Patient-reported outcomes of ocriplasmin for the treatment of vitreomacular traction: a systematic review and synthesis of the literature

Figures & data

Figure 1 Study flow diagram

Abbreviations: VMA, vitreomacular adhesion; MH, macular hole.

Table 1 Characteristics of studies included in the review (partially extracted from Neffendorf et al¹⁶)

PICOS	Study characteristics
Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes Stalmans et al^Citation11
Participants	Inclusion criteria: aged >18 years; focal VMA (vitreous adhesion to macula within 6 mm central retinal field surrounded by elevation of posterior vitreous cortex, as seen on OCT) that in the opinion of investigator was related to decreased visual function (eg, metamorphopsia, decreased visual acuity or other visual complaint); BCVA ≤20/25 in study eye; BCVA ≥20/800 in non-study eye. Exclusion criteria: any evidence of proliferative retinopathy or exudative AMD or retinal vein occlusion in study eye; people with any vitreous hemorrhage or any other vitreous opacification which precludes either: visualization of posterior pole by visual inspection OR adequate assessment of macula by either OCT or fluorescein angiogram (or both) in study eye; FTMH >400 µm in diameter in study eye; aphakia in study eye; high myopia (> –8 diopters); uncontrolled glaucoma; lenticular or zonular instability; history of retinal detachment in either eye; prior vitrectomy or prior laser photocoagulation of macula; treatment with ocular surgery, intravitreal injection or retinal laser photocoagulation in the previous 3 months.
Intervention and Comparator	Single intravitreal injection of ocriplasmin 125 µg in 0.10 mL volume. Single intravitreal injection of 0.10 mL placebo with identical drug vehicle diluted with saline.
Outcomes, including the PRO measure	Primary outcome, as defined in study reports: the primary endpoint was the proportion of eyes with nonsurgical resolution of VMA at day 28 post-injection, as determined by masked OCT evaluation obtained from the CRC Secondary outcomes, as defined in study reports: proportion of eyes with total PVD at day 28, as determined by B-scan ultrasound; need for vitrectomy; closure of a FTMH; gain ≥3-lines BCVA without vitrectomy; change from baseline in BCVA and VFQ-25 score at 6 months. Adverse events reported: yes Intervals at which outcomes assessed: 7, 14, 28, 90 and 180 days
Study design	Randomized controlled trials: MIVI 6 and MIVI 7, with pooled analysis Length of follow-up: 180 days Years study conducted: 2008–2010
Results of the 2-year ocriplasmin for treatment for symptomatic vitreomacular adhesion including macular hole (oasis) randomized trial Dugel et al^Citation12
Participants	Inclusion criteria: aged >18 years; presence of symptomatic VMA/VMT; BCVA ≤20/32 in study eye; BCVA ≥20/800 in non-study eye Exclusion criteria: history or current evidence of PR, exudative AMD or retinal vein occlusion in the study eye; people with any vitreous hemorrhage or any other vitreous opacification which precludes either visualization of the posterior pole by visual inspection OR adequate assessment of the macula by OCT; MH >400 µm in diameter in the study eye; presence of epiretinal membrane; aphakia in study eye; high myopia (> –8 diopters in study eye); history of rhegmatogenous retinal detachment in either eye; prior vitrectomy in study eye; previous participation in this trial or prior administration of ocriplasmin in study eye.
Intervention and Comparator	Single intravitreal injection of ocriplasmin 125 µg in 0.10 mL volume. Sham (the same syringe hub was pressed against the conjunctiva to simulate an injection).
Outcomes, including the PRO measure	Primary outcome, as defined in study reports: Proportion of subjects with pharmacological VMA/VMT resolution at day 28. Pharmacological VMA resolution without anatomical defect, based on spectral domain optical coherence tomography and determined by the masked CRC, with post-resolution vitrectomy considered as a failure. Secondary outcomes, as defined in study reports, were assessed at 24 months and irrespective of vitrectomy (where applicable): proportion of subjects with a ≥2-lines improvement in BCVA from baseline at month 24; proportion of FTMHs that closed without vitrectomy as determined by the CRC; proportion of subjects receiving a vitrectomy; proportion of subjects with a ≥3-line improvement in BCVA from baseline; mean change in BCVA from baseline; and proportion of subjects with a ≥5-point improvement in the VFQ-25 composite score from baseline. Adverse events reported: yes Intervals at which outcomes assessed: 7 and 28 days; 3, 6, 9, 12, 15, 18, 21 and 24 months
