Original Article

Prognostic Factors Associated with Ocriplasmin
Efficacy for the Treatment of Symptomatic

Vitreomacular Adhesion and Full-thickness Macular
Hole: Analysis from Four Studies

Brian C. Joondeph, MD, MPS1; Paul Willems, MD2; Thomas Raber, PhD2; Luc Duchateau, PhD3

Joseph Markoff, PhD, MD4,5

1Colorado Retina Associates, Denver, Colorado, USA
2Oxurion, Leuven, Belgium

3Biometrics Research Group, Ghent University, Gent, Belgium
4Wills Eye Hospital, Philadelphia, Pennsylvania, USA

5Thomas Jefferson Medical College, Philadelphia, Pennsylvania, USA

ORCID:
Brian C. Joondeph: https://orcid.org/0000-0001-8781-4370

Abstract

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 𝜇g 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.

Keywords: Ocriplasmin; Full-thickness Macular Hole; Vitreomacular Adhesion; Symptomatic
Vitreomacular Adhesion; Vitreomacular Traction; Vitreoretinal Interface

J Ophthalmic Vis Res 2021; 16 (1): 42–55

42 © 2021 JOONDEPH ET AL. THIS IS AN OPEN ACCESS ARTICLE DISTRIBUTED UNDER THE CREATIVE COMMONS ATTRIBUTION LICENSE | PUBLISHED
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Patient Baseline Characteristics and Ocriplasmin Efficacy; Joondeph et al

INTRODUCTION

Aging of the eye often leads to separation
between the posterior vitreous cortex and the
internal limiting membrane, known as posterior
vitreous detachment (PVD).[1, 2] This process may
be affected by vitreomacular adhesion (VMA), or
adherence of the vitreous cortex to the macula
after partial detachment.[3–5] Symptomatic VMA
(also referred to as vitreomacular traction) can
occur if mechanical forces are large enough to
cause anatomical changes to the macula.[6, 7]
Effects resulting from symptomatic VMA may
also lead to the development of a full-thickness
macular hole (FTMH).[4] The occurrence of VMA
and FTMH can lead to visual disturbances
such as decreased visual acuity, photopsia,
metamorphopsia, scotomas, and may result in
irreversible vision loss if left untreated.[3, 4, 8–12]

Treatment options for symptomatic VMA include
watchful waiting, vitrectomy, pneumatic vitreolysis,
and pharmacological vitreolysis with ocriplasmin.
Ocriplasmin was approved in the US in 2012
and the EU in 2013 based on the results of two
pivotal phase 3 clinical trials (MIVI-TRUST) that
established its efficacy and safety in patients with
symptomatic VMA with or without an associated
FTMH ≤400 𝜇m.[13] An earlier post hoc analysis
of the pivotal trials suggested that the efficacy of
ocriplasmin may be increased by patient baseline
characteristics, including younger age, phakic lens
status, focal VMA, absence of epiretinal membrane
(ERM), and presence of FTMH.[14] Subsequently,
both prospective and retrospective studies ranging
from 5 to 74 eyes were undertaken that assessed
the effect of these baseline factors with respect to
VMA release.[13, 15–32] VMA release rates in these
studies ranged from 0% to 71%, with 14 of 18 studies
showing higher efficacy than the pivotal phase 3
trial rate of 26.5% VMA release at Day 28.[13] A
meta-analysis of these studies, which also included

Correspondence to:

Brian C. Joondeph, MD, MPS. 8101 E. Lowry Blvd, Suite
210 Denver, Colorado 80230 (303) 261-1600, USA.
E-mail: bjoondeph@retinacolorado.com
Received: 02-06-2020 Accepted: 23-10-2020

Access this article online

Website: https://knepublishing.com/index.php/JOVR

DOI: 10.18502/jovr.v16i1.8250

the phase 3 pivotal trials, confirmed that focal VMA,
absence of ERM, phakic lens status, and younger
age were all positive predictive factors for VMA
release.[33]

The rate of FTMH closure for ocriplasmin-treated
eyes was 40.6% in the pivotal clinical trials and
30.0% in the OASIS study.[13, 34] Although analysis
of baseline predictive factors has resulted in real-
world rates of VMA release higher than those in the
pivotal phase 3 trials, multiple real-world studies
have reported FTMH closure rates lower than those
observed in these studies, suggesting that the
predictive factors for FTMH closure may not be the
same as those for VMA release and are not as well
understood.[24, 28, 35] For instance, the absence of
ERM did not have a clear association with FTMH
closure in the MIVI-TRUST trials.[36] In addition,
the predictive value of successful VMA release
on FTMH closure remains unclear; there was no
clear association between VMA release and FTMH
closure in the MIVI-TRUST trials,[36] although a
recent study showed a strong association between
VMA release and FTMH closure.[37]

Although the baseline factors associated with
VMA resolution and FTMH closure have been
investigated individually, to our knowledge no
study has assessed factors that may predict
both VMA resolution and FTMH closure following
ocriplasmin treatment. The current study aimed
at assessing the baseline factors that may be
predictive of both VMA release together with FTMH
closure in patients treated with ocriplasmin in the
completed phase 3/4 studies.

