and -0.7 (0.5 mg), respectively. The mean change from baseline BCVA at month 12 in central RVO patients was -4.2 (sham/0.5 mg), -5.2 (0.3/0.5 mg), and -4.1 (0.5 mg), respectively. No new safety events were identified with long-term use of ranibizumab; rates of SAEs potentially related to treatment were consistent with prior ranibizumab trials. Reduced follow-up and fewer ranibizumab injections in the second year of treatment were associated with a decline in vision in central RVO patients, but vision in branch RVO patients remained stable. Results suggest that during the second year of ranibizumab treatment of RVO patients, follow-up and injections should be individualized and, on average, central RVO patients may require more frequent follow-up than every 3 months.
    Ophthalmology 01/2012; 119(4):802-9. · 5.56 Impact Factor
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    ABSTRACT: Assess the 12-month 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. We included 392 patients with macular edema after CRVO. Eligible patients were randomized 1:1:1 to receive 6 monthly intraocular injections of 0.3 mg or 0.5 mg of ranibizumab or sham injections. After 6 months, all patients with BCVA ≤20/40 or central subfield thickness ≥250 μm could receive ranibizumab. Mean change from baseline best-corrected visual acuity (BCVA) letter score at month 12, additional parameters of visual function, central foveal thickness (CFT), and other anatomic changes were assessed. Mean (95% confidence interval) change from baseline BCVA letter score at month 12 was 13.9 (11.2-16.5) and 13.9 (11.5-16.4) in the 0.3 mg and 0.5 mg groups, respectively, and 7.3 (4.5-10.0) in the sham/0.5 mg group (P<0.001 for each ranibizumab group vs. sham/0.5 mg). The percentage of patients who gained ≥15 letters from baseline BCVA at month 12 was 47.0% and 50.8% in the 0.3 mg and 0.5 mg groups, respectively, and 33.1% in the sham/0.5 mg group. On average, there was a marked reduction in CFT after the first as-needed injection of 0.5 mg ranibizumab in the sham/0.5 mg group to the level of the ranibizumab groups, which was sustained through month 12. No new ocular or nonocular safety events were identified. On average, treatment with ranibizumab as needed during months 6 through 11 maintained the visual and anatomic benefits achieved by 6 monthly ranibizumab injections in patients with macular edema after CRVO, with low rates of ocular and nonocular safety events. After sham injections for 6 months, treatment with ranibizumab as needed for 6 months resulted in rapid reduction in CFT in the sham/0.5 mg group to a level similar to that in the 2 ranibizumab treatment groups and an improvement in BCVA, but not to the same level as that in the 2 ranibizumab groups. Intraocular injections of ranibizumab provide an effective treatment for macular edema after CRVO. Proprietary or commercial disclosure may be found after the references.
    Ophthalmology 06/2011; 118(10):2041-9. · 5.56 Impact Factor
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    ABSTRACT: 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.
    Ophthalmology 06/2011; 118(8):1594-602. · 5.56 Impact Factor
  • Ophthalmology 09/2010; 117(9):1860-1. · 5.56 Impact Factor
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    ABSTRACT: To assess efficacy and safety of intraocular injections of 0.3 mg or 0.5 mg ranibizumab in patients with macular edema following branch retinal vein occlusion (BRVO). Prospective, randomized, sham injection-controlled, double-masked, multicenter clinical trial. A total of 397 patients with macular edema following BRVO. Eligible patients were randomized 1:1:1 to receive monthly intraocular injections of 0.3 mg 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 16.6 (14.7-18.5) and 18.3 (16.0-20.6) in the 0.3 mg and 0.5 mg ranibizumab groups and 7.3 (5.1-9.5) 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 55.2% (0.3 mg) and 61.1% (0.5 mg) in the ranibizumab groups and 28.8% in the sham group (P<0.0001 for each ranibizumab group vs sham). At month 6, significantly more ranibizumab-treated patients (0.3 mg, 67.9%; 0.5 mg, 64.9%) had BCVA of > or =20/40 compared with sham patients (41.7%; P<0.0001 for each ranibizumab group vs sham); and CFT had decreased by a mean of 337 microm (0.3 mg) and 345 microm (0.5 mg) in the ranibizumab groups and 158 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 97.0% and 97.6% in 0.3 mg and 0.5 mg groups and 27.9% in the sham group. More patients in the sham group (54.5%) received rescue grid laser compared with the 0.3 mg (18.7%) and 0.5 mg (19.8%) ranibizumab groups. The safety profile was consistent with previous phase III ranibizumab trials, and no new safety events were identified in patients with BRVO. Intraocular injections of 0.3 mg or 0.5 mg ranibizumab provided rapid, effective treatment for macular edema following BRVO with low rates of ocular and nonocular safety events.
    Ophthalmology 06/2010; 117(6):1102-1112.e1. · 5.56 Impact Factor
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    ABSTRACT: 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.
    Ophthalmology 04/2010; 117(6):1124-1133.e1. · 5.56 Impact Factor
