Purpose
To characterize anatomic and visual outcomes in patients with full-thickness macular hole (FTMH) at baseline in ocriplasmin phase 3 clinical trials, focusing on the relationship between resolution of vitreomacular adhesion and FTMH closure.
Design
Two multicenter, randomized, double-masked clinical trials.
Methods
Pharmacologic FTMH closure was one of multiple secondary endpoints. OCT scans were obtained at baseline and at all postinjection visits, and for patients with baseline FTMH, evaluated for FTMH width, vitreomacular adhesion, and epiretinal membrane.
Results
FTMH closure was observed in a greater proportion of ocriplasmin- vs vehicle-injected patients with baseline FTMH width ≤250 μm (58.3% vs 16.0%, P < .001) and >250 to ≤400 μm (36.8% vs 5.3%, P = .009). Among FTMH patients in the ocriplasmin group, ≥2-line visual acuity gains at month 6 were achieved by a greater percentage of those who achieved hole closure at day 28 vs those who did not achieve this outcome (72.1% vs 25.4%).
Conclusions
Ocriplasmin demonstrated efficacy in closure of small and medium FTMH, and in FTMH without epiretinal membrane at baseline. Visual acuity gains occurred more frequently when hole closure was achieved after ocriplasmin treatment compared to when this outcome did not occur. Ocriplasmin treatment is an additional option for the management of patients with FTMH and vitreomacular adhesion.
Incomplete posterior vitreous detachment from the macula (vitreomacular adhesion, VMA) can lead to vitreomacular traction and full-thickness macular hole (FTMH). An FTMH is a continuous lesion that interrupts all retinal layers from the internal limiting membrane to the retinal pigment epithelium, and is characterized according to multiple anatomic features, including but not limited to vitreous anatomy, hole diameter, presence of cystoid parafoveal changes, presence of epiretinal membrane, location of the hole center relative to the foveola, and configuration of the hole edges on the retina surface. Symptoms and signs of FTMH include metamorphopsia, reduced visual acuity, and central scotoma. Untreated FTMH can lead to irreversible retinal damage and vision loss. Delays in treatment can lead to suboptimal outcomes, and early diagnosis is therefore critical for preserving visual function.
Ocriplasmin (Jetrea; ThromboGenics, Leuven, Belgium) is a pharmacologic treatment option for patients with symptomatic VMA. The safety and efficacy of ocriplasmin for symptomatic VMA was demonstrated in 2 phase 3 clinical trials (the Microplasmin for Intravitreous Injection–Traction Release without Surgical Treatment, or MIVI-TRUST, trials). Ocriplasmin has proteolytic activity that degrades extracellular matrix components of the vitreous body and the vitreomacular interface, including collagen, laminin, and fibronectin. This activity is thought to induce vitreous liquefaction and separation of the vitreous cortex from the inner retina. Ocriplasmin achieved the primary efficacy endpoint in the phase 3 trials: pharmacologic VMA resolution at day 28 after injection. Several secondary efficacy endpoints were also met, including pharmacologic closure of FTMH at day 28 after injection.
The current analysis evaluates anatomic and visual outcomes in the subgroup of patients with VMA and concomitant FTMH in the ocriplasmin phase 3 clinical trials. This analysis will identify factors affecting FTMH closure and help define future treatment strategies.
Methods
The efficacy and safety of ocriplasmin for the treatment of symptomatic VMA was demonstrated in 2 pivotal phase 3 randomized, double-masked, vehicle-controlled trials. The trials are registered in the US National Institutes of Health clinicaltrials.gov database ( NCT00781859 and NCT00798317 ). Study design, Institutional Review Board approval, and Informed Consent approval were previously reported. Enrolled patients were analyzed by time-domain optical coherence tomography (TD-OCT) at a central reading center (CRC) to confirm the presence of VMA. The eligibility of the patients was assessed by the study investigators; however, assessment of the images was also performed independently by the central reading center. The CRC measurements are standardized across all sites and patients, and for statistical analysis those measurements were used. In some instances, measurements made by the investigator on site differed from the measurement by the CRC.