METHODS

Study Population

Patients diagnosed with both symptomatic VMA
and FTMH at baseline and receiving treatment of
ocriplasmin 125 𝜇g were pooled from the MIVI-
TRUST, OASIS, and ORBIT studies. MIVI-TRUST

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How to cite this article: Joondeph BC, Willems P, Raber T, Duchateau
L, Markoff J. Prognostic Factors Associated with Ocriplasmin Efficacy for
the Treatment of Symptomatic Vitreomacular Adhesion and Full-thickness
Macular Hole: Analysis from Four Studies. J Ophthalmic Vis Res 2021;16:42–
55.

JOURNAL OF OPHTHALMIC AND VISION RESEARCH VOLUME 16, ISSUE 1, JANUARY-MARCH 2021 43

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Patient Baseline Characteristics and Ocriplasmin Efficacy; Joondeph et al

(NCT00781859 and NCT00798317) consisted of
two phase 3, prospective, randomized, multicenter,
double-blind, placebo-controlled clinical trials
(TG-MV-006 and TG-MV-007) in which patients
were randomized to receive a single intravitreal
ocriplasmin (125 𝜇g) or placebo injection.[13] OASIS
(NCT01429441) was a phase 3b, randomized,
multicenter, double-masked, sham-controlled
clinical trial in which patients were randomized
to receive a single intravitreal ocriplasmin 125
𝜇g injection or sham treatment.[34] ORBIT
(NCT02079883) was a phase 4, prospective,
multicenter, observational study to assess a single
intravitreal ocriplasmin injection of 125 𝜇g.[38]
Full details of individual study designs, treatment
plans, and adherence to ethics practices have
been published elsewhere.[13, 34, 38]

Baseline Demographics and Patient
Characteristics

The following baseline demographic and ocular
characteristics were evaluated in the study
population based on availability across datasets:
age (<65 years, ≥65 years), lens status (phakic,
pseudophakic), ERM status (present, absent),
ellipsoid zone (EZ) status (normal, abnormal),
subretinal fluid (SRF) status (present, absent),
BCVA (<65, 65–75, >75 ETDRS letters), diameter
of VMA (≤1500 𝜇m, >1500 𝜇m), width of FTMH
(≤250, >250–400, >400 𝜇m), and width of FTMH
at the retinal pigment epithelium (RPE) (≤600 𝜇m,
>600 𝜇m) (Supporting Information Table S1).

For the MIVI-TRUST trials, the presence and
size of VMA and FTMH status at baseline were
assessed by a central reading center (CRC),
using mandatory time-domain optical coherence
tomography (TD-OCT) as required per protocol;
additional spectral-domain (SD)-OCT readings if
available were only used as supportive information
for evaluation of individual cases.[13] FTMH was
defined as a macular hole with bare/exposed
RPE, with the largest of the minimum hole width
measurements considered as the hole width based
on macular thickness map (MTM) or fast macular
thickness map (FMTM) scans. In the more recent
OASIS study, the presence and size of VMA
and FTMH status at baseline were assessed
by a CRC using SD-OCT.[34] FTMH diameter
was defined as the largest of the minimum
hole width measurement. Although patients were

enrolled in the OASIS trial based on favorable
baseline characteristics,[14] determination of ocular
characteristics differed between investigator and
CRC assessment, resulting in inclusion of some
patients despite their CRC assessment meeting
exclusion criteria in retrospect (FTMH > 400 𝜇m,
presence or ERM).[34] In the ORBIT study, the
presence of VMA and FTMH was determined by
SD-OCT according to the treating physician before
enrollment and reviewed independently by a CRC
in retrospect. FTMH diameter was defined as the
greatest width of the minimum distance between
sides of the FTMH measured within the middle two
thirds of the retina (not at surface and not at RPE)
in any line of the 49-line volume scan. The review
of the presence of VMA and FTMH by the CRC was
performed post-treatment in all studies and was not
used for treatment decisions.

EZ status was evaluated in the central macular
region in all studies. SRF assessments were
defined in each of the studies. In the MIVI-TRUST
trials, SRF was a measure of the fluid beneath
retina to other material perpendicular to Bruch’s
membrane at the foveal center from the retina
to the RPE, not including fluid within the retinal
layer (cysts) or fluid below the RPE. In the OASIS
study, three foveal center point measurements
were taken, including SRF, RPE elevation and/or
subretinal hyper-reflective material (SHRM) such
as choroidal neovascularization, and total retinal
thickness. The total retinal thickness measurement
included the RPE layer, RPE elevation, any SHRM,
any SRF, and the retina at the foveal center.
When a value was not reported for SRF or RPE
elevation and/or SHRM, it was considered not
present or ungradable. In the ORBIT study, SRF was
considered present if it was identified in any line
scan in the absence of FTMH.

