A, Mean change in NEI VFQ-25 composite and subscale scores (baseline to month 6). B, Patients with at least a 5-point improvement or worsening in NEI VFQ-25 scores (baseline to month 6).
aP < .05 for ocriplasmin vs placebo.
aP < .05 for ocriplasmin-treated VMA responders vs ocriplasmin-treated VMA nonresponders.
eTable. Patient Demographic and Ocular Characteristics at Baseline in the 2 Randomized MIVI-TRUST Phase 3 Trials (Studies 006 and 007)
Varma R, Haller JA, Kaiser PK. Improvement in Patient-Reported Visual Function After Ocriplasmin for Vitreomacular AdhesionResults of the Microplasmin for Intravitreous Injection–Traction Release Without Surgical Treatment (MIVI-TRUST) Trials. JAMA Ophthalmol. 2015;133(9):997-1004. doi:10.1001/jamaophthalmol.2015.1746
The impact of vitreomacular adhesion (VMA) resolution on patient-reported visual function in symptomatic VMA/vitreomacular traction (VMT) has not yet been documented, to our knowledge.
To determine the impact of intravitreal ocriplasmin on patient-reported visual function using the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) during a 6-month follow-up in patients with symptomatic VMA.
Design, Setting, and Participants
Two multicenter, randomized, masked, phase 3 clinical trials (studies TG-MV-006 [between December 2008 and April 2010] and TG-MV-007 [between December 2008 and July 2010]) at clinic-based centers in the United States and Europe. A total of 652 patients with symptomatic VMA/VMT, including when associated with a macular hole 400 μm or smaller, were studied. Analysis was by intent-to-treat population and performed in May 2013.
Patients with symptomatic VMA/VMT were randomly assigned (2:1 or 3:1 in study TG-MV-006 and study TG-MV-007, respectively) to receive a single intravitreal injection of ocriplasmin, 125 μg, or placebo-injected vehicle (placebo). The NEI VFQ-25 was administered at baseline and 6 months following ocriplasmin injection.
Main Outcomes and Measures
Mean changes between baseline and 6-month follow-up NEI VFQ-25 composite and subscale scores and the proportion of patients with a clinically meaningful change (≥5 points) in scores.
Across the 2 studies, 464 patients received ocriplasmin and 188 received placebo. At 6 months, the ocriplasmin group reported greater mean improvements from baseline in the NEI VFQ-25 composite score than the placebo group (mean change, 3.4 vs 0.7, respectively; P = .005). Improvements were also noted in subscale scores, with the following respective mean changes for the ocriplasmin vs placebo groups: vision-related dependency, 1.7 vs −2.1 (P = .009); driving difficulty, 2.7 vs −1.5 (P = .03); distance vision activities, 4.1 vs 0.8 (P = .03); and general vision, 6.1 vs 2.1 (P = .003). A higher proportion of the ocriplasmin group had a clinically meaningful (≥5-point) improvement in NEI VFQ-25 composite score from baseline than the placebo group (36.0% vs 27.2%, respectively; P = .03). Fewer ocriplasmin-treated patients had a clinically meaningful worsening in their visual function than the placebo group (15.0% vs 24.3%, respectively; P = .005). Changes in NEI VFQ-25 composite score and various subscale scores were observed in ocriplasmin-treated patients who achieved VMA resolution at day 28.
Conclusions and Relevance
Ocriplasmin produces clinically meaningful improvement in patient-reported visual function in symptomatic VMA/VMT.
clinicaltrials.gov Identifiers: NCT00781859 and NCT00798317
Physiological posterior vitreous detachment (PVD) develops with aging and is due to simultaneous vitreous liquefaction (synchysis), fibrillar collapse (syneresis), and weakening of vitreoretinal adhesion caused by biochemical alterations in the extracellular matrix.1- 3 If vitreous liquefaction and fibrillar collapse occur without a complete release of the vitreoretinal adhesion, a partial PVD with persistent vitreomacular adhesion (VMA) can result, potentially producing focal traction. With progressive traction, vitreomacular traction (VMT) and associated symptoms such as reductions in visual acuity, metamorphopsia, micropsia, and central visual field defects, along with increased visual disability, may occur.2- 4 To our knowledge, no previous study has documented the impact of symptomatic VMA on self-reported visual function.
