Calculating the individual probability of successful ocriplasmin treatment in eyes with vitreomacular traction-Validation and refinement of a multivariable prediction model.

PURPOSE: To evaluate a multivariable model predicting the individual probability of successful intravitreal ocriplasmin (IVO) treatment in eyes with vitreomacular traction (VMT). METHODS: Data from three prospective, multicenter IVO studies (OASIS, ORBIT, and INJECT) were pooled. Patients were included if they were treated for a symptomatic VMT without a full-thickness macular hole. A prediction model for VMT resolution using the factors 'age' and 'horizontal VMT diameter' was validated by receiver operating characteristic analysis and according to grouped prediction after calibration. Multivariable regression analysis was performed to check robustness and explore further improvements. RESULTS: Data from 591 eyes was included. In the univariate analysis all key factors (age, gender, VMT diameter, lens status, ERM) significantly correlated to treatment success. The prediction model was robust and clinically applicable to estimate the success rate of IVO treatment (AUC of ROC: 0.70). A refinement of the model was achieved through a calibration process. CONCLUSION: The developed multivariable model using 'horizontal VMT diameter' and 'age' is a valid tool for prediction of VMT resolution upon IVO treatment.

Predicting the individual probability of macular hole closure following intravitreal ocriplasmin injections for vitreomacular traction release using baseline characteristics.

The primary objective was to create and establish a new formula that predicts the individual probability of macular hole closure for eyes with full thickness macular holes (FTMH) accompanied by vitreomacular traction (VMT) which received enzymatic vitreolysis using intravitreally administered ocriplasmin. The secondary objective was to evaluate the forecast reliability of a previously published formula for VMT resolution in VMT-only eyes (OddsIVO-Success = eIntercept × ORyears × ORln(µm); ProbabilityIVO-Success = OddsIVO-Success/(OddsIVO-Success + 1)) on VMT resolution using the current dataset of eyes with FTMH accompanied by VMT. Retrospective analysis of the OASIS, ORBIT, and INJECT-studies. Patients with FTMH and VMT with complete information (n = 213) were included. The effect of gender, age, FTMH diameter, lens status and the presence of epiretinal membranes (ERM) on FTMH closure was assessed using separate univariate logistic regression analyses. With regard to VMT release separate univariate regression analyses were carried out and results were compared with formerly published data of VMT resolution in eyes with VMT only. Overall, 126 eyes (63%) experienced VMT resolution within 28 days. Younger age (p < 0.0001) and VMT diameter (p = 0.041) had a significant impact on VMT release. Overall, 81 eyes (38%) treated with ocriplasmin showed FTMH closure within 28 days. Univariate analysis of the different predictors analyzed revealed that FTMH diameter < 250 µm had a significant impact on treatment success (p = 0.0495). It was not possible to calculate and establish a new multivariate formula that can predict the individual FTMH closure probability for eyes with FTMHs and VMT. However, the results of VMT release prediction in eyes with FTMHs accompanied by VMT matched the prediction of VMT release in eyes with VMT only when using the previously published formula. All in all, predictors for calculating the individual probability of VMT resolution on the one hand and FTMH closure on the other hand are different suggesting diverse pathophysiological mechanisms.

Prognostic Factors Associated with Ocriplasmin Efficacy for the Treatment of Symptomatic Vitreomacular Adhesion and Full-thickness Macular Hole: Analysis from Four Studies.