Statistical Analysis

The integrated database included all patients who
presented with symptomatic VMA and FTMH at
baseline, were treated with ocriplasmin 125 𝜇g,
and had both a baseline assessment and at least
one follow-up visit. Three different variables
(i.e., treatment response) were considered:
pharmacological resolution of VMA by Day
28 (VMAres), nonsurgical FTMH closure by
Month 6 (MHclos), and combined success when
experiencing both events (VMAres + MHclos). First,

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Patient Baseline Characteristics and Ocriplasmin Efficacy; Joondeph et al

Table 1. Patient demographics and ocular baseline characteristics in the four studies and the integrated dataset

Characteristic MIVI-TRUST*(N = 106) OASIS (N = 50) ORBIT(N = 118) Integrated(N = 274)
Age (years)
Mean (SD) 68.7 (7.4) 66.5 (6.3) 66.7 (7.3) 67.5 (7.2)
Median 69.0 65.5 66.0 67.0
Min, Max 48, 85 49, 79 45, 88 45, 88
Age group (years), n (%)
<65 years 31 (29.2) 20 (40.0) 42 (35.6) 93 (33.9)
≥65 years 75 (70.8) 30 (60.0) 76 (64.4) 181 (66.1)
Sex, n (%)
Male 22 (20.8) 10 (20.0) 28 (23.7) 60 (21.9)
Female 84 (79.2) 40 (80.0) 90 (76.3) 214 (78.1)
Race, n (%)
White 99 (93.4) 46 (92.0) 105 (89.0) 250 (91.3)
Black or African American 3 (2.8) 4 (8.0) 9 (7.6) 16 (5.8)
Asian 2 (1.9) 0 (0) 3 (2.5) 5 (1.8)
Other 2 (1.9) 0 (0) 1 (0.9) 3 (1.1)
Lens status, n (%)
Phakic 81 (76.4) 43 (86.0) 93 (78.8) 217 (79.2)
Pseudophakic 25 (23.6) 7 (14.0) 24 (20.3) 56 (20.4)
Aphakic 0 (0) 0 (0) 1 (0.9) 1 (0.4)
ERM status, n (%)
Present 18 (17.0) 6 (12.0) 14 (11.9) 38 (13.9)
Absent 82 (77.3) 44 (88.0) 104 (88.1) 230 (83.9)
Missing 6 (5.7) 0 (0) 0 (0) 6 (2.2)
EZ status, n (%)
Abnormal 0 (0) 49 (98.0) 116 (98.3) 165 (60.2)
Normal 0 (0) 1 (2.0) 2 (1.7) 3 (1.1)
Missing 106 (100) 0 (0) 0 (0) 106 (38.7)
SRF status, n (%)
Present 77 (72.7) 49 (98.0) 0 (0) 126 (46.0)
Absent 26 (24.5) 1 (2.0) 118 (100) 145 (52.9)
Missing 3 (2.8) 0 (0) 0 (0) 3 (1.1)
BCVA (ETDRS letters), n (%)
<65 89 (84.0) 37 (74.0) 96 (81.4) 222 (81.0)
65–75 16 (15.1) 12 (24.0) 19 (16.1) 47 (17.2)
>75 1 (0.9) 1 (2.0) 3 (2.5) 5 (1.8)
FTMH size, n (%)
≤250 𝜇m 48 (45.3) 23 (46.0) 66 (55.9) 137 (50.0)
>250–400 𝜇m 38 (35.9) 17 (34.0) 33 (28.0) 88 (32.1)
>400 𝜇m 19 (17.9) 10 (20.0) 19 (16.1) 48 (17.5)
Missing 1 (0.9) 0 (0) 0 (0) 1 (0.4)
VMA diameter, n (%)
≤1500 𝜇m 90 (84.9) 43 (86.0) 110 (93.2) 243 (88.7)
>1500 𝜇m 3 (2.8) 2 (4.0) 1 (0.9) 6 (2.2)
Missing 13 (12.3) 5 (10.0) 7 (5.9) 25 (9.1)
FTMH width at RPE (𝜇m)
n 104 50 0 154
Mean (SD) 647.1 (283.8) 634.2 (320.8) – 642.9 (295.4)
Median 611.0 596.0 – 611.0
Min, Max 113, 1572 164, 2120 – 113, 2120
FTMH width at RPE, n (%)
≤600 𝜇m 49 (46.2) 25 (50.0) 0 (0) 74 (27.0)
>600 𝜇m 55 (51.9) 25 (50.0) 0 (0) 80 (29.2)
Missing 2 (1.9) 0 (0) 118 (100) 120 (43.8)

∗MIVI-TRUST consisted of two phase 3 clinical trials (NCT00781859 and NCT00798317)
BCVA, best-corrected visual acuity; ERM, epiretinal membrane; ETDRS, Early Treatment Diabetic Retinopathy Study; EZ,
ellipsoid zone; FTMH, full-thickness macular hole; RPE, retinal pigment epithelium; SD, standard deviation; SRF, subretinal fluid;
VMA, vitreomacular traction

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Patient Baseline Characteristics and Ocriplasmin Efficacy; Joondeph et al

Table 2. Rates of VMA resolution and FTMH closure in the four studies and the integrated dataset

MIVI-TRUST* n (%) OASIS n (%) ORBIT n (%) Integrated n (%)

