Clinical trial NCT02681809
Conditions: Diabetic Retinopathy Posterior Vitreous Detachment Disease Progression
Sponsor: ThromboGenics
Start date: 2015-12-01; Completion date: 2019-11-18
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the efficacy and safety of up to 3 intravitreal injections of ocriplasmin (0.0625mg or 0.125mg), in subjects with moderate to very severe non-proliferative diabetic retinopathy (NPDR), to induce total posterior vitreous detachment (PVD) in order to reduce the risk of disease progression to proliferative diabetic retinopathy (PDR).

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: ocriplasmin 0.0625mg intervention 2: ocriplasmin 0.125mg intervention 3: Sham injection
Intervention descriptions: intervention 1: Up to 3 intravitreal injections of ocriplasmin 0.0625mg approximately 1 month apart intervention 2: Up to 3 intravitreal injections of ocriplasmin 0.125mg approximately 1 month apart intervention 3: 3 sham injections approximately 1 month apart. No actual injections. No medication is used.

Protocol documents:
Prot_000.pdf: 
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CLARIFICATION NOTE 
Recruitment in the study was discontinued early due to slow recruitment rate. As a consequence, 
a total of 48 subjects were randomised instead of the planned 115.  
This led to the following changes to the analyses planned in the study protocol: 
• A single analysis dataset was used instead of the 3 listed in the protocol. 
• The first and third quartiles, and 5th and 95th percentiles were not included in the 
summary statistics of continuous variables. 
• No statistical testing was performed. 
• The last-observation-carried-forward method for data imputation was not used, and 
no sensitivity analysis was performed. 
• The stratification variable, NPDR severity, was not taken into account in any 
summary statistics.  
• The following exploratory endpoints were not summarised:  
− A ≥ 2-step progression on the ETDRS Severity Scale from baseline, at Month 15 
and at Month 24, based on 7 standard field stereo colour fundus photography, as 
assessed by the masked CRC 
− Improvement of ≥ 2 steps on the ETDRS Severity Scale from baseline, at Month 
15 and at Month 24, based on 7 standard field stereo colour fundus photography, 
as assessed by the masked CRC 
− Neovascularisation as compared to baseline, at Month 15 and at Month 24, based 
on 7 standard field stereo colour fundus photography, as assessed by the masked 
CRC 
− Vitreous / pre-retinal haemorrhage by Month 24, based on 7-standard field stereo 
colour fundus photography, as assessed by the masked CRC 
− Development of iris neovascularisation as compared to baseline, at each study 
visit, based on slit lamp examination 
 
 
 
 
 


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STUDY CONTACTS 
Table 1: 
Contact Information 
Role in Study 
Name 
Address and Telephone 
Number 
Sponsor Medical Expert 
Petra Kozma-Wiebe, MD, PhD 
Gaston Geenslaan 1 
B-3001 Leuven 
Belgium 
+32.491.07.23.42 
 


PERSONS AUTHORISED TO SIGN PROTOCOL AND AMENDMENTS 
Table 2: 
Persons Authorised to Sign Protocol and Amendments 
Name 
Name 
Petra Kozma-Wiebe, MD, PhD 
Andy De Deene, MD 
Title 
Title 
Sponsor Medical Expert 
Global Head of Development 
 


SPONSOR SIGNATURE PAGE 
PROTOCOL TG-MV-015 
 
 
 
 
 
AMENDMENT 2 DATE: 
28-OCT-2016 
 
 
A PHASE 2, RANDOMISED, DOUBLE-MASKED, SHAM-CONTROLLED, MULTI-
CENTRE STUDY TO EVALUATE THE EFFICACY AND SAFETY OF OCRIPLASMIN IN 
INDUCING TOTAL POSTERIOR VITREOUS DETACHMENT (PVD) IN SUBJECTS WITH 
NON-PROLIFERATIVE DIABETIC RETINOPATHY (NPDR) (CIRCLE) 
 
 
 
 
 
 
 
 
 
On behalf of ThromboGenics 
 
 
 
 
Signed:____________________________  
___________________ 
 
Andy De Deene, MD  
 
 
Date 
 
Global Head of Development 


INVESTIGATOR’S AGREEMENT 
PROTOCOL TG-MV-015 
 
AMENDMENT 2 DATE: 
28-OCT-2016 
 
A PHASE 2, RANDOMISED, DOUBLE-MASKED, SHAM-CONTROLLED, MULTI-
CENTRE STUDY TO EVALUATE THE EFFICACY AND SAFETY OF OCRIPLASMIN IN 
INDUCING TOTAL POSTERIOR VITREOUS DETACHMENT (PVD) IN SUBJECTS WITH 
NON-PROLIFERATIVE DIABETIC RETINOPATHY (NPDR) (CIRCLE) 
 