Extracellular matrix components such as fibronectin and laminin are thought to mediate the adhesion between the posterior vitreous cortex and the internal limiting lamina of the retina.2,3,5 Ocriplasmin, a recombinant serine protease that hydrolyzes fibronectin and laminin,6,7 was developed to treat symptomatic VMA/VMT.8,9 Ocriplasmin induced complete PVD, with no apparent morphologic damage to the retina, in donor eyes and in vivo.7 Two multicenter, randomized, double-masked, placebo-controlled, phase 3 clinical trials (study TG-MV-006 and study TG-MV-007, hereinafter referred to as studies 006 and 007, part of the Microplasmin for Intravitreous Injection–Traction Release Without Surgical Treatment [MIVI-TRUST] program) were subsequently designed to assess the efficacy and safety of ocriplasmin in patients with symptomatic VMA/VMT, including when associated with macular hole (MH).6 The primary end point of the studies was met with a single intravitreal injection of ocriplasmin being superior to placebo in the proportion of patients having nonsurgical resolution of VMA as verified with optical coherence tomography (OCT) at day 28. In addition, secondary outcomes such as induction of a total PVD, MH closure at day 28, and an improvement in best-corrected visual acuity (BCVA) of 3 or more lines at month 6 (prespecified secondary end points) were also superior with ocriplasmin injection.6
Symptomatic VMA is defined as VMA with an associated reduction in visual acuity and/or visual function. Patients with BCVA measured on an Early Treatment Diabetic Retinopathy Study (ETDRS) chart as 20/25 or worse were eligible to participate in studies 006 and 007.6 However, because metamorphopsia, micropsia, and other symptoms of VMA are not quantifiable on ETDRS charts, another measure was needed to evaluate changes in vision-related function.
The 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) is a validated instrument designed to measure patients’ subjective assessments of their visual function.10
We present analyses from the 2 randomized clinical trials comparing change in patient-reported visual function, as assessed by NEI VFQ-25 composite and subscale scores, in patients receiving ocriplasmin compared with placebo. We also report the change in patient-reported visual function in patients who responded to treatment with ocriplasmin (as demonstrated by nonsurgical resolution of VMA) compared with those who did not respond to ocriplasmin.
The impact of intravitreous ocriplasmin on patient-reported visual function using the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) was assessed in patients with symptomatic vitreomacular adhesion or vitreomacular traction.
At 6 months, ocriplasmin-treated patients reported greater mean improvements from baseline in the NEI VFQ-25 composite score than placebo-treated patients.
At 6 months, the ocriplasmin-treated group had a clinically meaningful (≥5-point) improvement in patient-reported visual function (NEI VFQ-25 composite score) from baseline compared with the placebo-treated group.
These data suggest that ocriplasmin can improve patient-reported visual function in patients with symptomatic vitreomacular adhesion or vitreomacular traction.
