Single Intravitreal Injection Of Ocriplasmin Research Articles

Resolution of outer retinal abnormalities in eyes with vitreomacular traction without macular hole in the OASIS trial

Background/aimsTo describe the clinical impact of external limiting membrane (ELM) disruption, ellipsoid zone (EZ) disruption and subretinal fluid (SRF) seen on optical coherence tomography (OCT) in eyes with vitreomacular traction...

Short-Term Results of Ocriplasmin Versus Prompt Vitrectomy for Macular Hole. Which Performs Better?

In this retrospective study, we compared the anatomical and functional changes in patients with vitreomacular traction associated with macular holes between the following groups: (1) Patients who were treated with a single intravitreal injection of ocriplasmin (the OCRIALONE group); (2) those who failed the ocriplasmin treatment and underwent vitrectomy one month later (the OCRIVIT group); and (3) patients who directly underwent par plana vitrectomy (VITREALONE group). A total of 38 patients, 19 in the OCRIALONE group + OCRIVIT group (seven and 12 patients, respectively) and 19 in the VITREALONE group with focal vitreomacular adhesion associated with macular holes were evaluated with spectral domain optical coherence tomography. Functional examinations included best-corrected visual acuity (BCVA) and microperimetry analysis. Visual function changes were compared between the OCRIALONE group + OCRIVIT group and VITREALONE group up to three months. Furthermore, a subgroup analysis compared the OCRIVIT group and the VITREALONE group. BCVA values and the mean retinal sensitivity showed statistically significant improvement in all groups (p < 0.001). Specifically, the retinal sensitivity values at the end of the follow-up were significantly higher in the OCRIALONE group + OCRIVIT group than in the VITREALONE group. These functional findings were also confirmed when the statistical analysis was conducted between the OCRIVIT group and the VITREALONE group. Although the OCRIALONE group + OCRIVIT group exhibited faster retinal thinning than the VITREALONE group (p = 0.006), the analysis of the OCRIVIT group versus the VITREALONE group did not show any statistically significant difference. The better functional results and similar anatomical findings suggest that ocriplasmin can be used as a first-line treatment, and that prompt pars plana vitrectomy as primary surgery does not provide better outcomes in comparison with pars plana vitrectomy after ocriplasmin injection.

Longitudinal ellipsoid zone and subretinal fluid mapping following ocriplasmin injection in the prospective observational ORBIT trial

BackgroundOcriplasmin is approved for the treatment of symptomatic vitreomacular traction (VMT). However, several retrospective reports have identified ellipsoid zone (EZ) alterations on spectral domain optical coherence tomography (SDOCT) after ocriplasmin...

Flare changes after intravitreal injection of ocriplasmin in symptomatic vitreomacular traction syndrome.

To evaluate the changes in anterior chamber flare after a single intravitreal injection of ocriplasmin (125μg), in patients with symptomatic vitreomacular traction syndrome (VMT). An institutional review board-approved single-center not randomized prospective study. Fifteen eyes of fifteen patients (9 women, 6 men) underwent intravitreal injection with ocriplasmin for symptomatic VMT (width of attachment ≤ 1500μm). Anterior segment flare was measured with a laser flare meter (Kowa) before intravitreal injection and 1day, 1week, 1month after injection. The changes in flare were analyzed; the resolution of VMT was evaluated with spectral-domain OCT. The mean anterior chamber flare was 10.5 ± 1.9 photons per millisecond (photons/ms) before the injection. After 1day it increased to 13.6 ± 2.7 photons/ms (p = 0.027) and after 1week to 14.4 ± 2.5 photons/ms (p = 0.005); after 1month it decreased to 12.3 ± 2.3 photons/ms (p = 0.123). At 1day and 1week after injection, mean anterior chamber flare of fellow eyes was significantly lower than study eyes, while at 1month this difference was not significant (12.3 ± 2.3 vs. 10.5 ± 1.8 photons/ms, p = 0.124, for study and fellow eyes). There was no statistically significant difference in the changes in flare between women and men or between phakic (N = 10) and pseudophakic (N = 5) eyes. No eye demonstrated intraretinal damage at any time-point. Also, 9 eyes showed resolution of VMT while 6 eyes demonstrated persistence of VMT. Our study shows that intravitreal injection of ocriplasmin can be a safe and effective approach to treat symptomatic VMT syndrome in selected patients.

