Sunil Patel

Ranibizumab for Diabetic Macular Edema: Results from 2 Phase III Randomized Trials: RISE and RIDE

PURPOSE To evaluate the efficacy and safety of intravitreal ranibizumab in diabetic macular edema (DME) patients. DESIGN Two parallel, methodologically identical, phase III, multicenter, double-masked, sham injection-controlled, randomized studies. PARTICIPANTS 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). INTERVENTION Monthly intravitreal ranibizumab (0.5 or 0.3 mg) or sham injections. Macular laser was available per-protocol-specified criteria. MAIN OUTCOME MEASURES Proportion of patients gaining ≥15 letters in BCVA from baseline at 24 months. RESULTS 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. CONCLUSIONS 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.

Long-term Outcomes of Ranibizumab Therapy for Diabetic Macular Edema: The 36-Month Results from Two Phase III Trials: RISE and RIDE

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.

Dexamethasone Intravitreal Implant For Treatment Of Diabetic Macular Edema In Vitrectomized Patients

Purpose: To evaluate the safety and efficacy of Ozurdex (dexamethasone intravitreal implant) 0.7 mg in the treatment of diabetic macular edema in vitrectomized eyes. Methods: This was a prospective, multicenter, open-label, 26-week study. Fifty-five patients with treatment-resistant diabetic macular edema and a history of previous pars plana vitrectomy in the study eye received a single intravitreal injection of 0.7-mg dexamethasone intravitreal implant. The primary efficacy outcome measure was the change in central retinal thickness from baseline to Week 26 measured by optical coherence tomography. Results: The mean age of patients was 62 years. The mean duration of diabetic macular edema was 43 months. The mean (95% confidence interval) change from baseline central retinal thickness (403 μm) was −156 μm (−190, −122 μm) at Week 8 (P < 0.001) and −39 μm (−65, −13 μm) at Week 26 (P = 0.004). The mean (95% CI) increase in best-corrected visual acuity from baseline (54.5 letters) was 6.0 letters (3.9, 8.1 letters) at Week 8 (P < 0.001) and 3.0 letters (0.1, 6.0 letters) at Week 26 (P = 0.046). At Week 8, 30.4% of patients had gained ≥10 letters in best-corrected visual acuity. Conjunctival hemorrhage, conjunctival hyperemia, eye pain, and increased intraocular pressure were the most common adverse events. Conclusion: Treatment with dexamethasone intravitreal implant led to statistically and clinically significant improvements in both vision and vascular leakage from diabetic macular edema in difficult-to-treat vitrectomized eyes and had an acceptable safety profile.

Cytomegalovirus papillitis in patients with acquired immune deficiency syndrome. Visual prognosis of patients treated with ganciclovir and/or foscarnet.

BACKGROUND Of those patients with acquired immune deficiency syndrome in whom cytomegaloviral retinitis develops, cytomegaloviral papillitis reportedly develops in up to 4% as well. Although occasionally patients have a good visual outcome, the majority have a poor visual prognosis, with a visual acuity of 20/200 or worse, even with treatment. METHODS To evaluate the effects of prolonged induction with foscarnet or ganciclovir on the visual prognosis of cytomegalovirus (CMV) papillitis, the records of 22 patients seen between 1990 and 1995 at the Los Angeles County-University of Southern California Eye Clinic were reviewed. Papillitis was defined as greater than 270 degrees of disc edema/blurring of the disc margins as seen on direct examination and on color fundus photographs. RESULTS Eighteen patients with a mean initial visual acuity of 20/69 (range, 20/ 15-20/400) were treated with induction doses of intravenous ganciclovir (range, 5-7.5 mg/kg twice daily) or foscarnet (range, 60-90 mg/kg twice or 3 times daily) for a mean of 3.3 weeks. The mean follow-up period was 4.8 months (range, 1-13 months). These patients maintained a mean final visual acuity of 20/68 (range, 20/ 25-20/400) with greater than 90% resolution of the papillitis. The remaining four patients had poor outcomes (visual acuity < 20/400) because of progressive CMV papillitis or retinitis. The median survival time was 4.5 months from the diagnosis of papillitis, but 7 months from the onset of CMV ocular infection. CONCLUSION Patients with CMV papillitis have good visual prognosis when managed with high and prolonged doses of intravenous foscarnet and/or ganciclovir.