 
 
 
I have read the protocol and by my signature below I agree that I will conduct this protocol as 
outlined therein and will make a reasonable effort to complete the study within the time 
designated. I agree to conduct this study in compliance with the Declaration of Helsinki, the ICH 
guideline for Good Clinical Practice, all applicable local and federal regulatory requirements and 
state / local customs or laws. 
I will provide copies of the protocol and access to information furnished by ThromboGenics to 
study personnel under my supervision. I will discuss this material with them to ensure they are 
fully informed about the drug and the study.  
I have read the Investigator’s Brochure. I agree to ensure the confidentiality of my subjects; 
however, I agree to make available to the CRO, the Sponsor of this clinical study or relevant 
regulatory authorities those sections of my subjects’ medical records which directly concern this 
study. I understand that the study may be terminated or enrolment suspended at any time by 
ThromboGenics, or by me if it becomes necessary to protect the best interests of the study 
subjects. 
 
 
 
Signed:____________________________  
___________________ 
 
ADD INV. NAME AND TITLE 
 
Date 


PROTOCOL SYNOPSIS 
Name of Sponsor / Company: 
ThromboGenics 
Name of Test Products:  
ocriplasmin 0.0625mg 
ocriplasmin 0.125mg 
Name of Active Ingredient: 
ocriplasmin 
Protocol Title:  
A Phase 2, randomised, double masked, sham controlled, multi-centre study to evaluate the efficacy 
and safety of ocriplasmin in inducing total posterior vitreous detachment (PVD) in subjects with 
non-proliferative diabetic retinopathy (NPDR) (CIRCLE) 
Protocol Number: 
TG-MV-015 
Study Period:  
Estimated date first subject enrolled: December 2015 
Estimated date last subject completed: July 2019 
Phase of Development:  
2 
Objective: 
• 
To assess the efficacy and safety of up to 3 intravitreal injections of ocriplasmin (0.0625mg 
or 0.125mg), in subjects with moderate to very severe NPDR, to induce total PVD in order to 
reduce the risk of disease progression to proliferative diabetic retinopathy (PDR) 
Number of Subjects (Planned):  
Approximately 115 subjects (approximately 46 in each ocriplasmin arm and 23 in the sham arm) 
Study Population:  
Diabetic subjects with moderate to very severe NPDR (International Clinical Diabetic Retinopathy 
Disease Severity Scale [ETDRS] Levels 43A -53E), who do not have total PVD 
Study Design Overview:  
• 
Study design. Multi-centre, randomised, sham-controlled, double-masked, Phase 2 clinical 
study with 3 parallel treatment arms 
• 
Study arms and treatments. 
o 
Ocriplasmin 0.0625mg arm. Approximately 46 subjects will receive up to 
3 intravitreal injections of ocriplasmin 0.0625mg, approximately 1 month apart. All 
subjects assigned to this arm will receive an intravitreal injection of ocriplasmin 
0.0625mg at Day 0. These subjects will be re-treated with ocriplasmin 0.0625mg at 
Day 35 and at Day 70 if, by that time, they have not achieved total PVD on both 
B-scan ultrasound and spectral domain optical coherence tomography (SD-OCT), as 
assessed by the masked B-scan expert reader and the masked central reading centre 
(CRC), respectively. Subjects who have total PVD on both B-scan ultrasound and 
SD-OCT will receive subsequent sham injection(s) in place of ocriplasmin 
injection(s) 