ASSESSMENT OF ANATOMICAL AND FUNCTIONAL OUTCOMES WITH OCRIPLASMIN TREATMENT IN PATIENTS WITH VITREOMACULAR TRACTION WITH OR WITHOUT MACULAR HOLES

To evaluate the anatomical and functional outcomes with ocriplasmin in patients with vitreomacular traction (VMT) with or without macular hole (MH). In a Phase 4, multicenter, single-arm, open-label study, eligible patients (VMT with focal adhesion, without epiretinal membrane, and with MH ≤400 µm [if present]) received a single intravitreal injection of ocriplasmin. Nonsurgical resolution of VMT (Day 28 [primary endpoint]), best-corrected visual acuity, MH closure, vitrectomy rate, and safety were assessed through Day 180. Overall, 466 patients were included in the full analysis set, of whom 47.4% had VMT resolution by Day 28; resolution rates in patients with VMT without MH, VMT with MH ≤250 µm, and VMT with MH >250 to ≤400 µm were 43.4%, 68.6%, and 62.7%, respectively. Macular hole closure was higher in eyes with VMT and MH ≤250 µm (57.1%) than in eyes with VMT and MH >250 to ≤400 µm (27.5%) at Day 28. Overall, 30.8% of patients with VMT resolution gained ≥10 letters in best-corrected visual acuity at Day 180. Adverse events were consistent with the known safety profile of ocriplasmin. Ocriplasmin is effective for resolution of VMT without or with MH (≤400 μm); treatment outcomes can be optimized with patient selection.

Subfoveal Lucency after Treatment of Vitreomacular Traction without Macular Hole in the Phase 3 Trials of Ocriplasmin Vitreolysis

To describe the clinical impact of subfoveal lucency (SFL) seen on OCT before and after treatment of vitreomacular traction (VMT) or symptomatic vitreomacular adhesion (VMA) without macular hole (MH) in the prospective phase 3 trials of ocriplasmin vitreolysis. Randomized double-blind placebo-controlled multicenter study. Four hundred ninety-nine eyes with VMT or VMA without MH. Eyes were randomized to either a single intravitreal injection of ocriplasmin or placebo treatment and were followed up for 6 months. Eyes were analyzed for presence, dimensions, and course of SFL on OCT, release of VMT, and their effect on visual acuity (VA). Among eyes without baseline SFL, new SFL was more frequent after ocriplasmin than placebo at week 1 (23.1% vs. 6.54%; P= 0.0002) and week 2 (19.7% vs. 3.85%; P= 0.0001), but was similar in frequency by week 4 (8.37% vs. 7.69%; P= 0.83). Six-month VA for eyes demonstrating SFL after ocriplasmin during the first 2 weeks was comparable with those without SFL at any point in the study (P= 0.12). In placebo-treated eyes but not ocriplasmin-treated eyes, SFL was associated with worse VA at all visits. The increase in SFL width from baseline to week 2 was significantly greater with ocriplasmin than placebo (P= 0.029). Among ocriplasmin-treated eyes at month 6, those with SFL and VMT release had better VA than those with SFL and persistent adhesion (P= 0.037) and similar VA to those with persistent adhesion without SFL (P= 0.17). In the placebo group, those with baseline SFL showed low rates of spontaneous VMT release at month 6 compared with those without baseline SFL (3/21 eyes vs. 33/99 eyes; P= 0.045). Compared with placebo, SFL occurred more frequently only in the initial weeks after treatment with ocriplasmin. When SFL developed after ocriplasmin administration, VA was not impacted at the 6-month visit. Persistent SFL in ocriplasmin-treated eyes at month 6 was associated with poorer vision if VMT had not released. Eyes with SFL at baseline had low rates of spontaneous VMT release and may need treatment.

Six months follow up of a single intravitreal injection of ocriplasmin for symptomatic vitreomacular adhesion

Purpose: To evaluate the efficacy and the safety of the enzymatic vitreolysis with a single intravitreal injection of ocriplasmin 125μg across a group of patients with symptomatic vitreomacular adhesion (sVMA) during 6 months follow up.Design: A randomized, placebo-controlled, double-masked, 6-month follow up study.Participants: A total of 28 patients (12 M / 16F) (19 receiving ocriplasmin; 9 receiving placebo), mean aged 71 years old,diagnosed with sVMA, VMT, FTMH e ERM by optical coherence tomography.Methods: A single intravitreal injection of ocriplasmin 125 μg or placebo. Primary endpoint was sVMA resolution or FTMHclosure. Secondary endpoint included the integrity of the external membrane and the inner and outer segments of the photoreceptorinterface using OCT. The evaluation was carried out at baseline and during 6 months after intravitreal injection of ocriplasmin orplacebo.Results: After a 6 months follow-up period, the rate of VMA resolution was 42.1% in the Ocriplasmin group vs the 22% in theplacebo group. FTMH closure rate was 50% in the Ocriplasmin group vs 0% in the placebo group. The best results were optainedwithin 28 days from the treatment. No case of uveitis, endophthalmitis, retinal tears, retinal detachment or bleeding during followupwere reported. One patient reported floaters and transitional photopsias.Conclusions: The study confirmed the efficacy and safety of Ocriplasmin injection for patients with VMT, including whenassociated with full-thickness macular holes during six months follow up. Long term studies are certainly needed to confirm theseresults.