A total of 652 patients were treated with a single intravitreal injection of ocriplasmin 125 μg (n = 464) or vehicle (n = 188). A post hoc analysis was performed to evaluate visual and anatomic outcomes after ocriplasmin injection in patients from the phase 3 trials who had symptomatic VMA with FTMH at baseline (106 in the ocriplasmin group and 47 in the vehicle group). Visual acuity was measured as Early Treatment Diabetic Retinopathy Study (ETDRS) letters. OCT scans were analyzed from baseline and all postinjection visits through the end of the study. Macular hole diameter was defined as the shortest linear distance between the edges of the hole using a line parallel to the retinal pigment epithelium. The shortest linear distance was chosen based on previous work that analyzed and defined success for macular hole closure based on a size determined from the shortest distance across the full-thickness defect. The measurement was based on 6 radial scans as defined in the clinical study protocol commonly used for Stratus OCT. Ocular features derived from OCT imaging included FTMH diameter, VMA resolution status, and epiretinal membrane presence.
Summary statistics for continuous variables included number of observations (n), mean, standard deviation (SD), median, minimum, and maximum. Categorical variables were summarized using group counts and percentages for each category. Results of statistical testing included values for each treatment, crude and stratified differences between treatments (categorical variables only), and 2-sided 95% confidence interval (CI) and P values. For categorical endpoints, differences between treatments were evaluated using the Cochran-Mantel-Haenszel test, stratified by study (integrated studies). For continuous endpoints, differences between treatments were evaluated using analysis of variance (ANOVA) with factor for study in the integrated analysis.
Results
Baseline Ocular Characteristics Among Patients With Full-Thickness Macular Hole at Baseline
The mean FTMH diameter from patients enrolled in the phase 3 trials who presented with an FTMH at baseline was 282.7 μm and 247.0 μm in the ocriplasmin-treated and vehicle-treated groups, respectively ( Table ). Out of a total of 153 patients who presented with FTMH, 73 (48%) presented with a small FTMH (diameter ≤250 μm, 48 of 106 [45.3%] in the ocriplasmin group and 25 of 47 [53.2%] in the vehicle group). Although large FTMH (diameter >400 μm) was an exclusion criterion, 19 of 106 (17.9%) patients in the ocriplasmin group and 3 of 47 (6.4%) patients in the vehicle group had large FTMH at baseline ( Table ). These 22 patients were ultimately included in the analysis population.
| Baseline OCT Characteristic | Vehicle a (N = 47) | Ocriplasmin a (N = 106) |
|---|---|---|
| Mean FTMH diameter (μm) | 247.0 | 282.7 |
| FTMH diameter ≤250 μm, n (%) | 25 (53.2) | 48 (45.3) |
| FTMH diameter >250 to ≤400 μm, n (%) | 19 (40.4) | 38 (35.8) |
| FTMH diameter >400 μm, n (%) | 3 (6.4) | 19 (17.9) |
| Presence of epiretinal membrane, n (%) | 5 (10.9) | 18 (18.0) |
a One patient in the ocriplasmin group did not have an FTMH diameter measurement at baseline. One patient in the vehicle group and 6 patients in the ocriplasmin group were not evaluable for epiretinal membrane status at baseline.
Overall Rates of Full-Thickness Macular Hole Closure
After injection, 43 of 106 (40.6%) patients in the ocriplasmin group and 5 of 47 (10.6%) patients in the vehicle group achieved FTMH closure by day 28 ( P < .001). The proportion of patients with FTMH closure at month 6 was 40.6% in the ocriplasmin group and 17.0% in the vehicle group ( P = .004).
Full-Thickness Macular Hole Closure by Hole Size at Baseline
The rate of FTMH closure at day 28 was determined in subgroups of patients by the FTMH diameter at baseline. The prespecified analysis plan was to evaluate hole closure rates in holes with diameter ≤250 μm and >250 μm. An additional post hoc analysis was done to include the subgroup of patients who presented with holes with diameter >250 to ≤400 μm. The following subgroups showed differential responses to ocriplasmin treatment compared to vehicle treatment: the small FTMH subgroup (58.3% vs 16.0%, P < .001) and the medium FTMH subgroup (diameter >250 to ≤400 μm, 36.8% vs 5.3%, P = .009) ( Figure 1 ). The study subgroup of >250 μm showed a rate of FTMH closure of 24.6% in the ocriplasmin group vs 4.5% in the placebo group ( P = .031). No large (>400 μm) FTMH patients achieved hole closure with either ocriplasmin or vehicle treatment.