Number of patients 106 50 118 274

VMA resolution 53 (50.0) 27 (54.0) 74 (62.7) 154 (56.2)

FTMH closure 43 (40.6) 15 (30.0) 38 (32.2) 96 (35.0)

VMA resolution: Yes
FTMH closure: Yes 24 (22.6) 8 (16.0) 30 (32.2) 62 (22.6)

VMA resolution: Yes
FTMH closure: No 29 (27.4) 19 (38.0) 44 (37.3) 92 (33.6)

VMA resolution: No
FTMH closure: Yes 19 (17.9) 7 (14.3) 8 (6.8) 34 (12.4)

VMA resolution: No
FTMH closure: No 24 (22.6) 8 (16.0) 30 (25.4) 86 (31.4)

*MIVI-TRUST consisted of two phase 3 clinical trials (NCT00781859 and NCT00798317)
FTMH, full-thickness macular hole; VMA, vitreomacular adhesion

Table 3. Univariable logistic regression analysis for the effect of patient demographics and ocular baseline characteristics on
VMA resolution by Day 28 and FTMH closure by Month 6 in the integrated dataset

VMA resolution FTMH closure VMA resolution + FTMH closure

Characteristic Status Success (%) P-value Success (%) P-value Success (%) P-value

Age <65 years 65/93 (69.9) 0.0015 32/93 (34.4) 0.9783 22/93 (23.7) 0.735
≥65 years 89/181 (49.2) 64/181 (35.4) 40/181 (22.1)

Lens Status Phakic 130/217 (59.9) 0.0129 71/217 (32.7) 0.1888 47/217 (21.7) 0.647
Pseudophakic 23/56 (41.1) 24/56 (42.9) 14/56 (25.0)

ERM status Present 12/38 (31.6) 0.0028 13/38 (34.2) 0.7999 4/38 (10.5) 0.067
Absent 137/230 (59.6) 81/230 (35.2) 56/230 (24.3)

EZ status Normal 1/3 (33.3) 0.3667 3/3 (100) 0.9852 1/3 (33.3) 0.645
Abnormal 100/165 (60.6) 50/165 (30.3) 37/165 (22.4)

SRF status Present 67/126 (53.2) 0.2874 48/126 (38.1) 0.2327 28/126 (22.2) 0.124
Absent 85/145 (58.6) 46/145 (31.7) 33/145 (22.8)

BCVA (ETDRS
letters)

<65 127/222 (57.2)
0.6215

71/222 (32.0)
0.0606

49/222 (22.1)
0.645

65–75 25/47 (53.2) 22/47 (46.8) 13/47 (27.7)
>75 2/5 (40.0) 3/5 (60) 0/5 (0)

VMA diameter ≤1500 µm 144/243 (59.3) 0.7324 87/243 (35.8) 0.8514 56/243 (23.0) 0.489
>1500 µm 3/6 (50) 2/6 (33.3) 2/6 (33.3)

FTMH size ≤250 µm 75/137 (54.7)
0.3412

67/137 (48.9)
<0.0001

41/137 (29.9)
0.009>250–400 µm 54/88 (61.4) 26/88 (29.6) 19/88 (21.6)

>400 µm 24/48 (50) 2/48 (4.2) 1/48 (2.2)
FTMH width at
RPE

≤600 µm 40/74 (54.1) 0.5185 38/74 (51.4) 0.0004 21/74 (28.4) 0.015

>600 µm 39/80 (48.8) 19/80 (23.8) 10/80 (12.5)

BCVA, best-corrected visual acuity; ERM, epiretinal membrane; ETDRS, Early Treatment Diabetic Retinopathy Study; EZ, ellipsoid
zone; FTMH, full-thickness macular hole; RPE, retinal pigment epithelium; SRF, subretinal fluid; VMA, vitreomacular adhesion

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Patient Baseline Characteristics and Ocriplasmin Efficacy; Joondeph et al

Table 4. univariable logistic regression analysis for the effect of patient demographics and ocular baseline characteristics on
FTMH closure by Month 6 for patients with VMA resolution by Day 28 in the integrated dataset

Patient Characteristic Status Success (%) P-value

Age <65 years 22/65 (33.8) 0.177
≥65 years 49/89 (55.1)

Lens Status Phakic 47/130 (36.2) 0.027
Pseudophakic 14/23 (60.9)

ERM status Present 4/12 (33.3) 0.619
Absent 56/137 (40.9)

EZ status Normal 1/1 (100.0) 0.986
Abnormal 37/100 (37.0)

SRF status Present 28/67 (41.8) 0.231
Absent 33/85 (38.8)

BCVA (ETDRS letters) <65 49/127 (38.6)
0.43465–75 13/25 (52.0)

>75 2/2 (100.0)
VMA diameter ≤1500 µm 56/144 (38.9) 0.311

>1500 µm 2/3 (66.7)
FTMH size ≤250 µm 41/75 (54.7)

0.001>250–400 µm 19/54 (35.2)
>400 µm 1/24 (4.2)