Study design	Randomized controlled trial Length of follow-up; 24 months Years of study conducted: 2011–2014
Association between anatomical resolution and functional outcomes in the mivi-trust studies using ocriplasmin to treat symptomatic vitreomacular adhesion/vitreomacular traction, including when associated with macular hole Gandorfer et al^Citation23
Participants	Pooled MIVI 6 and MIVI 7 study population as reported by Stalmans et al.^Citation11
Intervention and Comparator	Single intravitreal injection of ocriplasmin 125 µg in 0.10 mL volume. Single intravitreal injection of 0.10 mL placebo with identical drug vehicle diluted with saline.
Outcomes, including the PRO measure	BCVA: mean and categorical changes from baseline in BCVA (irrespective of vitrectomy). VFQ-25: mean changes from baseline in the VFQ-25 scores. Responder analyses by success or failure to achieve nonsurgical resolution of VMA at day 28 and nonsurgical FTMH closure at day 28.
Study design and notes	Analyses from randomized controlled studies MIVI 6 and MIVI 7 An ANOVA model with factors for subgroup (success/failure on the anatomical endpoint), study, and baseline visual acuity category (<65, 65–75, >75 letters) was used to compare between responder subgroups. A similar model was used for VFQ-25 with a factor adjusting for baseline in the VFQ-25. For categorical changes in BCVA, the Cochran–Mantel– Haenszel test, stratified by study, was used to make comparisons between responder subgroups.
Improvement in patient-reported visual function after ocriplasmin for vitreomacular adhesion results of the microplasmin for intravitreous injection-traction release without surgical treatment (mivi-trust) trials Varma et al^Citation29
Participants	Pooled MIVI 6 and MIVI 7 study population as reported by Stalmans et al.^Citation11
Intervention and Comparator	Single intravitreal injection of ocriplasmin 125 µg in 0.10 mL volume. Single intravitreal injection of 0.10 mL placebo with identical drug vehicle diluted with saline.
Outcomes, including the PRO measure	VFQ-25 composite and subscale scores Mean changes between baseline and 6-month follow-up. Proportion of patients with a clinically meaningful change (≥5 points) in scores.
Study design and notes	Analyses from 2 randomized controlled clinical trials comparing change in patient-reported visual function. Comparison ocriplasmin vs placebo: (1) mean changes from baseline in VFQ-25 scores*; (2) proportion of patients with ≥5-point improvement or worsening in VFQ-25 scores.** Comparison ocriplasmin patients who met the primary endpoint vs those who did not: (1) mean changes from baseline in VFQ-25 scores;* (2) proportions of patients with ≥5-point improvement or worsening in VFQ-25 scores.**
Visual function response to ocriplasmin for the treatment of vitreomacular traction and macular hole Jackson et al^Citation26
Participants	Pooled MIVI 6 and MIVI 7 study population as reported by Stalmans et al.^Citation11
Intervention and Comparator	Single intravitreal injection of ocriplasmin 125 µg in 0.10 mL volume. Single intravitreal injection of 0.10 mL placebo with identical drug vehicle diluted with saline.
Outcomes, including the PRO measure	The main outcome measure was visual function response at 6 months, defined as either a BCVA improvement of ≥2 lines; or an improvement in the composite score of the VFQ-25 exceeding the MCID, estimated using the standard error of measurement approach; or an improvement in the VFQ-25 driving subscale score exceeding the MCID.
Study design	Post hoc analysis of prespecified secondary endpoints in two multicenter, randomized, double-masked, Phase III clinical trials
Visual function response to ocriplasmin for the treatment of vitreomacular traction and macular hole: the oasis study Lescrauwaet et al^Citation30
Participants	OASIS study population as reported by Dugel et al.^Citation12
Intervention and Comparator	Single intravitreal injection of ocriplasmin 125 µg. Sham
Outcomes, including the PRO measure	The main outcome measure was the visual function response at month 6, with further assessments at months 12 and 24. VFR was defined as either a VA improvement of ≥2 lines or an improvement exceeding the MCID in the composite or the mental health subscale scores of the VFQ-25. The MCID was estimated using the standard error of measurement approach.
Study design	Prespecified analysis of secondary endpoints from a randomized controlled trial (OASIS study).

Notes:

* ANOvA model, with treatment, age, sex, race, baseline vFQ-25 score, and study as covariates.