PURPOSE: To assess the effect of patient baseline characteristics on the efficacy of ocriplasmin treatment for symptomatic vitreomacular adhesion (VMA) with full-thickness macular hole (FTMH) from phase 3/4 studies. METHODS: Patients with symptomatic VMA and FTMH at baseline and receiving ocriplasmin treatment 125 µ g were pooled from the MIVI-TRUST, OASIS, and ORBIT studies. Multivariable logistic regression analysis was used to evaluate whether patient baseline characteristics were predictors of having VMA resolution by Day 28 and FTMH closure by Month 6. RESULTS: Two hundred and seventy-four patients receiving ocriplasmin treatment were assessed. Overall, 22.6% (62/274) of the patients experienced both VMA resolution by Day 28 and non-surgical FTMH closure by Month 6. Patients with FTMH ≤ 250 µm at baseline had a significantly higher success rate compared to those with FTMH > 400 µm (29.9% [41/137] vs 2.2% [1/48]; P = 0.009). In patients with VMA resolution by Day 28, both small FTMH size (P = 0.001) and FTMH width at RPE (P = 0.012) were significantly associated with a higher FTMH closure rate. Patients with VMA resolution had higher rates of FTMH closure. Previously identified baseline predictive factors, including age, lens status, or presence of epiretinal membrane (ERM) were not found to be predictive of both VMA release and FTMH closure. CONCLUSION: The analysis revealed that FMTH ≤ 250 µm was the only factor predictive for achieving both pharmacological VMA resolution by Day 28 and nonsurgical FTMH closure by Month 6; neither lens status or presence of ERM, previously identified baseline characteristics favoring VMA resolution, showed statistically significant predictive power for both outcomes.

OCRIPLASMIN FOR VITREOMACULAR TRACTION IN CLINICAL PRACTICE: The INJECT Study.

PURPOSE: Randomized clinical trials have demonstrated the safety and efficacy of ocriplasmin in patients with vitreomacular traction (VMT), including those with macular hole (MH). The INJECT study prospectively evaluated ocriplasmin in the setting of clinical practice. METHODS: INJECT was a Phase 4, multicenter, prospective observational study. Patients were followed up for 12 months. Assessments included nonsurgical VMT resolution, nonsurgical MH closure, best-corrected visual acuity, occurrence of vitrectomy, and adverse events. RESULTS: The efficacy population (N = 395) received an ocriplasmin injection and had optical coherence tomography-confirmed VMT at baseline. At Day 28, the rate of nonsurgical VMT resolution was 40.7% in the overall group, and the rate of nonsurgical MH closure was 36.0% in the VMT with MH group. At Month 12, the rate of ≥2-line best-corrected visual acuity gain (irrespective of vitrectomy) was 36.8% in the overall group and 59.6% in the VMT with MH group. The percentage of patients who underwent vitrectomy in the study eye was 29.1% in the overall group and 55.6% in the VMT with MH group. Photopsia (9.8%) and vitreous floaters (6.8%) were the most frequent adverse events. CONCLUSION: The INJECT study showed that ocriplasmin is effective in a clinical setting in patients with VMT, with or without MH. No new safety signals were identified from this large and surgeon-selected patient group, although the significant limitations of the study design without an image reading center and scheduled study visit timings should be noted.

Determination of the trypanocidal drug melarsoprol and its conversion products in biological fluids with HPLC-ICPMS/ESMS.

Although melarsoprol, an organoarsenic compound, is widely used for the treatment of trypanosomiasis (human African sleeping sickness), very little is known about its fate in the human body, its active metabolites passing the blood-brain barrier and the mode of action. Previous pharmacological studies based on the determination of melarsoprol by HPLC-UV or by a bioassay method produced different results. We report a HPLC-ICPMS method suitable for determining melarsoprol and its metabolites in biological fluids. The arsenic selective capability of the method allowed the quantitative measurement of melarsoprol and two arsenic-containing conversion products produced when melarsoprol was incubated with human serum and blood. The major product was identified as melarsen [4-[(4,6-diamino-1,3,5-triazin-2-yl)amino]phenyl]arsonic acid by HPLC/electrospray MS, and by accurate mass measurements. Investigations about the stability of melarsoprol in serum showed that within 30 h about 10% of melarsoprol is converted to melarsen. In blood, however, most of the melarsoprol was bound to proteins and only 1% was converted to melarsen after 30 hours. The limit of detection for melarsoprol and its conversion products were in the range of 1 µg AsL(-1) (13 nmol As L(-1)) based on signal to noise ratio of 3 with a 10 µL injection volume allowing direct determination of the compounds in blood and serum (after protein precipitation) at therapeutically realistic concentrations.