FTMH Width at RPE ≤600 µm 21/40 (52.5) 0.012
>600 µm 10/39 (25.6)

BCVA, best-corrected visual acuity; ERM, epiretinal membrane; ETDRS, Early Treatment Diabetic Retinopathy Study; EZ, ellipsoid
zone; FTMH, full-thickness macular hole; RPE, retinal pigment epithelium; SRF, subretinal fluid; VMA, vitreomacular adhesion

the effect of each patient baseline characteristic on
success was evaluated separately in a univariable
logistic regression model that also included study
as a fixed-effects factor to accommodate for the
clustering in the data due to combining data
from different studies. Next, all patient baseline
characteristics that were significant at the 5%
significance level were included in a multivariable
regression analysis to identify independent patient
baseline characteristics that were significantly
associated with treatment success. Additionally,
the same analysis was performed for MHclos for
those patients that experienced VMAres.

RESULTS

Demographics and Baseline Characteristics

A total of 274 patients were pooled from the MIVI-
TRUST, OASIS, and ORBIT studies on the basis

of having both symptomatic VMA and FTMH at
baseline and having received a single intravitreal
injection of ocriplasmin 125 𝜇g. Demographics and
ocular characteristics are shown in Table 1. Overall,
the demographics and ocular characteristics
were generally comparable in patients across
the three datasets. The mean age of the patients
was 67.5 years, with an age range of 45–88
years. Seventy-nine percent of the patients
had phakic lens status. A majority (60.2%) of
patients had EZ status categorized as abnormal,
and 46.0% of patients had SRF present (Table
1).

VMA Resolution

An average of 56.2% (154/274) of eligible patients
experienced VMA resolution by Day 28 (Table
2). The proportion of patients experiencing VMA
resolution by Day 28 in this patient subpopulation

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Patient Baseline Characteristics and Ocriplasmin Efficacy; Joondeph et al

Supplemental Table 1. Availability of baseline characteristics and outcome measures in the ocriplasmin studies

MIVI-TRUST OASIS ORBIT

Outcome measures

Pharmacological VMA
resolution at Day 28,
post-resolution vitrectomy
considered as a failure

Yes Yes No

Pharmacological VMA
resolution at Day 28,
post-resolution vitrectomy
not considered as a failure

Yes Yes Yes

Non-surgical FTMH closure
by end of study
(post-closure vitrectomy
not considered as a failure)

EOS (up to M6) M6 EOS (up to M24) M6 M12

Baseline characteristics

Age (Years) Available Available Available

Lens status Phakic
Pseudophakic

Phakic
Pseudophakic

Phakic Pseudophakic
Aphakic

ERM Present
Absent

Present Minimal
Present Significant
Absent

Present*
Absent*

EZ Not available Definitely Fully Intact
Likely site(s) of Incomplete EZ
Definite site(s) of Incomplete EZ
Unable to grade

Normal*
Abnormal*

SRF Present
Absent

Present
Absent

Present*
Absent*

BCVA (ETDRS) Available Available Available after
transformation

FTMH size (𝜇m) Available Available Available
VMA diameter Available Available Available

FTMH width at RPE Available Available Not available

*Assessed by SD-OCT
BCVA, best-corrected visual acuity; ELM, external limiting membrane; EOS, end of study; ERM, epiretinal membrane; ETDRS,
Early Treatment Diabetic Retinopathy Study; EZ, ellipsoid zone; FTMH, full-thickness macular hole; M, month; RPE, retinal
pigment epithelium; SD-OCT, spectral-domain optical coherence tomography; SRF, subretinal fluid; VMA, vitreomacular adhesion

with FTMH at baseline was consistently higher
than or equal to 50% for all studies (Table
2).

VMA resolution by Day 28 was achieved
significantly more frequently in younger patients,
in the absence of ERM at baseline and for eyes
with phakic lens status at baseline (Table 3).
In the multivariable model including these three
variables, age (P = 0.006) and ERM status at

baseline (P = 0.010) remained significant, but not
lens status at baseline (P = 0.179).

FTMH Closure

The average rate of FTMH closure by Month
6 in the integrated dataset was 35.0% (96/274)
(Table 2). Closure rates varied from 30.0% for the
OASIS database and 32.2% for the ORBIT study

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Patient Baseline Characteristics and Ocriplasmin Efficacy; Joondeph et al

to 40.6% for the MIVI-TRUST trials (Table 2). FTMH
closure by Month 6 occurred significantly more
often with smaller FTMH size and smaller FTMH
width at RPE (Table 3). We did not construct the
multivariable model as these two variables are
highly interrelated: the percentage of patients with
FTMH width at RPE ≤600 µm decreases from
64.8% (46/71) to 45.5% (25/55) and 10.7% (3/28) for
the ≤250 µm, >250–400 µm, and >400 µm FTMH
size categories, respectively.