Improved efficacy of ocriplasmin for vitreomacular traction release and transient changes in optic disk morphology.

To determine the efficacy and safety of ocriplasmin for vitreomacular traction (VMT) resolution and to study changes in optic disk and peripapillary region. Retrospective, single-center, observational case series. In 38 eyes with VMT (10 with concomitant full-thickness macular hole), determined by optical coherence tomography, a single intravitreal injection of ocriplasmin was administered. Baseline ocular characteristics included the presence/absence of epiretinal membrane, lens status, and vitreomacular adhesion size. Spectral domain optical coherence tomography and Heidelberg retinal tomography were performed at baseline and follow-up visits. A total of 71.1% of eyes treated with ocriplasmin had VMT resolution, improving to 83.9% after applying MIVI-TRUST selection criteria. A total of 90% of eyes with full-thickness macular hole showed VMT resolution, with 40% of those achieving full-thickness macular hole closure. Subretinal fluid in the macular region was observed in 36.8% of eyes 1 day after injection, and all cleared spontaneously by Day 42. A significant difference was observed in cup/disk area ratio between patients who achieved VMT resolution and patients who did not. Careful patient selection improves ocriplasmin efficacy. Transient optic disk morphology changes such as decreased cup/disk area ratio may occur in patients without VMT resolution.

Pharmacologic vitreolysis with ocriplasmin: rationale for use and therapeutic potential in vitreo-retinal disorders.

With increased knowledge about the origins and pathophysiology of vitreo-retinal disorders—and, in particular, the central role of anomalous posterior vitreous detachment in vitreo-maculopathies—a paradigm shift from surgery to pharmacotherapy is taking place with the development of pharmacologic vitreolysis. The first approved agent for pharmacologic vitreolysis therapy is ocriplasmin, a truncated form of the nonspecific serine protease plasmin. Twelve studies comprise the current ocriplasmin clinical trial program, demonstrating the efficacy and safety of a single intravitreal injection of ocriplasmin for the treatment of patients with symptomatic vitreo-macular adhesion or vitreo-macular traction, including patients with macular holes. Although post-approval implementation of ocriplamsin in clinical practice has shown success rates of up to 78%, there have been recent case reports of acute, transient visual dysfunction. There are thus new initiatives to further refine clinical indications for case selection and to identify possible untoward effects. Although more studies are warranted, it appears that ocriplasmin offers a good alternative to surgery. The future lies in pharmacologic vitreolysis, and the future of pharmacologic vitreolysis lies in prevention. Thus, long-term studies are needed to define a role for pharmacologic vitreolysis, in particular with ocriplasmin, in the prevention of progressive diabetic retinopathy and age-related macular degeneration.

Does ocriplasmin affect the RPE–photoreceptor adhesion in macular holes?

BackgroundTo evaluate the anatomical outcome of patients after vitrectomy due to persisting symptomatic vitreomacular traction (VMT), including full-thickness macular holes (FTMHs) of less than 400 µm, after ocriplasmin treatment.MethodsRetrospective, single...

Efficacy of Intravitreal Ocriplasmin for Treatment of Vitreomacular Adhesion: Subgroup Analyses from Two Randomized Trials

To evaluate the efficacy of a single intravitreal injection of ocriplasmin 125 μg across relevant subpopulations of patients with symptomatic vitreomacular adhesion (VMA)/vitreomacular traction (VMT), including when associated with macular hole. Two multicenter, randomized, placebo-controlled, double-masked, 6-month studies. A total of 652 randomized patients (464 receiving ocriplasmin; 188 receiving placebo). A single intravitreal injection of ocriplasmin 125 μg or placebo in the study eye. Prespecified subgroup analyses were conducted to evaluate the effects on the proportion of patients with nonsurgical resolution of focal VMA at day 28, nonsurgical full-thickness macular hole (FTMH) closure at month 6, and categoric improvement in best-corrected visual acuity (BCVA) at month 6. Resolution of VMA at day 28 was achieved more often in younger patients (<65 years), eyes without epiretinal membrane, eyes with FTMH, phakic eyes, and eyes with a focal VMA ≤ 1500 μm. Eyes with FTMH width ≤ 250 μm were more likely to achieve nonsurgical FTMH closure. Categoric ≥ 2-line and ≥ 3-line improvement in BCVA occurred more often in younger patients (<65 years) and in patients with a lower baseline BCVA (<65 letters). Treatment differences in favor of ocriplasmin were generally observed across each subgroup of subpopulations studied. Subgroup analyses confirmed the positive effect of ocriplasmin across relevant subpopulations.