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    ABSTRACT: To assess the value of sampling aqueous humor for measurement of potential molecular targets and for pharmacokinetic analysis. Substudy within the context of clinical trials. Forty patients with macular edema caused by central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO), 11 patients with diabetic macular edema (DME), and 8 patients with neovascular age-related macular degeneration (NVAMD). Assays for potential molecular targets were performed on aqueous samples from patients participating in drug studies (CRVO, BRVO, and DME) or patients receiving standard care (NVAMD). Ranibizumab levels were measured in patients with CRVO or BRVO after the first and second injections of ranibizumab. Aqueous levels of vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-1beta, tumor necrosis factor (TNF)-alpha, and ranibizumab. Aqueous levels of VEGF were significantly higher in patients with DME than in patients with CRVO, which were significantly higher than those in patients with BRVO. Patients with NVAMD had aqueous VEGF levels in an intermediate range, significantly higher than those in patients with BRVO. One month after the second injection of ranibizumab, 27 of 39 patients with vein occlusions had no residual edema; mean aqueous levels of IL-6, IL-1beta, and TNF-alpha were not greater in patients with residual edema; this provides a blueprint for definitive studies with larger cohorts. There was no significant difference in aqueous ranibizumab levels 1 month after the first injection of 0.5 mg versus injection of 0.3 mg, but 1 month after the second injection ranibizumab levels were significantly higher in eyes injected with 0.5 mg. There were substantial differences in levels among patients, but levels in the same patient at months 1 and 2 were highly correlated. No significant difference in aqueous ranibizumab levels was detected between phakic and pseudophakic patients who received the same dose. These data suggest that aqueous samples are useful for investigating potential involvement of molecular targets in various disease processes and for pharmacokinetic or pharmacodynamic studies.
    Ophthalmology 09/2009; 116(11):2158-64. · 5.56 Impact Factor
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    ABSTRACT: To evaluate the safety and efficacy of intravitreal ranibizumab in a large population of subjects with neovascular age-related macular degeneration (AMD). Twelve-month randomized (cohort 1) or open-label (cohort 2) multicenter clinical trial. A total of 4300 subjects with angiographically determined subfoveal choroidal neovascularization (CNV) secondary to AMD. Cohort 1 subjects were randomized 1:1 to receive 0.3 mg (n = 1169) or 0.5 mg (n = 1209) intravitreal ranibizumab for 3 monthly loading doses. Dose groups were stratified by AMD treatment history (treatment-naïve vs. previously treated). Cohort 1 subjects were retreated on the basis of optical coherence tomography (OCT) or visual acuity (VA) criteria. Cohort 2 subjects (n = 1922) received an initial intravitreal dose of 0.5 mg ranibizumab and were retreated at physician discretion. Safety was evaluated at all visits. Safety outcomes included the incidence of ocular and nonocular adverse events (AEs) and serious adverse events (SAEs). Efficacy outcomes included changes in best-corrected VA over time. Some 81.7% of cohort 1 subjects and 49.9% of cohort 2 subjects completed the 12-month study. The average total number of ranibizumab injections was 4.9 for cohort 1 and 3.6 for cohort 2. The incidence of vascular and nonvascular deaths during the 12-month study was 0.9% and 0.7% in the cohort 1 0.3 mg group, 0.8% and 1.5% in the cohort 1 0.5 mg group, and 0.7% and 0.9% in cohort 2, respectively. The incidence of death due to unknown cause was 0.1% in both cohort 1 dose groups and cohort 2. The number of vascular deaths and deaths due to unknown cause did not differ across cohorts or dose groups. Stroke rates were 0.7%, 1.2%, and 0.6% in the 0.3 mg and 0.5 mg groups and cohort 2, respectively. At month 12, cohort 1 treatment-naïve subjects had gained an average of 0.5 (0.3 mg) and 2.3 (0.5 mg) VA letters and previously treated subjects had gained 1.7 (0.3 mg) and 2.3 (0.5 mg) VA letters. Intravitreal ranibizumab was safe and well tolerated in a large population of subjects with neovascular AMD. Ranibizumab had a beneficial effect on VA. Future investigations will seek to establish optimal dosing regimens for persons with neovascular AMD. Proprietary or commercial disclosure may be found after the references.
    Ophthalmology 08/2009; 116(9):1731-9. · 5.56 Impact Factor

Publication Stats

692 Citations
104.27 Total Impact Points

Institutions

  • 2013
    • University of California, San Francisco
      • Department of Ophthalmology
      San Francisco, CA, United States
  • 2012
    • University of Southern California
      • Doheny Eye Institute
      Los Angeles, CA, United States
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 2011–2012
    • Johns Hopkins Medicine
      Baltimore, Maryland, United States
  • 2010
    • Johns Hopkins University
      • Wilmer Eye Institute
      Baltimore, Maryland, United States
    • Beverly Hills Cancer Center
      Florida, United States
  • 2009
    • Retina-Vitreous Associates Medical Group
      Los Angeles, California, United States