VMA resolution by Day 28 was a positive
predictor for FTMH closure by Month 6. Patients
with VMA resolution by Day 28 had a higher
percentage of MH closure of 40.3% (62/154)
compared to patients without VMA release equal
to 28.3% (34/120) (P = 0.028). Within the group
of patients who had VMA resolution by Day 28,
MH closure by Month 6 occurred significantly
more for eyes with pseudophakic lens status at
baseline, with smaller FTMH size and smaller FTMH
width at RPE (Table 4). In the multivariable models
including lens status with one of the two FTMH
measurements at a time, lens status was no longer
significant (P = 0.244 with FTMH size and P = 0.173
with FTMH width at RPE), nor was the FTMH size
(P = 0.057), but the FTMH width at RPE remained
significant (P < 0.001).

VMA Resolution and FTMH Closure

Overall, 22.6% (62/274) of patients in this analysis
experienced both VMA resolution by Day 28 and
FTMH closure by Month 6 (Table 2). In contrast,
12.4% (34/274) experienced FTMH closure by
Month 6 without VMA resolution by Day 28; 33.6%
(92/274) experienced VMA resolution by Day 28
without FTMH closure by Month 6; and 31.4%
(86/274) showed neither VMA resolution by Day 28
nor non-surgical FTMH closure by Month 6 (Table
2).

Univariable logistic regression analysis revealed
a statistically significant effect for FTMH size at
baseline on treatment success (P = 0.009; Table
3), with success increasing from 2.2% for patients
with FTMH size at baseline >400 µm to 21.6% for
patients with FTMH size at baseline between 250
and 400 µm, and further to 29.9% for patients
with FTMH size at baseline <250 µm. Similarly,
FTMH width at RPE at baseline had a significant
effect on treatment success in the univariable
logistic regression analysis (P = 0.015; Table 3),

with treatment success increasing from 12.5%
for patients with FTMH width at baseline >600
µm to 28.4% for patients with FTMH width at
baseline <600 µm. None of the other patient
characteristics previously shown to be predictive
for VMA resolution, including younger age, phakic
lens status, or absence of ERM,[14, 33] showed a
statistically significant association with treatment
success (Table 3). As the two significant patient
baseline characteristics are necessarily highly
correlated, and additionally FTMH width at RPE at
baseline was unavailable for the OASIS dataset,
they were not used jointly in a multivariable logistic
regression analysis.

Case studies

Two patients are herein presented as case studies
to exemplify real-world clinical findings with
ocriplasmin use in patients with symptomatic VMA
and FTMH.

Case 1

A 71-year-old white woman had initial presentation
of blurred central vision for four–six weeks and
ghosting of letters while reading in the left eye.
Medical and ocular history were noncontributory.
Visual acuity was 20/60 at initial visit. SD-OCT
revealed VMA with tractional macular hole of 300
𝜇m, with no presence of ERM (Figure 1A). The left
eye had phakic lens status. The patient opted for
ocriplasmin treatment and received the intravitreal
injection 18 days after initial visit. Visual acuity was
20/60 pre-injection.

One week following the ocriplasmin injection,
VMA resolved and the macular hole closed (Figure
1B). However, there was increased presence of
SRF (Figure 1B). Visual acuity remained at 20/50.
At seven weeks post-treatment, macular hole
remained closed with no evidence of SRF (Figure
1C). Visual acuity improved to 20/40.

Case 2

A 63-year-old White woman initially presented with
symptoms of blurred central vision for two–three
months in the left eye. Medical history included
essential hypertension. Visual acuity was 20/150
at initial visit. Patient had phakic lens status in
the left eye. Upon examination, SD-OCT showed

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Patient Baseline Characteristics and Ocriplasmin Efficacy; Joondeph et al

Figure 1. Case 1. Spectral domain optical coherence tomography of a 71-year-old female with VMA and a tractional macular hole
in the left eye. (A) Baseline visit. No presence of ERM; BCVA 20/60. (B) One week post ocriplasmin injection. VMA resolved and
macular hole closed, but increased presence of SRF; BCVA 20/50. (C). Seven weeks post treatment. Macular hole remains closed,
no evidence of SRF; BCVA 20/40. BCVA, best-corrected visual acuity; ERM, epiretinal membrane; INJ, injection; M, month; SRF,
subretinal fluid; W, week

FTMH with VMA, with no ERM or presence of
SRF (Figure 2A). The size of the tractional macular
hole size at baseline was 145 𝜇m, minimum linear
diameter (MLD). The patient opted for ocriplasmin
treatment and received the intravitreal injection 14
days after the initial visit. Pre-injection visual acuity
was 20/150.

One month following the treatment with
ocriplasmin, the VMA released, but the macular
hole remained open, enlarging to a size of 428
𝜇m, MLD (Figure 2B). Visual acuity decreased
to 20/200. The patient underwent standard
macular hole repair via vitrectomy, internal
limiting membrane peeling, and gas injection.
The hole did not close and subsequent surgery
including an internal limiting membrane patch
and silicone oil was performed with macular
hole closure. At the last examination, visual
acuity was count fingers (CF) at 4 ft with a

dense cataract and macular hole closure by
OCT.