** Cochran–Mantel–Haenszel test, with stratification for age group, sex, race, and study. Reprinted with permission from Neffendorf JE, Kirthi V, Pringle E, Jackson TL. Ocriplasmin for symptomatic vitreomacular adhesion. Cochrane Database Syst Rev. 2017;10:CD011874, John Wiley and Sons.¹⁶

Abbreviations: BCVA, best corrected visual acuity; CRC, central reading center; FTMH, full-thickness macular hole; MH, macular hole; MCID, minimal clinically important difference; OCT, optical coherence tomography; PR, proliferative retinopathy; PVD, posterior vitreous detachment; PICOS, Participants Interventions Comparators Outcomes Study design; VFQ-25, Visual Function Questionnaire 25; VFR, visual function response; VMA, vitreomacular adhesion; VMT, vitreomacular traction; AMD, age-related macular degeneration.

Table 2 Baseline characteristics of patients with VMT in investigational studies

	MIVI 006 (N=326)	MIVI 007 (N=326)	OASISa (N=218)	Combined (N=870)
Demographics
Female N (%)	207 (63.5)	222 (68.1)	147 (67.4)	576 (66.2)
White race N (%)	292 (89.6)	310 (95.1)	195 (89.4)	797 (91.6)
Age, years: mean (SD)	71.3 (10.2)	72.0 (8.5)	69.1 (10.3)	71 (9.7)
Anatomical characteristics
FTMH present N (%)	89 (27.3)	64 (19.6)	76 (34.9)	229 (26.3)
ERM present N (%)	121 (37.7)	131 (40.9)	50 (22.9)	302 (35.2)
Ocular characteristics
BCVA, mean (SD)b	64.8 (10.5)	63.8 (13.2)	63.0 (9.8)	64.0 (11.5)
VFQ-25 composite scorec,d
VFQ-CS, mean (SD)	80.2 (14.1)	76.8 (15.8)	78.9 (14.4)	78.6 (14.9)

Notes:

a A total of 220 participants received trial treatment, however one subject in each treatment group did not attend a post-injection visit and both were therefore not included in the full analysis population.

b Baseline BCVA measurements were not available for 1 MIVI 006 and 1 OASIS participant.

c Composite score is calculated as the mean of the 11 vision-targeted subscale scores, excluding the general health question.²⁵

d Baseline VFQ-CS data were not available for 1 MIVI 006 and 2 MIVI 007 participants.

Abbreviations: ERM, epiretinal membrane; FTMH, full-thickness macular hole; VFQ-25, visual function questionnaire, 25-item form²⁴; BCVA, best-corrected visual acuity; VMT, Vitreomacular traction; MIVI, Microplasmin for Intravitreous Injection; OASIS, Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole.

Table 3 VFQ-25 subscale scores in selected vision conditions from the NEI VFQ field test sample (n=597) and in VMT studies

	Diabetic retinopathy	AMD	Glaucoma	Cataract	CMV retinitis	Low vision	Healthy reference group	VMT- MIVI, OASIS
	(N=123)	(N=108)	(N=77)	(N=93)	(N=37)	(N=90)	(N=122)	(N=870)
Subscales (mean ± SD)
General health	46±25	65±25a,b	62±25a,b	55±25	45±24	57±27	69±24	61±24
General vision	62±21	53±20	71±17	60±17	76±14b	38±18	83±15	63±16
Near vision	63±30	54±27	79±23	73±21	84±20b	36±23	92±13	69±21
Distance vision	66±30	56±29	77±25	73±22	84±18	38±26	93±11	75±20
Driving	55±40	39±36	75±28	63±30	80±28a,b	10±23	87±18	76±24
Peripheral vision	78±29	77±27	76±27	87±21	78±21	59±32	97±10	83±22
Color vision	90±22	85±25	93±17	90±20	98±9a,b	71±31	98±8	94±14
Ocular pain	88±17a,b	87±16a	89±14a,b	86±19b	90±16a,b	85±20a,b	90±15	84±19
Vision specific (mean ± SD)
Role difficulties	69±31	61±31	84±23	76±22	78±24	44±29	93±13	72±26
Dependency	77±30	72±30	92±19	88±20	89±12	51±31	99±5	88±20
Social functioning	81±26	73±29	89±20	87±19	96±9	50±31	99±3	91±16
Mental health	66±29	58±27	81±20	77±22	74±22	46±27	92±12	71±23
Composite score	72±22	65±21	82±17	78±14	84±11	49±19	93±7	79±15

Notes: Composite score data provided by Mangione and colleagues.

a Unadjusted t-test comparison with healthy reference group participants was nonsignificant (P<0.05).

b Linear regression result for 2-group comparison with the health reference group, adjusted for age, sex, race, and medical comorbidities, was nonsignificant (P<0.05).

c Data are presented as mean ± SD. All pairwise comparisons between each disease group and the healthy reference group were statistically significant at P<0.05, unless otherwise specified.