o 
Ocriplasmin 0.125mg arm. Approximately 46 subjects will receive up to 
3 intravitreal injections of ocriplasmin 0.125mg, approximately 1 month apart. All 
subjects assigned to this arm will receive an intravitreal injection of ocriplasmin 
0.125mg at Day 0. These subjects will be re-treated with ocriplasmin 0.125mg at 
Day 35 and at Day 70 if, by that time, they have not achieved total PVD on both 
B-scan ultrasound and SD-OCT, as assessed by the masked B-scan expert reader and 
the masked CRC, respectively. Subjects who have total PVD on both B-scan 
ultrasound and SD-OCT will receive subsequent sham injection(s) in place of 
ocriplasmin injection(s) 
o 
Sham arm. Approximately 23 subjects will receive 3 sham injections, approximately 
1 month apart. All subjects assigned to this arm will receive a sham injection at 
Day 0, Day 35 and Day 70 
• 
Test product, dose and mode of administration. Up to 3 intravitreal injections of 
ocriplasmin 0.0625mg or ocriplasmin 0.125mg 
• 
Reference therapy (comparator), dose and mode of administration. 3 sham injections 
• 
Treatment allocation. Eligible subjects will be sequentially assigned according to a 
computer-generated randomisation list to the ocriplasmin 0.0625mg arm, the ocriplasmin 
0.125mg arm or the sham arm in a 2:2:1 allocation ratio. Randomisation will be stratified by 
baseline NPDR severity (moderate and moderately severe, i.e. ETDRS Level 43A-47D vs. 
severe and very severe NPDR, i.e. ETDRS Level 53A-E). It is expected that more subjects 
with moderate and moderately severe than with severe and very severe NPDR will be 
enrolled, as a reflection of the natural population. Therefore, enrolment in the moderate and 
moderately severe NPDR stratum may become capped in the course of the study 
• 
Study duration. For each subject enrolled, the study duration will be approximately 
24 months from the first injection 
Inclusion and Exclusion Criteria: 
Subjects can have only 1 eye treated as part of this study. For eligible subjects where both eyes are 
eligible for injection, the eye with the more advanced NPDR stage (as determined by the CRC) will 
be selected as the study eye. 
Inclusion Criteria 
• 
Male or female aged 18 years or older 
• 
Best corrected visual acuity (BCVA) of 65 letters read or greater (Snellen equivalent of 20/50 
or better) in the study eye 
• 
BCVA of 20 letters read or greater (Snellen equivalent of 20/400 or better) in the fellow eye 
• 
Clear ocular media for adequate fundus imaging in the study eye 
• 
HbA1c ≤ 12%, as assessed by the central laboratory 
• 
Moderate to very severe NPDR as per ETDRS Severity Scale (Levels 43A-53E), based on 
7-standard field stereo colour fundus photograph, as assessed by the CRC 
• 
Central subfield thickness (CST) of ≤ 340µm on Spectralis SD-OCT or ≤ 320µm on 
non-Spectralis SD-OCT in the study eye, as assessed by the CRC, with or without mild 
centre-involved DME (CI-DME) (mild CI-DME is defined as cysts or intraretinal fluid in the 
central subfield on SD-OCT that in the Investigator’s opinion will not require treatment with 
an anti-VEGF for at least up to 3 months after randomisation) 
• 
No evidence of total PVD in the study eye, based on both B-scan ultrasound and SD-OCT, as 
assessed by the B-scan expert reader and the CRC, respectively 


• 
Written informed consent obtained from the subject prior to screening procedures 
Exclusion Criteria 
• 
History of or current ocular condition in the study eye that may interfere with the assessment 
of the progression to PDR (e.g. vitreomacular traction [VMT], exudative age-related macular 
degeneration [AMD], retinal vein occlusion [branch or central vein], uveitis, angioid streaks, 
histoplasmosis, toxoplasmosis, rhegmatogenous retinal detachment, retinal tear, fibrovascular 
proliferation, lattice degeneration, macular hole, ocular tumours) 
• 
Significant ocular trauma in the study eye within 6 months prior to screening (including 
corneo-scleral laceration, lens subluxation, cryo-retinopexy) 
• 
Corneal, lenticular, or ocular media abnormalities in the study eye that preclude observation 
with the slit lamp or accurate readings with a tonometer 
• 
Presence of epiretinal membrane in the study eye, based on SD-OCT, as assessed by the CRC 
• 
Presence of foveal ischemia in the study eye, based on fluorescein angiograph, as assessed by 
the CRC 
• 
Presence of pre-retinal or vitreous haemorrhage in the study eye 
• 
Presence of iris or angle neovascularisation in the study eye 
• 
Any active ocular / intraocular infection or inflammation in either eye (e.g. blepharitis, 
infectious conjunctivitis, keratitis, scleritis, endophthalmitis, uveitis) 
• 
Uncontrolled glaucoma in the study eye (uncontrolled glaucoma is defined as intraocular 
pressure [IOP] ≥ 26mmHg despite treatment with anti-glaucoma medication) 
• 
More than 8D high myopia in the study eye  
• 
Aphakic study eye 
• 
Previous treatments / procedures as follows: 
Treatment / Procedure In the Study Eye 
Excluded Period prior to Randomisation 
Vitrectomy 
Any time 
Pan-retinal photocoagulation (PRP) 
Any time 
Intraocular surgery 
4 months 
Focal / grid laser photocoagulation 
3 months 
Intravitreal anti vascular endothelial growth 
factor (anti-VEGF) 
1 month 
Topical ocular steroids 
1 month 
Intravitreal and peri-ocular steroids  
4 months 
Steroid implants 
Any time 
• 
Uncontrolled hypertension in the opinion of the Investigator (e.g. systolic blood pressure 
> 160mmHg or diastolic blood pressure > 100mmHg for at least 30 days prior to screening 
despite antihypertensive treatment, or any finding in the Investigator’s opinion suggesting 
hypertensive retinopathy) 
• 
Pseudoexfoliation, Marfan’s syndrome, phacodonesis or any other finding in the 
Investigator’s opinion suggesting lens / zonular instability 