Efficacy and tolerability of the fixed combination of brinzolamide 1% and timolol 0.5% in daily practice.

INTRODUCTION: The purpose of this study was to document the efficacy and tolerability of the new fixed-combination (FC) brinzolamide 1%/timolol 0.5% as used in daily practice throughout Germany. METHODS: An open-label, multicenter, observational study of patients was performed that evaluated the transition from prior medication to brinzolamide/timolol FC for the reduction of intraocular pressure (IOP). Ophthalmologists measured IOP at baseline and 4-6 weeks after transition and assessed their satisfaction with brinzolamide/timolol FC. Patients assessed the tolerability of both their previous and new regimens, judged their satisfaction with brinzolamide/timolol, and reported their preference between their previous and new regimens. Patients transitioning from other FC products to brinzolamide/timolol FC were analyzed separately. RESULTS: Data from 14,025 patients from 1161 centers were analyzed. Four to 6 weeks after transition to brinzolamide/timolol, patients experienced a mean IOP decrease of 3.9 ± 4.3 mm Hg (P < 0.0001). All of the predefined patient subgroups (grouped by previous therapy) demonstrated a significant mean IOP reduction following transition to brinzolamide/timolol (P < 0.0001). Patients judged brinzolamide/timolol tolerability more positively than they did their previous therapies (87.2% vs 53.7% favorable assessments) and reported a high satisfaction rating with brinzolamide/timolol (93.4%). Brinzolamide/timolol was preferred over previous therapy at a ratio of almost 9:1. Patients who transitioned from dorzolamide/timolol to brinzolamide/timolol (n = 2937) demonstrated a significant decrease in mean IOP (P < 0.0001), rated brinzolamide/timolol more tolerable than dorzolamide/timolol (88.9% vs 28.9%), and preferred brinzolamide/timolol at a ratio of more than 9:1. Patients who transitioned from brimonidine/timolol (n = 209) demonstrated a significant decrease in mean IOP (P < 0.0001), rated brinzolamide/timolol more tolerable (86.5% vs 32.1%), and preferred brinzolamide/timolol at a ratio of 11.5:1. CONCLUSIONS: The FC brinzolamide 1%/timolol 0.5% produced better IOP control than all previous therapies analyzed and demonstrated favorable tolerability and a high satisfaction rating, resulting in a strong patient preference for brinzolamide/timolol over previous therapies.

Observational study results in glaucoma patients undergoing a regimen replacement to fixed combination travoprost 0.004%/timolol 0.5% in Germany.

With the launch of the fixed combination of travoprost 0.004%/timolol 0.5% (trav/tim) in Germany in May 2006, a noninterventional observational study designed as an open-label, multicenter, 6-week trial was initiated in order to evaluate the efficacy and tolerability of this new drug combination in glaucoma patients. Participants were grouped into categories according to previous drug regimens: those on timolol monotherapy; those on prostaglandin analog (PGA) monotherapy; those on concomitant therapy with a PGA and timolol; and those on fixed combinations. Trav/tim was well accepted by the patients, with 87.9% judging the tolerability of the therapy as good, very good, or excellent. Analysis of intraocular pressure (IOP) measurements showed statistically significant IOP decreases in all four categories examined in our study after regimen substitution with fixed-combination trav/tim. Fixed-combination prostaglandin analog/beta-blocker formulations are an attractive therapeutic option due to their strong IOP-lowering efficacy with once-daily dosing. In this study, glaucoma patients who underwent a regimen modification to fixed-combination trav/tim showed further reductions in IOP, irrespective of which selected monoor multiple therapies had been used previously.