Multicenter, Prospective, Randomized Study of Dexamethasone Intravitreal Implant in Patients with Center-Involved Diabetic Macular Edema in the Asia-Pacific Region.

PURPOSE: To evaluate the safety and efficacy of dexamethasone intravitreal implant 0.7 mg (DEX) compared with laser photocoagulation in patients with diabetic macular edema (DME). PATIENTS AND METHODS: This Phase 3, multicenter, randomized, efficacy evaluator-masked, parallel-group, 12-month clinical study enrolled adults in China and the Philippines with reduced visual acuity secondary to fovea-involved DME in the study eye. Participants were randomized 1:1 to study eye treatment with laser photocoagulation every 3 months as needed (n = 139) or DEX every 5 months (n = 145). The main efficacy measures were best-corrected visual acuity (BCVA), central retinal thickness (CRT), and leakage area. The primary endpoint was the average change in BCVA from baseline over 12 months (area-under-the-curve method). Preplanned subgroup analyses evaluated outcomes in Chinese patients. RESULTS: Mean average change in BCVA from baseline during the study (letters) was 4.3 with DEX (n = 145) versus 1.4 with laser (n = 127) overall (P = 0.001) and 4.6 with DEX (n = 129) versus 0.6 with laser (n = 113) in Chinese patients (P < 0.001). At Month 12, mean change in CRT from baseline was -209.5 µm with DEX versus -120.3 µm with laser (P < 0.001) and mean change in total leakage area from baseline was -8.367 mm2 with DEX versus -0.637 mm2 with laser (P < 0.001). The most common treatment-emergent adverse events in the DEX group were increased intraocular pressure and cataract. CONCLUSION: DEX administered every 5 months provided significantly greater improvement in BCVA, CRT, and total leakage area compared with laser treatment. DEX demonstrated an acceptable safety profile, consistent with an intraocular corticosteroid, and similar to that reported in completed global registration studies.

Post-marketing surveillance study of the safety of dexamethasone intravitreal implant in patients with retinal vein occlusion or noninfectious posterior segment uveitis.

PURPOSE: To evaluate the long-term safety of dexamethasone intravitreal implant (DEX) in patients treated for macular edema associated with retinal vein occlusion (RVO) or noninfectious posterior segment uveitis (NIPSU) in clinical practice. PATIENTS AND METHODS: Multicenter (102 sites in France, Germany, Spain, UK), prospective, observational, post-authorization safety study in adult patients treated with DEX. Data collected up to 2 years after enrollment included serious adverse events (SAEs) and adverse events of special interest (AESIs; adverse drug reactions that are considered important risks associated with DEX and listed in the European Union Ozurdex Risk Management Plan). RESULTS: Overall, 803 patients (652 RVO, 151 NIPSU) received on-study DEX treatment, and 73.1% completed 24 months of follow-up; 72.6% were DEX-naïve. Median number of on-study injections per treated eye was 2 (range, 1-7); median reinjection interval was 27.1 weeks. Nonocular SAEs affected 9.5% of patients; none were considered DEX-related. Ocular SAEs (most common: cataract progression) occurred in 3.2% of treated eyes. SAEs were similar in eyes stratified by previous DEX use and number of on-study DEX injections (≤2 or >2), in both RVO and NIPSU. The most common AESIs were cataract formation and progression (20.0% and 19.2% of treated phakic eyes, n=551), increased intraocular pressure (19.0% of treated eyes), and vitreous hemorrhage (3.3% of treated eyes). Cataract progression was more frequent in baseline phakic eyes that were previously treated with DEX or received >2 on-study DEX injections. CONCLUSION: The long-term safety profile of DEX was acceptable. No new safety concerns were identified.

Safety and efficacy of dexamethasone intravitreal implant for treatment of macular edema secondary to retinal vein occlusion in Chinese patients: randomized, sham-controlled, multicenter study.