Safety and Complications of Ocriplasmin

Our ability to examine the vitreoretinal interface has been greatly improved by the invention of spectral-domain optical coherence tomography (OCT). It has allowedearlier andmore accurate diagnosis of abnormalities of vitreomacular adhesion (VMA) that may contribute to vision loss and may benefit fromintervention.While subtle abnormalitiesofVMAmay be observed, symptomatic VMA or that associated with fullthicknessmacularhole (FTMH) requires surgical intervention.1 With improvements in vitreoretinal surgical techniques and better understanding of these conditions, outcomes of surgicalmanagementofVMA-relateddisorders areexcellent.1However, even in thehandsof themost experiencedsurgeon, there are associated surgical risks. There is also expected discomfort to the patient, delay in visual recovery, high cost, and, in cases of surgery for FTMH, postoperative positioning. Furthermore, advanced surgical skills are required for epiretinal membrane or internal limiting membrane peeling. Ocriplasmin (Jetrea) is a recombinant truncated form of human plasminwith amolecularweight of 27.2 kDa. It is a recombinantproteasewithactivity against fibronectinand laminin, which are components of the vitreoretinal interface.2 In 2 phase 3 clinical trials comparing a single intravitreal injection of ocriplasmin (0.125 mg/0.1mL)with aplacebo injection (drug vehicle diluted with saline) inpatientswith symptomaticVMA,where theprimaryendpointwas resolutionofVMAatday28, 26.5%ofocriplasmin-injected eyes had resolution comparedwith 10.1%of placebo-injectedeyes (P < .001).3Nonsurgical closureofmacular holeswas achieved in 40.6%of ocriplasmin-injected eyes, as compared with 10.6% of placebo-injected eyes (P < .001). Consequently, ocriplasminwas approved by the US Food and DrugAdministration (FDA) foruse in symptomaticVMA inOctober 2012. It is notable that ocriplasmin is a first-in-class pharmacologic agent that has been FDA approved to manage symptomatic VMA. Furthermore, the primary end point in the pivotal studieswasbasedonOCTchanges rather thanonvisual acuity improvement, the first time, to my knowledge, that OCT has beenusedas theprimaryoutcomeforaclinical trial inophthalmology. Finally, even when patients do not achieve release of abnormal VMA or closure of FTMH following intravitreal ocriplasmin injection, they can still undergo surgical management.Therefore,ocriplasminofferscliniciansanadditional tool tomanage the anatomical abnormalities of symptomatic VMA in a less invasivemanner thanwith surgery in select cases. However, since the real-worlduseof thedrugbegan, there have been unfavorable anecdotal reports of visual disturbancesafterocriplasmin injection, including transientbutprofound visual decline, raising concerns regarding its safety. While it is not possible to know the frequency of these events in postmarketing surveillance, it is worthwhile to pay attention to safety-related reports. In the report of phase 3 trials of ocriplasmin, ocular adverse events such as vitreous floaters, photopsia, conjunctival hemorrhage, blurred vision, and visual impairment were found to be significantly higher in the treatment group comparedwith theplacebogroup.3However, theauthors state that “most of the adverse events were transient and mild in severity.”3 TheWarnings and Precautions section of the package insert for ocriplasmin4 includesdecreaseof 3ormore lines of best-correctedvisual acuity in 5.6%ofpatients treatedwith ocriplasmin (comparedwith 3.2% in the control group), intravitreal injectionprocedure–associated effects (intraocular inflammation, intraocular hemorrhage, increased intraocular pressure), potential for lens subluxation, retinal breaks, and dyschromatopsia. It states that “dyschromatopsia (generally described as yellowish vision) was reported in 2% of all patients injectedwith Jetrea. In approximatelyhalf of thesedyschromatopsia cases therewerealsoelectroretinographic (ERG) changes reported (aand b-wave amplitude decrease).”4 According to the FDA Advisory Committee briefing document, 9 patients receiving ocriplasmin in various clinical trialswere reportedtohaveexperiencedanacutedecrease invisionwithin 24hours of injection, some to the handmotions level.5 In 8 of 9 patients, vision returned to baseline with a median recovery time of 2 weeks. Dyschromatopsia reportedly resolved within a median time of 3 months. Of the 141 ocriplasmintreatedpatientswhounderwentERGtesting, 11 (7.8%)hadERG changes and 9 of these patients also had dyschromatopsia. Among the 11 patientswithERGchanges, theERGchanges resolved in 6 patients (median time, 6 months), 3 did not have follow-up ERGs, 1 was still undergoing follow-up, and 1 case did not resolve and was thought to be due to concurrent vitelliform dystrophy. Recently, there was a report of a patient with symptomatic VMA, epiretinal membrane, and an impending FTMH who experienced transient vision loss after ocriplasmin injection.6 The patient was found to have disruption of the outer retina, in particular the ellipsoid zone (previously known as the inner segment/outer segment junction), on spectral-domain OCT that partially recovered by 3 weeks along with improvement in visual acuity.6 Two brief reports Related articles pages 484 and 487 Opinion