• 
Current use of or possible need for systemic medications known to be toxic to the lens, retina 
or optic nerve, including Deferoxamine, Chloroquine / hydroxychloroquine (Plaquenil), 
Tamoxifen, Phenothiazines and Ethambutol 
• 
Known hypersensitivity to ocriplasmin, its excipients or any of the medications that will be 
used for study procedures (e.g. fluorescein, antibiotics, anaesthetic eye drops, eye drops for 
pupil dilation) 
• 
Pregnant or lactating female, or female of child-bearing potential not utilising an adequate 
form of contraception, or male of reproductive potential not utilising contraception (where 
1 method is barrier at the minimum) 
• 
Previous ocriplasmin injection in the study eye 
• 
History and / or current evidence of a systemic medical condition or any other reason that 
may, in the Investigator’s opinion, preclude adherence to the scheduled study visits / 
assessments and safe participation in the study 
• 
Concurrent participation in another clinical study, at any time during the entire study period, 
in which the subject has been or will be exposed to an investigational or a non-investigational 
product (pharmaceutical product or device) 
• 
Use of any investigational, non-registered or off-label product within 30 days prior to 
screening, or planned use during the entire study period 
Diabetic Retinopathy-related Treatment: 
Escape Criteria 
• 
Subjects may be treated with pan-retinal photocoagulation (PRP) following the confirmation 
of progression from NPDR to PDR, as assessed by the masked CRC. No minimum time 
interval between study treatment and PRP needs to be considered 
• 
Subjects may be treated with an anti-VEGF treatment following the confirmation of 
development of CI-DME with CST of ≥ 340µm on Spectralis SD-OCT or ≥ 320µm on 
non-Spectralis SD-OCT, or an increase of 50µm from baseline in CST, based on SD-OCT, as 
assessed by the masked CRC. There are no clinical data on concomitant use of ocriplasmin 
with anti-VEGF treatment, however, as ocriplasmin is a proteolytic enzyme with serine 
protease activity which could be present in the eye for several days after intravitreal injection, 
administration in close temporal association with other medicinal products in the same eye 
may affect the activity of both medicinal products and is therefore not recommended. A 
minimum time of 7 days between study treatment and anti-VEGF injection is therefore 
required 
Study Masking: 
The study will be conducted in a double-masked manner up to the Month 15 analysis. As of the 
Month 15 analysis, the Sponsor will be unmasked, while the masking will be kept for the B-scan 
expert reader, the CRCs, the masked study staff and the subjects up to the end of the study.   
In order to maintain the masking, the following measures will be taken: 
• 
Study staff. In order to maintain the masking, 2 teams of study staff will be identified. 
One (1) team will be masked while the other will be unmasked. The unmasked team will 
include an unmasked treating investigator who will be performing the (sham) injections and 
will ensure immediate follow-up of the subject after injection (1-hour post-injection 
assessment) 
• 
Drug kits. Each carton will contain a single vial (ocriplasmin or sham). The carton and the 
vial label will be masked. However, as ocriplasmin vials will have a different appearance 