Details of the study designs and patient populations for studies 006 and 007 have been published previously.6 Briefly, both studies were multicenter, randomized, double-masked, placebo-controlled, phase 3 clinical trials designed to test the efficacy and safety of a single intravitreal injection of ocriplasmin in patients with symptomatic VMA/VMT, including when associated with MH. Study 006 was performed between December 2008 and April 2010 and study 007 was performed between December 2008 and July 2010. This analysis was performed in May 2013. Eligible patients were aged 18 years or older, had symptoms of central vision loss attributable to focal VMT observed on OCT, and had BCVA on the ETDRS chart of 20/25 or worse in the study eye.6 Patients were randomly assigned to an intravitreal injection of ocriplasmin (125 µg in a 0.10-mL volume) or placebo (0.10 mL of an identically diluted drug vehicle). Assessments, including a complete ophthalmic examination, OCT, and patient-reported visual function, were performed before injection and on days 7, 14, 28, 90, and 180 (month 6) after injection. Investigators were permitted to recommend and perform vitrectomy if the underlying condition deteriorated at any time or had not improved within 4 weeks after the injection or if BCVA worsened by more than 2 lines from baseline.6
The studies were conducted in accordance with the Declaration of Helsinki. Institutional review board or ethics committee approval was obtained at each site, and written informed consent was obtained from all patients before enrollment.6
Patient-reported visual function was assessed at baseline and month 6 using the NEI VFQ-25, which measures dimensions of patient-reported vision-targeted health status that are most important to people with eye disease.10 The NEI VFQ-25 includes 11 subscales and a global composite score. Scoring was based on the NEI VFQ-25 scoring algorithm (August 2000 version), whereby higher scores are indicative of less function (0 indicates the worst possible score; 100, the best possible score). An increase in NEI VFQ-25 score from baseline of at least 5 points was considered a clinically meaningful improvement in patient-reported visual function.11- 13
Statistical analyses were conducted on the intent-to-treat population, which included all randomized patients in studies 006 and 007. Combined analysis was planned and documented prior to unmasking, based on the similarity in design (with the exception of the randomization ratio and region) and data collection of the 2 studies. The appropriateness of the combined analysis was further confirmed when the homogeneity of odds ratios for treatment comparisons from the studies was supported by the Breslow-Day test. The change from baseline in NEI VFQ-25 scores at month 6 was a predetermined secondary end point of studies 006 and 007.6 Mean changes from baseline in NEI VFQ-25 scores at month 6 were compared between patients in the ocriplasmin group vs the placebo group using an analysis of variance model, with treatment, age, sex, race, baseline VFQ-25 score, and study as covariates. Multivariate logistical regression was used to assess treatment and study interaction, further supporting acceptability of combining the 2 studies. Mean changes from baseline in NEI VFQ-25 scores were compared between ocriplasmin-treated patients who met the primary end point and those who did not, using an analysis of variance model with the same covariates as noted earlier. Comparisons were also made between the proportions of patients with at least a 5-point increase (improvement) or decrease (worsening) in NEI VFQ-25 scores in the ocriplasmin vs placebo groups. Analyses were performed to compare the improvements in patient-reported visual function in patients treated with ocriplasmin who did or did not meet the primary end point of studies 006 and 007 (nonsurgical resolution of VMA at day 28 as determined by OCT evaluation at the central reading center).6 These comparisons were performed using a Cochran-Mantel-Haenszel test, with stratification for age group, sex, race, and study.
Of the 652 patients in studies 006 or 007, 464 were randomized to receive an intravitreal ocriplasmin injection and 188 were randomized to receive an intravitreal placebo injection.6 In the pooled data, the worse eye was treated in 355 patients receiving ocriplasmin and 148 receiving placebo (while the better eye was treated in 109 receiving ocriplasmin and 40 receiving placebo). Study treatment interaction was shown to be nonsignificant for various comparisons between studies, including randomized treatment (ocriplasmin vs placebo, P = .06), study (006 vs 007, P = .45), and study-by-treatment interaction (P = .49). Baseline demographic characteristics, disease characteristics, and NEI VFQ-25 scores for the pooled data from studies 006 and 007 are presented in the eTable in the Supplement.6 Of the patients who did not meet the primary end point at day 28, 46 of 169 (27.2%) of those receiving placebo and 57 of 341 (16.7%) of those receiving ocriplasmin treatment underwent vitrectomy by month 6 (odds ratio = 0.56; 95% CI, 0.35-0.89; P = .009). Of the patients who did achieve the primary end point, 4 of 19 (21.1%) of the patients who received placebo and 25 of 123 (20.3%) of the ocriplasmin-treated patients needed vitrectomy by month 6 (odds ratio = 0.98; 95% CI, 0.28-4.49; P = .98). All patients who underwent vitrectomy are included in this analysis.