Abbreviations: CMV, cytomegalovirus; AMD, age-related macular degeneration; VFQ-25, Visual Function Questionnaire 25; VMT, vitreomacular traction; MIVI, Microplasmin for Intravitreous Injection; OASIS, Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole.

Figure 2 VFQ-25 composite and subscale scores for VMT patients (investigational and healthy reference groups).

Notes: All pairwise combinations between VMT patients from investigational studies (MIVI, OASIS) vs the healthy reference groups were statistically significant at P<0.05. Composite score for healthy reference group calculated as mean of 11 subscale scores, excluding general health item (courtesy of Mangione and colleagues).
Abbreviations: VFQ-25, Visual Function Questionnaire 25; VMT, vitreomacular traction; MIVI-TRUST, Microplasmin for Intravitreous Injection – Traction Release without Surgical Treatment; OASIS, Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole.

Table 4 Responder analysis for VFQ-25 composite score across studies (month 6 data) – irrespective of vitrectomy

Response criteria: composite scorea	Ocriplasmin % (n/N)	Control % (n/N)	Difference (%) (95% CI)b	P-valuec
Change from baseline ≥5 points
MIVI-TRUST	36.0 (154/428)	27.2 (47/173)	8.8 (0.8, 16.9)	0.045
OASISd	39.3 (57/145)	21.9 (16/73)	17.4 (5.0, 29.8)	0.010
Combined	36.8	25.4	11.8 (3.8, 19.7)	0.004

Notes:

a The composite score is calculated as the mean of the 11 vision-targeted subscale scores, excluding the general health question.

b Difference and CI between treatment groups are based on the percentage of responses.

c For individual studies, the P-value is from Fisher’s exact test, comparing control and ocriplasmin. For combined studies, pooling of risk differences was based on random effects model using the method of DerSimonian and Laird.²⁸

d Estimate based on non-stratified treatment effect, not weighted by FTMH strata.

Abbreviations: N, number of subjects in the dataset; n, number of subjects with a success for the endpoint; FTMH, full thickness macular hole; MIVI-TRUST, Microplasmin for Intravitreous Injection -Traction Release without Surgical Treatment; VFQ-25, Visual Function Questionnaire 25; OASIS, Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole.

Figure 3 Responder rates for visual function response variables by treatment (month 6). (A) MIVI. (B) OASIS.

Abbreviations: BCVA, best corrected visual acuity; VFR, visual function response; VFQ-CS, Visual Function Questionnaire 25-composite score; VFQ-Driving, Visual Function Questionnaire 25-driving; VFQ-MHS, Visual Function Questionnaire 25-mental health subscale; MIVI-TRUST, Microplasmin for Intravitreous Injection – Traction Release without Surgical Treatment; OASIS, Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole.

Table 5 Responder analysis for VFR across studies (month six data)

Response criteria	Ocriplasmin % (n/N)	Control % (n/N)	Difference (%) (95%CI)b	P-valuec
Visual Function Responsea
MIVI-TRUST	55.1 (217/394)	34.2 (53/155)	20.9 (11.9, 29.8)	<0.001
OASISd	51.0 (74/145)	23.3 (17/73)	27.7 (15.1, 40.4)	<0.001
Combined	54.0	30.1	23.2 (15.9, 30.5)	<0.001

Notes:

a Response criteria based on overall VFR composed of 3 dimensions determined by the PCA output (in MIVI-TRUST: VFQ-CS, VFQ-driving, BCVA; in OASIS VFQ-CS, VFQ-MH, BCVA.

b Difference and CI between treatment groups are based on the percentage of responses.

c For individual studies, the P-value is from Fisher’s exact test, comparing control and ocriplasmin. For combined studies, pooling of risk differences was based on random effects model using the method of DerSimonian and Laird.²⁸

d Estimate based on non-stratified treatment effect, not weighted by FTMH strata.

Abbreviations: N, number of subjects in the dataset; n, number of subjects with a success for the endpoint; VFR, visual function response; PCA, principal component analysis; VFQ-CS, visual Function Questionnaire 25-composite score; VFQ-Driving, visual Function Questionnaire 25-driving subscale; VFQ-MHS, visual Function Questionnaire 25-mental health subscale; FTMH, full thickness macular hole; BCVA, best corrected visual acuity; MIVI-TRUST, Microplasmin for Intravitreous Injection – Traction Release without Surgical Treatment; OASIS, Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole.