United States comparative costs and absenteeism of diabetic ophthalmic conditions

Abstract Objective: This retrospective cohort study examined the impact of diabetic macular edema (DME), diabetic retinopathy (DR), or diabetes on annual health benefit costs and absenteeism in US employees. Methods: Claims data from 2001 to 2012 was extracted from the Human Capital Management Services Group Research Reference Database on annual direct/indirect health benefit costs and absences for employees aged ≥ 18 years. Employees with DME, DR, or diabetes were identified by International Classification of Diseases, Ninth Revision, Clinical Modification codes. Employees were divided into two groups, drivers or nondrivers, and examined in separate analyses. For drivers and nondrivers, the DME, DR, and diabetes cohorts were compared with their respective control groups (without diabetes). Two-part regression models controlled for demographics and job-related characteristics. Results: A total of 39,702 driver and 426,549 nondriver employees were identified as having ≥ 1 year’s continuous health plan enrollment. Direct medical costs for drivers with DME, DR, or diabetes were

Oral tyrosine kinase inhibitor for neovascular age-related macular degeneration: A phase 1 dose-escalation study

6470,

Use of the Ganciclovir Implant in the Treatment of Recurrent Cytomegalovirus Retinitis

8021, and

Enhanced Benefit in Diabetic Macular Edema from AKB-9778 Tie2 Activation Combined with Vascular Endothelial Growth Factor Suppression.

5102, respectively (>2.8 times higher and statistically significant compared with driver controls). Nondrivers with DME and DR incurred significantly higher sick leave and short-term disability costs compared with the nondrivers with diabetes and nondriver controls. In drivers with DME, the majority of days of absence were for short- and long-term disability (12.41 and 11.43 days, respectively). In drivers with DR, the majority of days of absence were for short-term disability (10.70 days). In nondrivers with DME and nondrivers with DR, the majority of days of absence were for sick leave (5.74 and 4.93 days, respectively) and short-term disability (5.08 and 4.93 days, respectively). Conclusion: DME and DR are associated with substantial direct medical cost and absenteeism in this real-world sample of medically insured employees. This research highlights the negative impact of DME and DR on annual costs and absenteeism and may assist employers in assessing the impact of these conditions on employees.

A multicenter, 12-month randomized study comparing dexamethasone intravitreal implant with ranibizumab in patients with diabetic macular edema

Importance An oral treatment for neovascular age-related macular degeneration would be less burdensome than repeated intravitreous injections. X-82 is an oral tyrosine kinase inhibitor active against vascular endothelial growth factor (VEGF) and platelet-derived growth factor. Objective To undertake safety testing of oral X-82 administered for the treatment of neovascular AMD. Design, Setting, and Participants Phase 1, open-label, uncontrolled, dose-escalation study at 5 US retinal clinics between November 2012 and March 2015 (Retina-Vitreous Associates Medical Group, Beverly Hills, California; Blanton Eye Institute, Houston Methodist Hospital, Retina Consultants of Houston, Houston, Texas; New England Retina Associates, Guilford, Connecticut; Elman Retina Group, Baltimore, Maryland; and Retina Research Institute of Texas, Abilene). Thirty-five participants with neovascular age-related macular degeneration, 7 of whom were treatment naive. Interventions Participants received oral X-82 for 24 weeks at 50 mg alternate days (n = 3), 50 mg daily (n = 8), 100 mg alternate days (n = 4), 100 mg daily (n = 10), 200 mg daily (n = 7), and 300 mg daily (n = 3), with intravitreous anti-VEGF therapy using predefined retreatment criteria. Every 4 weeks, participants underwent best-corrected visual acuity measurement, fundus examination, and spectral-domain optical coherence tomography. Main Outcomes and Measures The main outcome was adverse events. Other outcomes included visual acuity, central subfield retinal thickness, and number of anti-VEGF injections. Results Of the 35 participants, the mean age was 76.8 years, 16 were men and 19 were women, and 33 were white and 2 were nonwhite. Of 25 participants (71%) who completed the 24 weeks of X-82 treatment, all except 1 maintained or improved their visual acuity (mean [SD], +3.8 [9.6] letters). Fifteen participants (60%) required no anti-VEGF injections (mean, 0.68). Mean [SD] central subfield thickness reduced by −50 [97] &mgr;m, with 8 participants (all receiving at least 100 mg daily) demonstrating sustained reductions despite no anti-VEGF injections. The most common adverse events attributed to X-82 were diarrhea (n = 6), nausea (n = 5), fatigue (n = 5), and transaminase elevation (n = 4). A dose relationship to the transaminase elevations was not identified; all normalized when X-82 was discontinued. All but 1 were asymptomatic. Ten participants withdrew consent or discontinued prematurely, 6 owing to adverse events attributed to X-82 including leg cramps (n = 2), elevated alanine aminotransferase (n = 2), diarrhea (n = 1), and nausea/anorexia (n = 1). Conclusions and Relevance X-82 can be associated with reversible, elevated liver enzymes; hence, liver function testing is needed to identify those unsuited to treatment. Although 17% of participants discontinued X-82 owing to AEs, those who completed the study had lower than expected anti-VEGF injection rates. Further studies appear justified, with a phase 2 randomized clinical study under way.