In all eyes across the 2 studies, mean increases in the NEI VFQ-25 composite score from baseline to the 6-month postinjection follow-up assessment in patients in the ocriplasmin group were significantly greater than those in the placebo group (mean change, 3.4 vs 0.7, respectively; P = .005). Similar results were seen in mean changes for the ocriplasmin-treated patients compared with the placebo group in the following subscale scores: vision-related dependency, 1.7 vs −2.1 (P = .009); driving difficulty, 2.7 vs −1.5 (P = .03); distance vision activities, 4.1 vs 0.8 (P = .03); and general vision, 6.1 vs 2.1 (P = .003) (Figure 1A). A greater proportion of patients treated with ocriplasmin had at least a 5-point increase in the NEI VFQ-25 composite score from baseline at month 6 vs the placebo group (36.0% [95% CI, 31.6%-40.6%] vs 27.2% [95% CI, 21.1%-34.2%], respectively; P = .03), considered clinically meaningful in the NEI VFQ-25 composite score (Figure 1B), or had at least a 10-point improvement (21% vs 13%, respectively; P = .03). Similarly, a lower proportion of patients treated with ocriplasmin had at least a 5-point decrease in the NEI VFQ-25 composite score compared with those in the placebo group (15.0% [95% CI, 11.9%-18.6%] vs 24.3% [95% CI, 18.5%-31.2%], respectively; P = .005). In general, a numerically higher proportion of patients treated with ocriplasmin had at least a 5-point improvement in the NEI VFQ-25 subscale scores from baseline at month 6, and a lower proportion of ocriplasmin-treated patients had at least a 5-point worsening in subscale scores compared with those in the placebo group, with statistically significant changes favoring a greater improvement in disability in the ocriplasmin group evident for both measures in the general vision subscale (Figure 1B).
Resolution of VMA as verified on OCT was observed in 123 ocriplasmin-treated patients (26.5%) and 19 patients receiving placebo (10.1%) at day 28. The mean change from baseline 6 months after injection for ocriplasmin vs placebo for the NEI VFQ-25 subscales was assessed in patients who had success in achieving VMA release (primary end point) compared with those who failed to achieve VMA release (Table 1). The mean improvement in the NEI VFQ-25 composite score at month 6 was significantly higher in ocriplasmin-treated patients who had VMA release compared with ocriplasmin-treated patients who did not have VMA release (5.7 vs 2.6, respectively; P = .003) (Figure 2). In patients receiving placebo, mean improvement in NEI VFQ-25 composite scores at month 6 was not significantly different between the patients who had VMA release and those who did not (−0.2 vs 0.7, respectively; P = .66). Similarly, mean improvements in the NEI VFQ-25 subscale scores (with the exception of the driving difficulty subscale) at month 6 were numerically higher in ocriplasmin-treated patients who had VMA release than in those who did not, with statistically significant improvements observed in 6 of the 11 subscales: vision-related dependency, 4.4 vs 0.8 (P = .03); general vision, 8.4 vs 5.3 (P = .02); vision-related mental health, 8.4 vs 4.5 (P = .03); near activities, 9.1 vs 4.0 (P = .003); ocular pain, 3.8 vs 0.7 (P = .04); and vision-related role function, 10.3 vs 3.1 (P = .001) (Table 1 and Figure 2). Even the ocriplasmin-treated patients without complete VMA release at day 28 had higher numeric improvements in most NEI VFQ-25 subscale scores at 6 months compared with patients treated with placebo.
A total of 82 ocriplasmin-treated patients and 50 placebo-treated patients underwent vitrectomy. The effect of treatment was comparable in vitrectomized and nonvitrectomized study eyes (Table 2).