Figure 4 Responder rates for visual function response measures by anatomical outcome (Month 6). (A) MIVI. (B) OASIS.

Abbreviations: BCVA, best corrected visual acuity; VMA, vitreomacular adhesion; VFR, visual function response; VFQ-CS, Visual Function Questionnaire 25-composite score; VFQ-Driving, Visual Function Questionnaire 25-driving subscale; VFQ-MHS, Visual Function Questionnaire 25-mental health subscale.

Table 6 VFR responder analysis by VMA outcome across studies (month six data)

Response criteria	VMA release % (n/N)	Persisting VMA % (n/N)	Difference (%) (95%CI)b	P-valuec
Visual Function Responsea
MIVI-TRUST	62.5 (80/128)	45.1 (190/421)	17.4 (7.7, 27.0)	0.001
OASISd	56.7 (38/67)	35.1 (53/151)	21.6 (7.5, 35.7)	0.004
Combined	60.6	42.3	18.7 (10.8, 26.7)	<0.001

Notes:

a Response criteria based on overall VFR composed of three dimensions determined by the PCA output (in MIVI-TRUST: VFQ-CS, VFQ-driving, BCVA; in OASIS VFQ-CS, VFQ-MH, BCVA.

b Difference and CI between treatment groups are based on the percentage of responses.

c For individual studies, the P-value is from Fisher’s exact test, comparing VMA release and persisting VMA. For combined studies, pooling of risk differences was based on random effects model using the method of DerSimonian and Laird.²⁸

d Estimate based non-stratified treatment effect, not weighted by FTMH strata.

Abbreviations: N, number of subjects in the dataset. n, number of subjects with a success for the endpoint; VFR, visual function response; PCA, principal component analysis; VFQ-CS, Visual Function Questionnaire 25-composite score; VFQ-driving, Visual Function Questionnaire 25-driving subscale; VFQ-MHS, Visual Function Questionnaire 25-mental health subscale; FTMH, full thickness macular hole; MIVI-TRUST, Microplasmin for Intravitreous Injection – Traction Release without Surgical Treatment; OASIS, Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole.

Figure 5 Visual function outcomes by VMA subgroups. (A) Overall visual function response. (B) Visual function composite score. Abbreviations: VMA, vitreomacular adhesion; VFQ-25, Visual Function Questionnaire 25.

Table 7 VFR response at month 6, by VMA status at day 28

	Ocriplasmin % (n/N)	Control % (n/N)	Difference (%) (95%CI)b	P-valuec
VMA release at day 28
MIVI-TRUST	64.3 (72/112)	50.0 (8/16)	14.3 (–11.8, 40.3)	0.283
OASISd	59.7 (37/62)	20.0 (1/5)	39.7 (2.6, 76.8)	0.158
Combined	62.7	40.2	23.5 (–8.0, 47.8)	0.058
Persisting VMA at day 28
MIVI-TRUST	51.4 (145/282)	32.4 (45/139)	19.0 (9.3, 28.8)	<0.001
OASISd	44.6 (37/83)	23.5 (16/68)	21.0 (6.4, 35.7)	0.010
Combined	49.8	29.1	19.7 (11.5–27.8)	<0.001

Notes:

a Response criteria based on overall VFR composed of three dimensions determined by the PCA output (in MIVI-TRUST: VFQ-CS, VFQ-driving, BCVA; in OASIS VFQ-CS, VFQ-MH, BCVA.

b Difference and CI between treatment groups are based on the percentage of responses.

c For individual studies, the P-value is from Fisher’s exact test, comparing control and ocriplasmin. For combined studies, pooling of risk differences was based on random effects model using the method of DerSimonian and Laird.²⁸

d Estimate based non-stratified treatment effect, not weighted by FTMH strata.

Abbreviations: N, number of subjects in the dataset; n, number of subjects with a success for the endpoint; VFR, visual function response; VMA; vitreomacular adhesion; PCA, principal component analysis; VFQ-CS, Visual Function Questionnaire 25-composite score; VFQ-driving, Visual Function Questionnaire 25-driving subscale; VFQ-MHS, Visual Function Questionnaire 25-mental health subscale; FTMH, full thickness macular hole; MIVI-TRUST, Microplasmin for Intravitreous Injection – Traction Release without Surgical Treatment; OASIS, Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole; BCVA, best corrected visual acuity.

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Data availability

The database with data extraction and analyses can be obtained upon request.