DISCUSSION

This study is the first to examine the baseline
predictors of success for both VMA resolution
and FTMH closure following ocriplasmin treatment.
Our results show that FTMH ≤ 250 𝜇m at
baseline is significantly associated with VMA
release by Day 28 and FTMH closure by Month
6 (P = 0.009), and may be the only positive
baseline predictor for both pharmacological VMA
release and nonsurgical FTMH closure, including
previously identified predictors such as age, lens
status, and absence of ERM.

Baseline factors associated with successful VMA
release following ocriplasmin treatment have been

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Patient Baseline Characteristics and Ocriplasmin Efficacy; Joondeph et al

Figure 2. Case 2. Spectral domain optical coherence tomography of a 63-year-old female showing VMA with FTMH. (A) Baseline
visit. No ERM or presence of SRF; BCVA 20/150. (B) One month post treatment. VMA released, but macular hole remained open,
with the base enlarging to 1323 𝜇m. BCVA decreased to 20/200. BCVA, best-corrected visual acuity; ERM, epiretinal membrane;
INJ, injection; M, month; SRF, subretinal fluid

widely studied following approval in 2012.[14–32]
A post hoc analysis of the phase 3 MIVI-TRUST
trials revealed that baseline characteristics such as
younger age, focal adhesions (VMA ≤ 1500 𝜇m),
phakic lens status, and absence of ERM promoted
VMA resolution,[14] and these characteristics have
since been confirmed in multiple studies.[15–32]
These predictive characteristics were also shown
to statistically favor VMA release (odds ratios 2.37–
7.85) in a meta-analysis of 19 studies published in
2016.[33]

However, in our current analysis, most of these
validated baseline factors were not shown to be
predictive when analyzed for both VMA release
and FTMH closure. The baseline factors of younger
age, absence of ERM, and lens status did not
reach statistical significance, with only FTMH size
of ≤ 250 𝜇m at baseline emerging as the only

statistically significant factor favoring both VMA
release and FTMH closure.

The fact that lens status was no longer significant
in the multivariable model is due to the correlation
between variables. The lens status of younger
patients was more frequently phakic compared to
older patients (93.6% vs 71.8%), and similarly, the
lens status of patients without ERM at baseline
was more frequently phakic compared to patients
with ERM at baseline (83.0% vs 57.9%). For FTMH,
the percentage of phakic lens status increases
with increasing FTMH size, with 80.0% (60/75),
85.2% (46/54), and 100.0% (24/24) for the ≤250
µm, >250–400 µm, and >400 µm FTMH size
categories, respectively, and with increasing FTMH
width, with 85.0% (34/40) and 89.7% (35/39) for
the ≤600 µm and >600 µm FTMH width at RPE
categories, respectively.

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Patient Baseline Characteristics and Ocriplasmin Efficacy; Joondeph et al

Historically, whether FTMH at baseline serves
as a predictive factor for successful VMA release
has remained unclear. The presence of FTMH
was initially identified as a predictive characteristic
in the post hoc analysis of the MIVI-TRUST
trials.[14] Subsequently, Chatziralli et al performed
a meta-analysis and did not conclude that the
presence of FTMH was a predictive factor
for VMA release.[33] However, only 8 of the
19 analyzed studies assessed MH size as a
predictive factor.[13, 15, 17, 23, 24, 28, 30, 32] Kuppermann
(2015)[39] reported the results of 10 retrospective
studies which assessed the presence of FTMH
on VMA resolution, including 4 studies not
included in Chatziralli et al.[40–43] Eight of these 10
studies[19, 23, 31, 32, 40–43] showed that the subgroup
of patients with a FTMH had higher VMA resolution
rates than those without.[39] These results were
also consistent with the prospective OASIS trial.[34]
However, other studies have not shown greater
rates of VMA resolution in patients with FTMH at
baseline.[28, 29] Therefore, the value of FTMH as a
predictive factor for VMA resolution needs to be
further elucidated.

In our current analysis, the majority of patients
failing to achieve both VMA resolution and FTMH
closure were due to lack of macular hole closure.
Whereas VMA resolution rates were 50% or
higher from all studies in this patient population
(i.e., those with symptomatic VMA and FTMH at
baseline treated with ocriplasmin with at least
one follow-up visit), FTMH closure rates for OASIS
and ORBIT studies were lower than that of the
original phase 3 MIVI-TRUST trials, albeit higher
than the closure rates experienced in the control
groups (15.4% and 10.6%, respectively). These
results suggest that the known baseline factors
predictive of VMA resolution, which were used
as key inclusion criteria for the OASIS study,
may be necessary but not sufficient to predict
FTMH closure. Nevertheless, consistent with our
findings, previous studies investigating FTMH
closure rates following ocriplasmin treatment have
repeatedly shown FTMH size at baseline to be the
most consistent predictive factor, with a greater
proportion of patients experiencing hole closure
with an FTMH ≤ 250 𝜇m compared to those with
an FTMH > 250–400 𝜇m.[14, 36, 37, 44] In contrast,
the natural history of untreated FTMH has revealed
that spontaneous closure rates are low, ranging
from 3–11%.[45–49] Although smaller holes have
a comparatively better chance of spontaneous

closure compared to larger ones, previous studies
have shown that the majority of stage 2 macular
holes (<400 𝜇m) progress to stage 3 and beyond if
left untreated.[50–53]

Whether VMA resolution is correlated with
FTMH closure has also remained unclear. Recently,
Feng et al demonstrated that successful VMA
resolution was a statistically significant positive
predictor for FTMH closure following ocriplasmin
treatment (P = 0.042).[37] This is consistent with
our findings, which showed that patients with
VMA resolution by Day 28 had a significantly
higher rate of FTMH closure compared to those
without VMA resolution. However, other analyses
have not shown an association between VMA
resolution and FTMH closure. In one study, 40% of
patients required surgical closure for macular holes
despite successful VMA resolution,[54] suggesting
that additional factors may impact FTMH closure.

