TG‐MV‐007 2012.

Methods	Study design: RCT, single treated eye. Number randomised: 326 total; 245 ocriplasmin; 81 placebo. Exclusions after randomisation: none. Number analysed: at 28 days: 326 total; 245 ocriplasmin; 81 placebo. At 180 days: 309 total; 235 ocriplasmin; 74 placebo. Unit of analysis: eyes. Losses to follow‐up: 17 participants total; 10 ocriplasmin group (5 withdrawal by participant, 2 lost to follow‐up, 2 adverse event, 1 death); 7 placebo group (1 physician decision, 4 withdrawal by participant, 2 lost to follow‐up). How was missing data handled? missing data not reported in study publications. Power calculation: 320 participants for > 90% power at 2‐sided alpha of 0.05 to assume a primary endpoint of 27.5% in ocriplasmin group and 10.0% rate in placebo group.
Participants	Countries: Belgium, Czech Republic, Germany, Poland, Spain, UK, USA. Mean age: 72.0 years overall; 72.6 years for ocriplasmin group; 70.2 years for placebo group. Gender: 222/326 (68.1%) women, 104/326 (31.9%) men total; 166/245 (67.8%) women, 79/245 (32.2%) men in ocriplasmin group; 56/81 (69.1%) women, 25/81 (30.9%) men in placebo group. 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 (e.g. 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 (including PDR or other ischaemic retinopathies involving vitreoretinal vascular proliferation) or exudative AMD or retinal vein occlusion in study eye; people with any vitreous haemorrhage or any other vitreous opacification which precludes either: visualisation of posterior pole by visual inspection OR adequate assessment of macula by either OCT or fluorescein angiogram (or both) in study eye; MH > 400 µm in diameter in study eye; aphakia in study eye; high myopia (> ‐8 dioptres); 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. Equivalence of baseline characteristics: no; pseudophakia more common in ocriplasmin group than in placebo group; more women in ocriplasmin group than in placebo group.
Interventions	Intervention: single intravitreal injection of ocriplasmin 125 µg in 0.10 mL volume. Comparator: single intravitreal injection of 0.10 mL placebo with identical drug vehicle diluted with saline. Length of follow‐up: planned 180 days, actual 180 days.
Outcomes	Primary outcome, as defined in study reports: "the primary end point was the proportion of subjects with nonsurgical resolution of VMA at day 28 post‐injection, as determined by masked OCT evaluation obtained from the central reading centre." Secondary outcomes, as defined in study reports: proportion of participants with total PVD at day 28, as determined by B‐scan ultrasound; need for vitrectomy; closure of an MH; 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.
Notes	Funding sources: study sponsored by ThromboGenics NV. Study period: 2 years; 2008‐2010. Reported subgroup analyses: yes. NCT00798317.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Supplementary material: "subjects will be randomised centralized through a telephone‐based Interactive Voice Response System (IVRS) to either microplasmin intravitreal injection or placebo in a 3:1 allocation ratio. Blocks of treatment will be assigned to sites in a manner expected to minimize the potential for imbalance in the desired randomization ratio." Protocol p. 17.
Allocation concealment (selection bias)	Low risk	Supplementary material: "subjects will be randomised centralized through a telephone‐based Interactive Voice Response System (IVRS) to either microplasmin intravitreal injection or placebo in a 3:1 allocation ratio. Blocks of treatment will be assigned to sites in a manner expected to minimize the potential for imbalance in the desired randomization ratio." Protocol p. 17.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Patients randomly assigned to the ocriplasmin group received an intravitreal injection of ocri‐ plasmin (125μg in a 0.10‐ml volume) drawn from a vial containing ocriplasmin into which 0.75ml of commercial saline had been injected (1875μg of ocriplasmin in a 0.75‐ml drug vehicle). Patients randomly assigned to placebo received an intravitreal injection of 0.10 ml of the identical drug vehicle diluted with saline, the method used being the same as that used to prepare ocriplasmin". p. 608.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Trained readers at a central reading center (Duke University OCT Reading Center, Durham, NC) who were unaware of the group assignments evaluated the OCT images. All ultrasonographic studies were standardized and performed by certified technicians who underwent special training for the study. Staging of posterior vitreous detachment was based on dynamic ultrasonographic evaluation and performed by an investigator who was unaware of the group assignments." p. 608.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	No description found in article, but 17 participants reported as not completing study on ClinicalTrials.gov. The corresponding author of Stalmans and colleagues (2012) was contacted to query this. ThromboGenics NV responded by confirming use of last observation carried forward (LOCF) approach to input missing data for visits postdiscontinuation. Their explanation was: "use of LOCF was appropriate when the outcome is not expected to change after discontinuation and is a conservative method when the outcome is expected to improve spontaneously over time. The primary endpoint, pharmacological VMA resolution in particular, is an outcome of that nature." As these losses to follow‐up were not reported in original paper, risk of attrition bias was deemed unclear.
Selective reporting (reporting bias)	Low risk	All defined outcomes in methods were reported.
Other bias	Unclear risk	Baseline imbalance between study groups as pseudophakia was more common in ocriplasmin group than in placebo group and there were more women in ocriplasmin group than in placebo group.

AMD: age‐related macular degeneration; BCVA: best corrected visual acuity; FTMH: full‐thickness macular hole; MH: macular hole; OCT: optical coherence tomography; PDR: proliferative diabetic retinopathy; PVD: posterior vitreous detachment; RCT: randomised controlled trial; sVMA: symptomatic vitreomacular adhesion; VFQ‐25: Visual Function Questionnaire 25; VMA: vitreomacular adhesion.