Full-Thickness Macular Hole Closure by Epiretinal Membrane Status at Baseline
Patients with FTMH at baseline were evaluated for the rate of FTMH closure by baseline epiretinal membrane status. A total of 23 patients were determined to have epiretinal membrane at baseline, with 18 of 100 (18.0%) patients in the ocriplasmin group and 5 of 46 (10.9%) patients in the vehicle group (6 patients in the ocriplasmin group and 1 patient in the vehicle group that were not evaluable for epiretinal membrane status were excluded from the analysis) ( Table ). For patients with epiretinal membrane at baseline and treated with ocriplasmin, 7 of 18 (38.9%) patients achieved FTMH closure by month 6 (end of study), compared to 1 of 5 (20.0%) in the vehicle group ( P = .463). For patients without epiretinal membrane at baseline and treated with ocriplasmin, 34 of 82 (41.5%) patients achieved FTMH closure, compared to 6 of 41 (14.6%) in the vehicle group ( P = .002) ( Figure 2 ).
Eyes With Pharmacologic Vitreomacular Adhesion Resolution and Full-Thickness Macular Hole Closure
Another clinical consideration is the relationship between VMA resolution and FTMH closure. For ocriplasmin-treated patients who achieved FTMH closure at month 6, 24 of 43 (55.8%) patients also achieved VMA resolution at day 28, whereas 19 (44.2%) did not ( Figure 3 ).
Hole Reopening After Full-Thickness Macular Hole Closure
The proportion of patients with FTMH reopening after FTMH closure was low: 4 of 43 (9.3%) patients in the ocriplasmin group and 0 of 8 (0.0%) patients in the vehicle group at month 6.
Visual Acuity Outcomes
Success in achieving FTMH closure was strongly associated with visual acuity improvement. For FTMH patients treated with ocriplasmin who achieved hole closure at day 28, 31 of 43 (72.1%) patients gained at least 2 lines at month 6, and 21 of 43 (48.8%) gained at least 3 lines at month 6. Interestingly, some FTMH patients without hole closure at day 28 also showed improvement in visual acuity: 16 of 63 (25.4%) ocriplasmin-treated patients gained at least 2 lines and 8 of 63 (12.7%) ocriplasmin-treated patients gained at least 3 lines at month 6. In FTMH patients with vehicle injection who achieved hole closure at day 28, 2 of 5 (40.0%) patients gained at least 2 lines and 2 of 5 (40.0%) gained at least 3 lines at month 6. In vehicle-injected patients without hole closure at day 28, 12 of 42 (29.3%) patients gained at least 2 lines and 4 of 42 (9.8%) gained at least 3 lines at month 6.
None of the FTMH patients treated with ocriplasmin who achieved hole closure at day 28 had a decrease in visual acuity of 2 lines or more at month 6. Some FTMH patients without hole closure at day 28 showed a decrease in visual acuity: 9 of 63 (14.3%) ocriplasmin-treated patients lost at least 2 lines and 7 of 63 (11.1%) ocriplasmin-treated patients lost at least 3 lines. For FTMH patients with vehicle injection who achieved hole closure at day 28, 1 of 5 (20.0%) patients lost at least 2 lines, while none lost 3 lines or more at month 6. In patients without hole closure after vehicle injection, 6 of 42 (14.6%) patients lost at least 2 lines and 5 of 42 (12.2%) lost at least 3 lines at month 6.
Postsurgical Outcomes in Eyes That Did Not Achieve Full-Thickness Macular Hole Closure
For patients not achieving FTMH closure after ocriplasmin or vehicle treatment and who underwent vitrectomy, the rates of FTMH closure after vitrectomy in both the ocriplasmin and the vehicle groups were high (37 of 47 [78.7%] patients and 24 of 27 [88.9%] patients, respectively) at month 6. Among patients that required vitrectomy to achieve hole closure, 12 of 37 (32.4%) eyes that had previously received ocriplasmin and 6 of 24 (26.1%, P = .622) that had previously received vehicle gained at least 2 lines at 6 months.
Selected Case
The following example is a patient from the phase 3 trials with VMA and FTMH with hole closure and visual acuity improvement after ocriplasmin treatment. Visual acuity was 20/63 at baseline ( Figure 4 , Top left). The FTMH had vitreous attachment to the inner retinal flap and the presence of cystoid spaces. Following ocriplasmin treatment, VMA resolution and initiation of FTMH closure occurred within 7 days ( Figure 4 , Top middle). Subretinal fluid was observed at days 7 and 14 ( Figure 4 , Top middle and Top right, respectively) but diminished over time ( Figure 4 , Bottom left and Bottom middle panels) and completely resolved by month 6 ( Figure 4 , Bottom right). Complete closure of the FTMH was evident at 6 months and the final visual acuity improved to 20/32.