Baseline characteristics predictive of pharmacologic vitreomacular adhesion resolution in the ocriplasmin MIVI‐TRUST program

AbstractPurpose The ocriplasmin MIVI‐TRUST program included two phase III, multicenter, randomized, double‐masked trials to determine the efficacy and safety of ocriplasmin for the treatment of vitreomacular traction (VMT). We sought to identify baseline characteristics that were predictive of pharmacologic vitreomacular adhesion (VMA) resolution at Day 28 after an injection of ocriplasmin or placebo.Methods Patients with OCT‐confirmed VMA were randomized to receive a single intravitreal injection of ocriplasmin 125 µg (n=464) or placebo (n=188). The primary end point was VMA resolution at 28 days post‐injection. A multivariate regression analysis was performed to determine independent baseline anatomic and non‐anatomic characteristics that were significantly associated with pharmacologic VMA at Day 28.Results Pharmacologic VMA resolution at Day 28 was observed in a significantly larger proportion of patients in the ocriplasmin group (26.5%) compared with placebo (10.1%; p&lt;0.001). Independent baseline anatomic characteristics predictive of VMA resolution included the presence of a full‐thickness macular hole (equivalent to stage II; p=0.019), VMA diameter ≤1500 µm (p&lt;0.001), phakic lens status (p&lt;0.001), and the absence of an epiretinal membrane (p&lt;0.001). Independent non‐anatomic baseline characteristics predictive of VMA resolution included treatment with ocriplasmin (p&lt;0.001) and age &lt;65 years (p&lt;0.001).Conclusion The identification of specific baseline anatomic characteristics predictive of response is informative in the consideration of treatment options for patients with VMT. Commercial interest

Enzymatic Vitreolysis with Ocriplasmin for Vitreomacular Traction and Macular Holes

BackgroundVitreomacular adhesion can lead to pathologic traction and macular hole. The standard treatment for severe, symptomatic vitreomacular adhesion is vitrectomy. Ocriplasmin is a recombinant protease with activity against fibronectin and laminin, components of the vitreoretinal interface.MethodsWe conducted two multicenter, randomized, double-blind, phase 3 clinical trials to compare a single intravitreal injection of ocriplasmin (125 μg) with a placebo injection in patients with symptomatic vitreomacular adhesion. The primary end point was resolution of vitreomacular adhesion at day 28. Secondary end points were total posterior vitreous detachment and nonsurgical closure of a macular hole at 28 days, avoidance of vitrectomy, and change in best-corrected visual acuity.ResultsOverall, 652 eyes were treated: 464 with ocriplasmin and 188 with placebo. Vitreomacular adhesion resolved in 26.5% of ocriplasmin-injected eyes and in 10.1% of placebo-injected eyes (P<0.001). Total posterior vitreous detachment was more prevalent among the eyes treated with ocriplasmin than among those injected with placebo (13.4% vs. 3.7%, P<0.001). Nonsurgical closure of macular holes was achieved in 40.6% of ocriplasmin-injected eyes, as compared with 10.6% of placebo-injected eyes (P<0.001). The best-corrected visual acuity was more likely to improve by a gain of at least three lines on the eye chart with ocriplasmin than with placebo. Ocular adverse events (e.g., vitreous floaters, photopsia, or injection-related eye pain — all self-reported — or conjunctival hemorrhage) occurred in 68.4% of ocriplasmin-injected eyes and in 53.5% of placebo-injected eyes (P<0.001), and the incidence of serious ocular adverse events was similar in the two groups (P=0.26).ConclusionsIntravitreal injection of the vitreolytic agent ocriplasmin resolved vitreomacular traction and closed macular holes in significantly more patients than did injection of placebo and was associated with a higher incidence of ocular adverse events, which were mainly transient. (Funded by ThromboGenics; ClinicalTrials.gov numbers, NCT00781859 and NCT00798317.)