PURPOSE: The purpose of this study was to evaluate the safety and efficacy of dexamethasone intravitreal implant 0.7 mg (DEX) for treatment of macular edema associated with retinal vein occlusion (RVO). METHODS: This study was a six-month, randomized, double-masked, sham-controlled, multicenter, phase 3 clinical trial with a 2-month open-label study extension. Patients with branch or central RVO received DEX (n = 129) or sham procedure (n = 130) in the study eye at baseline; all patients who met re-treatment criteria received DEX at month 6. Efficacy measures included Early Treatment Diabetic Retinopathy Study (ETDRS), best-corrected visual acuity (BCVA), and central retinal thickness (CRT) on optical coherence tomography. RESULTS: Time to ≥15-letter BCVA improvement from baseline during the first 6 months (primary endpoint) was earlier with DEX than sham (p < 0.001). At month 2 (peak effect), the percentage of patients with ≥15-letter BCVA improvement from baseline was DEX: 35%, sham: 12%; mean BCVA change from baseline was DEX: +10.6 letters, sham: +1.7 letters; and mean CRT change from baseline was DEX: -407 µm, sham: -62 µm (all p < 0.001). Outcomes were better with DEX than sham in both branch and central RVO. The most common treatment-emergent adverse event was increased intraocular pressure (IOP). Increases in IOP generally were controlled with topical medication. Mean IOP normalized by month 4, and no patient required incisional glaucoma surgery. CONCLUSIONS: DEX had a favorable safety profile and provided clinically significant benefit in a Chinese patient population with RVO. Visual and anatomic outcomes were improved with DEX relative to sham for 3-4 months after a single implant.

Safety and efficacy of dexamethasone intravitreal implant for treatment of macular edema secondary to retinal vein occlusionin Chinese patients: randomized, sham-controlled, multicenter study / 中华眼底病杂志

Objective To evaluate the safety and efficacy ofdexamethasone intravitreal implant 0.7 mg (DEX) for treatment of macular edema associated with retinal vein occlusion (RVO).Methods This study was a six-month,randomized,double-masked,sham-controlled,multicenter,phase 3 clinical trial with a 2-month open-label study extension.Patients with branch or central RVO received DEX (n=129) or sham procedure (n=130) in the study eye at baseline;all patients who met re-treatment criteria received DEX at month 6.Efficacy measures included Early Treatment Diabetic Retinopathy Study (ETDRS),best-corrected visual acuity (BCVA),and central retinal thickness (CRT) on optical coherence tomography.Results Time to ＞ 15-letter BCVA improvement from baseline during the first 6 months (primary endpoint) was earlier with DEX than sham (P＜ 0.001).At month 2 (peak effect),the percentage of patients with ≥ 15-letter BCVA improvement from baseline was DEX:34.9％,sham:11.5％;mean BCVA change from baseline was DEX:10.6± 10.4 letters,sham:1.7 ± 12.3 letters;and mean CRT change from baseline was DEX:-407 ± 212 μm,sham:-62 ± 224 μm (all P＜0.001).Outcomes were better with DEX than sham in both branch and central RVO.The most common treatment-emergent adverse event was in-creased intraocular pressure (IOP).Increase sin IOP generally were controlled with topical medication.Mean IOP normalized by month 4,and no patient required incisional glaucoma surgery.Conclusions DEX had a favorable safety profile and provided clinically significant benefit in a Chinese patient population with RVO.Visual and anatomic outcomes were improved with DEX relative to sham for 3-4 months after a single implant.

INTRAOCULAR PRESSURE IN PATIENTS WITH DIABETIC MACULAR EDEMA TREATED WITH DEXAMETHASONE INTRAVITREAL IMPLANT IN THE 3-YEAR MEAD STUDY.