The NEI VFQ-25 subscale scores were higher in treated patients who had MH closure at study end than in those not achieving MH closure. Furthermore, the effect of placebo on subscale scores was similar in patients achieving MH closure vs those who did not achieve MH closure (Table 3).
Patient-reported outcomes are increasingly being used to determine the value of treatment interventions in medicine and specifically in ophthalmic research. These measures complement clinical end points such as protocol visual acuity. Results from the phase 3 studies reported herein showed that patients with symptomatic VMA/VMT who were treated with a single intravitreal injection of ocriplasmin, 125 µg, had greater improvements in self-reported visual function and were less likely to have experienced worsening function at 6 months compared with patients randomized to the placebo group.
Until recently, the only option for the treatment of patients with VMA/VMT was vitrectomy. Several studies have reported the impact of vitrectomy on visual function due to MHs using the NEI VFQ-25 or the Japanese equivalent of the questionnaire and have demonstrated mean improvements from baseline in composite score at 3 months to 1 year postoperatively ranging from 3.2 to 8.0 points.14- 17 Among 59 patients who underwent pars plana vitrectomy for idiopathic MH, statistically significant improvement in the NEI VFQ-25 composite score was observed at 3 months (P = .03) and 1 year (P < .001) after surgery, with scores of 79.1 and 81.5, respectively, vs the preoperative score of 75.9.14 In another study involving 32 patients, a statistically significant improvement in the NEI VFQ-25 composite score was observed 3 months postoperatively in patients who underwent vitrectomy, gas tamponade, and cataract surgery for MH, with preoperative and postoperative scores of 70.5 and 77.4, respectively (P < .005).15 Similarly, mean improvements in composite score from 71.2 to 79.2 at 3 months postoperatively (P = .02) and from 76.2 to 82.4 at 4 months postoperatively (P = .02) were reported following surgery for MH in other studies.16,17
In the current study of patients with symptomatic VMA/VMT, approximately one-fourth had MHs at baseline and the mean improvement from baseline in the composite score was 3.4 at 6 months following a single injection of ocriplasmin, 125 µg.6 Resolution of VMA occurred in 26.5% of patients treated with ocriplasmin and 10.1% of patients treated with placebo. In the ocriplasmin subgroups, release correlated with greater improvements in patient-reported visual function, with an increase in mean composite score of 5.7 at month 6. This outcome would be expected as VMA release (partial or complete) correlates with improvement in symptoms and therefore improvement in patient-reported visual function. Of the 11 NEI VFQ-25 subscales, patients reported their disability at baseline as being the greatest for the general vision subscale, with a mean score of approximately 63. This score is similar to those reported for other disabling ocular conditions such as cataracts and diabetic retinopathy and is approximately 20 points lower than scores from the reference population tested during validation of the NEI VFQ-25.10 However, lower NEI VFQ-25 general vision subscale scores have been more recently reported for patients with various surgically approachable vitreoretinal disorders, including previtrectomy mean scores between 51 and 59 for patients with MHs.14- 17 That patients in both the ocriplasmin and vitrectomy studies identified the subscale of general vision as being the aspect contributing most to their visual function is consistent with the underlying diagnosis of VMA/VMT where not only reduced central visual acuity but also other symptoms such as metamorphopsia or micropsia contribute to morbidity.15
Statistically significant and clinically meaningful changes in general vision subscale scores favoring the ocriplasmin group over the placebo group were observed consistently at 6 months for all measures assessed (mean changes from baseline and ≥5-point improvement or worsening in scores). During the 6-month follow-up period of the studies, patients treated with ocriplasmin reported a mean increase in the general vision subscale score of 6.1, and ocriplasmin-treated patients with VMA resolution at day 28 reported a mean increase of 8.4. At this time, it is not known whether the full benefits of ocriplasmin were realized within the 6-month period or whether additional improvements increasing the general vision subscale score further toward values expected for the general population would be achieved with longer follow-up. For comparison, increases in the general vision subscale score of between approximately 11 and 13 have been observed in patients with MHs following vitrectomy when followed up for more than 6 months.14,16
Statistically significant improvements in patient-reported visual function were observed in the ocriplasmin group compared with the placebo group across several other subscales of the NEI VFQ-25, including vision-related dependency and distance vision, with additional improvements observed in patients with VMA resolution following ocriplasmin treatment. As with the vitrectomy studies, however, it was not unexpected that improvements in scores with ocriplasmin were not observed across all subscales,14- 17 given that for some NEI VFQ-25 items, most notably color vision and vision-related social function, scores at baseline in the ocriplasmin study were similar to those previously observed in controls with no evidence of underlying eye disease.10,16
In this study, patients reported improvements across several subscales of the NEI VFQ-25 with ocriplasmin treatment in the absence of complete VMA resolution. Thus, partial VMA release was sufficient to improve the traction and its related visual function.