Although our finding that VMA resolution
showed a positive correlation with FTMH closure
is notable, beyond initial hole size, baseline
characteristics predictive of macular hole closure
prior to treatment have remained elusive. For
instance, our findings are consistent with previous
analyses showing that, unlike for VMA resolution,
absence of ERM did not significantly impact
FTMH closure rates.[35, 36] Additional studies have
suggested that other factors, such as macular hole
architecture, may affect closure.[55, 56] Recently,
Steel et al found that macular hole “width factor,”
defined as the base diameter (BD) minus the MLD,
was the most predictive factor of macular hole
closure; holes having a BD close in size to the
MLD were shown to have higher probability of
closure compared to those with a wider base.[56]
A similar outcome is shown in Case 2, where
despite VMA resolution, the macular hole widens
at the base with the edge elevated by a cuff
of SRF. This is consistent with previous cases
showing failure of FTMH closure due to base
enlargement following ocriplasmin treatment and
subsequent VMA resolution.[37, 57] SRF did not
have a statistically significant predictive value in
our analysis; however, the number of patients
showing successful VMA resolution and FTMH
closure with SRF were strikingly different between
the MIVI-TRUST and OASIS vs ORBIT studies (SRF
present: 87% [20/23], 100% [8/8], and 0% [0/30],
respectively), perhaps owing in part to differences
in SRF measurement protocols at study enrollment

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Patient Baseline Characteristics and Ocriplasmin Efficacy; Joondeph et al

and therefore limiting interpretation. In Case 1,
presence of SRF did not impact VMA resolution
or FTMH closure, although visual acuity improved
following SRF resolution.

When selecting a treatment option for patients
with VMA and FTMH, the risks and benefits of
ocriplasmin versus vitrectomy should be carefully
considered. For these patients, vitrectomy is
considered the standard of care, with macular hole
closure rates reported for 87.5% of patients in a
meta-analysis.[33, 58, 59] However, persistence of a
macular hole after vitrectomy remains one of the
major complications of this type of surgery, with
approximately one in eight macular holes failing
to close.[58] A persistent macular hole typically
increases in diameter, with an accompanying loss
of visual acuity, and studies have shown lower
treatment success for subsequent surgery.[55, 58]
Additional complications of vitrectomy include
cataract formation, retinal detachment, and
hemorrhage.[33, 59–64] In addition, based on the
OASIS trial, patients who underwent vitrectomy
experienced retinal tear and retinal detachment
more often than patients receiving ocriplasmin.
Most adverse events in the ocriplasmin group
were transient in nature, had a short onset time,
and were mild to moderate in severity.[34]

Strengths of the current analysis include a robust
and homogeneous patient sample pooled from
multiple clinical trials, utilizing the same ocriplasmin
treatment regimen. Limitations include the post hoc
nature of the analysis, which was not prespecified
in the clinical trials, as well as the lack of availability
of certain baseline ocular characteristics in all
trials.

Since the pivotal clinical trials, continued study
and analysis has been undertaken to more fully
understand the efficacy and safety of ocriplasmin,
including the baseline characteristics predictive of
VMA resolution and FTMH closure. These results
suggest that patients presenting with symptomatic
VMA and FTMH ≤ 250 𝜇m may be ideal candidates
for ocriplasmin treatment.

Acknowledgements

The authors are thankful to all personnel involved
in this study and Michael Howell, PhD, for editorial
assistance in the preparation of this manuscript that
was supported by Oxurion.

Financial Support and Sponsorship

This study was funded by Oxurion. All authors,
including those affiliated with the study sponsor,
were involved in the design of the study,
interpretation of the data, writing of the manuscript,
and the decision to submit the manuscript for
publication.

Conflicts of Interest

The authors declare the following potential
conflicts of interest with respect to the research,
authorship, and/or publication of this article:

BJ: Consultant for Oxurion; PW: Consultant for
Oxurion; TR: Employee of Oxurion; LD: Consultant
for Oxurion; JM: Consultant for Oxurion.

Research involving human participants and
informed consent

This manuscript represents a retrospective
analysis of four prospective phase 3/4 clinical
trials.

Full details of adherence to ethics practices have
been previously published [13, 34, 38].

Author Contribution

All authors contributed to the conception or design
of the work, analysis and interpretation of the data,
critical revision of the manuscript, and approval of
the final version to be published.

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