PURPOSE: To evaluate the occurrence, management, and clinical significance of increases in intraocular pressure (IOP) in patients with diabetic macular edema treated with dexamethasone intravitreal implant (DEX implant). METHODS: Randomized, multicenter, 3-year, Phase III study. Patients (N = 1,048) with diabetic macular edema were randomized to DEX implant 0.7-mg, DEX implant 0.35-mg, or sham procedure with retreatment allowed at ≥6-month intervals (seven injections maximum). RESULTS: In the DEX implant 0.7-mg, DEX implant 0.35-mg, and sham groups, respectively, ≥10-mmHg IOP increases from baseline occurred in 27.7%, 24.8%, and 3.7% of patients, and their frequency did not increase with repeat injections. IOP-lowering medication was used by 41.5%, 37.6%, and 9.1% of patients. Only one patient (0.3%) in each DEX implant group had filtering surgery to manage a steroid-induced IOP increase. Among DEX implant 0.7-mg-treated patients with and without a ≥10-mmHg IOP increase, 21.9% (21 of 96) and 22.4% (57 of 255), respectively, achieved ≥15-letter best-corrected visual acuity gain at the end of the study, and mean average change in central retinal thickness from baseline was -127 µm and -106 µm, respectively. CONCLUSION: DEX implant demonstrated clear benefit of treatment despite increases in IOP. Sequential implants had no cumulative effect on IOP.

Dexamethasone Intravitreal Implant as Adjunctive Therapy to Ranibizumab in Neovascular Age-Related Macular Degeneration: A Multicenter Randomized Controlled Trial.

PURPOSE: To evaluate the efficacy and safety of dexamethasone intravitreal implant 0.7 mg (DEX) as adjunctive therapy to ranibizumab in neovascular age-related macular degeneration (nvAMD). PROCEDURES: This was a 6-month, single-masked, multicenter study. Patients were randomized to DEX implant (n = 123) or sham procedure (n = 120) and received 2 protocol-mandated intravitreal ranibizumab injections. The main outcome measure was injection-free interval to first as-needed ranibizumab injection. RESULTS: DEX increased the injection-free interval versus sham (50th percentile, 34 vs. 29 days; 75th percentile, 85 vs. 56 days; p = 0.016). 8.3% of DEX versus 2.5% of sham-treated patients did not require rescue ranibizumab (p = 0.048). Visual acuity and retinal thickness outcomes were similar in DEX and sham-treated patients. Only reports of conjunctival hemorrhage (18.2 vs. 8.5%) and intraocular pressure elevation (13.2 vs. 4.2%) were significantly different in the DEX versus the sham treatment groups. CONCLUSION: DEX reduced the need for adjunctive ranibizumab treatment and showed acceptable tolerability in nvAMD patients.

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.

Effects of pioglitazone on intramyocellular fat metabolism in patients with type 2 diabetes mellitus.

CONTEXT: Lipotoxicity (increased tissue fat content) has been implicated in the development of muscle insulin resistance and type 2 diabetes mellitus (T2DM). OBJECTIVE: The aim was to study the effect of pioglitazone on intramyocellular fat metabolism. RESEARCH DESIGN: Twenty-four T2DM subjects (glycosylated hemoglobin = 8.3 +/- 0.4%) participated in three similar study protocols before and after 4 months of 45 mg/d pioglitazone treatment: 1) 3-h euglycemic insulin (80 mU/m(2) . min) clamp with measurement of intramyocellular fat with proton nuclear magnetic resonance; 2) vastus lateralis muscle biopsy for measurement of LC-FACoAs 60 min before start of the insulin clamp; and 3) muscle biopsy for measurement of diacylglycerol 60 min before start of the insulin clamp. RESULTS: In all three protocols, pioglitazone similarly reduced (all P < 0.05) the glycosylated hemoglobin (Delta = 0.8-1.2%), fasting plasma glucose (39-76 mg/dl), fasting free fatty acid (132-236 mumol/liter), and increased insulin-stimulated glucose disposal (by 25-56%). Intramyocellular fat (protocol I) declined from 1.5 to 0.9% (P < 0.05) and correlated with the increase in glucose disposal rate (r = 0.65; P < 0.05). Long chain-fatty acyl-coenzyme A decreased from 12.5 to 8.1 nmol/g (P < 0.05) and correlated with the increase in disposal rate (r = 0.76; P < 0.05). Pioglitazone therapy had no effect on muscle diacylglycerol content. CONCLUSIONS: Pioglitazone improves insulin resistance in T2DM in association with mobilization of fat and toxic lipid metabolites out of muscle.

Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis.

UNLABELLED: Pioglitazone treatment improves insulin resistance (IR), glucose metabolism, hepatic steatosis, and necroinflammation in patients with nonalcoholic steatohepatitis (NASH). Because abnormal lipid metabolism/elevated plasma free fatty acids (FFAs) are important to the pathophysiology of NASH, we examined the impact of pioglitazone therapy on adipose tissue insulin resistance (Adipo-IR) during the treatment of patients with NASH. To this end, we assessed glucose/lipid metabolism in 47 patients with impaired glucose tolerance/type 2 diabetes mellitus and NASH and 20 nondiabetic controls. All individuals underwent a 75-g oral glucose tolerance test (OGTT) in which we measured glucose tolerance, IR, and suppression of plasma FFAs. We also measured Adipo-IR index (fasting, FFAs x insulin), hepatic fat by magnetic resonance spectroscopy, and liver histology (liver biopsy). Patients were randomized (double-blind) to diet plus pioglitazone (45 mg/day) or placebo for 6 months, and all measurements were repeated. We found that patients with NASH had severe Adipo-IR and low adiponectin levels. Fasting FFAs were increased and their suppression during the OGTT was impaired. Adipo-IR was strongly associated with hepatic fat (r= 0.54) and reduced glucose clearance both fasting (r=0.34) and during the OGTT (r=0.40, all P <0.002). Pioglitazone significantly improved glucose tolerance and glucose clearance, steatosis and necroinflammation (all P<0.01-0.001 versus placebo). Fasting/postprandial plasma FFAs decreased to levels of controls with pioglitazone (P<0.02 versus placebo). Adipo-IR decreased by 47% and correlated with the reduction of hepatic fat (r=0.46, P=0.009) and with the reduction in hepatic necroinflammation (r=0.47, P=0.0007). CONCLUSION: Patients with NASH have severe Adipo-IR independent of the degree of obesity. Amelioration of Adipo-IR by pioglitazone is closely related to histological improvement and plays an important role during treatment of patients with NASH.

Gastric electrical stimulation for gastroparesis improves nutritional parameters at short, intermediate, and long-term follow-up.

BACKGROUND: Nutritional depletion, either macronutrient- or micronutrient-related, is common in patients with drug-refractory gastroparesis (GP) for which there is often no effective treatment. We studied a group of 12 patients (4 men, 8 women; mean age, 35.7 years) who had symptoms of GP and were a subset of the Gastric ElectroMechanical Stimulation trial of gastric electrical stimulation. Patients' symptoms were of long duration (7.3 years) and associated with diabetes mellitus (3 patients) or were idiopathic (9 patients) as etiology. METHODS: The patients had permanent gastric electrical stimulation devices surgically implanted after a positive trial of temporary stimulation. Patients had baseline measures of gastrointestinal total symptom score (TSS), laboratory (albumin and related) measures, weight (kg), body mass index, and route of nutrition: oral feeding, enteral tubes, or hyperalimentation, repeated at 3, 6, and 12 months. Intermediate-term follow-up was done at 1 to 2 years, and long-term follow-up was done at 5 years and included gastrointestinal TSS, weekly vomiting frequency score, and nutrition and overall health-related quality-of-life measures. RESULTS: Gastric electrical stimulation was associated with rapid improvement over the short-term in TSS (35.6 at baseline to 16.6 at month 12; p < .05), body weight, body mass index, and serum albumin over the short term with most parameters improving by 3 to 6 months. Intermediate (1 to 2 years) and long-term (5 year) data showed continued improvement in TSS, vomiting frequency (weekly vomiting frequency score 3.9 at baseline to 1.7 at 5 years; p < .01), quality-of-life measures, and maintenance of weight gain. CONCLUSIONS: Gastric electrical stimulation implantation resulted in improvement of nutritional parameters throughout the first 12 months, as nausea and vomiting decreased and oral intake increased. This improvement in nutritional measures is maintained long-term and is associated with improvements in quality of life. Gastric electrical stimulation should be considered as a therapeutic option for any patients with refractory GP and nutritional compromise.