Resolution of VMA following an intravitreal injection of ocriplasmin, 125 µg, was associated with reduced visual disability in patients with symptomatic VMA/VMT, including when associated with MHs of 400 μm or smaller, as evidenced by favorable outcomes in NEI VFQ-25 composite and various subscale scores. In patients in whom VMA resolved, clinically meaningful improvements in patient-reported visual function, in addition to improvements in visual acuity, can be achieved.11,12 These reductions in vision-related disability were achieved without surgery, thereby avoiding the risks, possible complications, expense, and inconvenience of vitrectomy and its subsequent recovery period.
Corresponding Author: Rohit Varma, MD, MPH, Department of Ophthalmology, Keck School of Medicine, University of Southern California, 1450 San Pablo St, Room 4900, Los Angeles, CA 90033 (firstname.lastname@example.org).
Submitted for Publication: May 19, 2014; final revision received March 27, 2015; accepted April 28, 2015.
Published Online: June 11, 2015. doi:10.1001/jamaophthalmol.2015.1746.
Author Contributions: Dr Varma had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: All authors.
Acquisition, analysis, or interpretation of data: Haller, Kaiser.
Drafting of the manuscript: Varma, Kaiser.
Critical revision of the manuscript for important intellectual content: All authors.
Administrative, technical, or material support: Varma, Haller.
Study supervision: All authors.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Varma reported serving as a consultant for Allergan, AqueSys, Genentech, Replenish, and ThromboGenics and receiving financial support from Allergan, Genentech, and ThromboGenics. Dr Haller reported serving as a consultant for Advanced Cell Technology, Genentech, Merck, Regeneron, Second Sight, and ThromboGenics. Dr Kaiser reported serving as a consultant for Alcon, Allegro Ophthalmics, Bausch & Lomb, Bayer, Genentech, Novartis, Regeneron, and ThromboGenics; receiving financial support from Alcon, Novartis, and ThromboGenics; and serving as a speaker for ThromboGenics.
Funding/Support: The analyses included herein and the studies on which the analyses were based were supported by ThromboGenics NV.
Role of the Funder/Sponsor: ThromboGenics NV participated in the design and conduct of the study; analysis and interpretation of the data; and review of the manuscript.
Additional Contributions: Aniz Girach, MD, formerly of ThromboGenics, Leuven, Belgium, assisted in data preparation and assessment. Esmeralda Meunier, MS, ThromboGenics, and Mina Torres, MS, and Farzana Choudhury, MBBS, MPH, University of Southern California Eye Institute, Los Angeles, performed the statistical analysis. Karen Munro, PhD, Quintiles, Reading, England, and Diane Kwiatkoski, PhD, Quintiles, Parsippany, New Jersey, provided medical writing assistance and prepared the first draft for the authors to edit, which was funded by ThromboGenics NV. All received compensation as employees from their listed employers for these contributions. We thank the investigators included in the MIVI-TRUST study group for their contributions to studies 006 and 007.