than sham vials, it is important that drug kits are opened by unmasked study personnel only. 
The vials will have a peel-off label, which will be put in the accountability log 
• 
Administration kits. The carton label will be masked. As there will be 2 different types of 
administration kits, it is important that the kits are opened by unmasked study personnel only. 
All administration kits will contain 2 syringes, 2 needles 19-gauge (19G) and 1 needle 
30-gauge (30G). Some administration kits will also contain an ampoule of sodium chloride 
(NaCl) 9mg/mL (0.9%), whereas others will not. The administration kits will have a peel-off 
label, which will be put in the accountability log 
• 
Injection procedures. In order to maintain the subject masked, injection procedures will, as 
much as possible, be the same for the ocriplasmin and sham injections. Pre-injection 
procedures will be identical for ocriplasmin and sham injections, including antisepsis and use 
of topical anaesthesia. Study drug preparation will not be identical for ocriplasmin and sham 
injections and should be done outside of the subject’s view. A sterile drape may be used to 
cover the subject’s fellow eye and the subject will be asked to direct his / her gaze away at all 
times. Subjects in the sham arm will not receive an actual injection (no penetration of the 
globe will occur). For the sham injection, no needle will be attached to the syringe. The 
unmasked treating investigator will press the hub of the syringe firmly against the 
sclera / conjunctiva and slowly depress the plunger to mimic the test product injection 
procedure 
• 
B-scan expert reader and CRCs. The B-scan expert reader, the CRC readers and, where 
applicable, the adjudicators at the CRCs will be masked to the treatment assignment 
• 
Immunogenicity assessment. The laboratory in charge of the immunogenicity assay will be 
masked to the treatment assignment 
Safety: 
Withdrawal from Repeat Injection 
The following events should be assessed at Visit 4a (Day 28) and Visit 6a (Day 63), before repeat 
injection. If any of these events apply, no further injection(s) should be given. For events that are 
deemed to be temporary, the injection can be postponed, if this is feasible within the protocol-
specified study visit interval 
• 
Severe intraocular inflammation associated with previous injection 
• 
Active intraocular inflammation or infection in either eye at the time of repeat injection 
• 
Any signs or symptoms of lens subluxation associated with previous injection 
• 
Any condition associated with previous injection requiring surgical treatment (e.g. new 
macular hole, worsening of existing macular hole, retinal tear, retinal detachment, IOP 
increase) 
• 
Persistent presence of subretinal fluid or inner segment / outer segment (IS / OS) junction 
changes with functional impairment, associated with previous injection, at the time of repeat 
injection 
• 
Persistent complaint of dim vision, dark adaptation problems or impaired night vision, or 
afferent pupillary defect, associated with previous injection, at the time of repeat injection 
• 
BCVA decrease ≥ 15 letters from baseline or BCVA worse than 20/400, in the study eye, at 
the time of repeat injection 
• 
Significant ocular trauma in the study eye at the time of repeat injection 
• 
Any other intraocular injection since previous study injection 
• 
Pregnancy 


• 
Subject’s individual treatment assignment has been unmasked (emergency unmasking) 
In addition, subjects may be withdrawn from repeat injection at any time at the discretion of the 
Investigator (e.g. based on significant abnormalities on ophthalmic examination or functional test 
associated with previous injection not listed above)  
Safety Oversight 
In order to maintain a general safety oversight and to monitor the risk / benefit balance, a data 
monitoring committee (DMC) will be established for this study  
From the time the first subject is injected until the last subject completed the Month 3 visit (Visit 8), 
the following treatment-emergent adverse events (TEAEs) will be escalated to the DMC on an 
ongoing basis: 
• 
Lens subluxation  
• 
Iso-electric full-field electroretinograms (ffERGs)  
• 
Clinically significant increased intraocular inflammation after repeat (2nd or 3rd) injection 
• 
BCVA decrease ≥ 15 letters from baseline, without evidence of resolution or stabilisation 
within 24 hours 
• 
Foveal detachment or worsening of a foveal detachment 
• 
Any other event at the discretion of the Sponsor 
The DMC will conduct periodic reviews at the following pre-defined timepoints: 
• 
After approximately 20% of the subjects completed the Month 2 visit (Visit 6b) 
• 
After approximately 50% of the subjects completed the Month 3 visit (Visit 8) 
• 
After all subjects completed the Month 3 visit (Visit 8) 
• 
After all subjects completed the Month 15 visit (Visit 10) 
In addition, ad hoc DMC meetings may be organised 
The DMC will be empowered to make recommendations to the Sponsor on further study conduct. 
Such recommendations include continuing or terminating the study or modifications to the study. 
Another recommendation may be temporary suspension of enrolment and / or study treatment until 
some uncertainty is resolved 
Criteria for Evaluation: 
Efficacy 
Primary Efficacy Endpoint: 
• 
Total PVD by the Month 3 visit, confirmed on both B-scan ultrasound and SD-OCT (6mm), 
as assessed by the masked B-scan expert reader and the masked CRC, respectively  
Exploratory Efficacy Endpoints: 
• 
A ≥ 2-step progression on the ETDRS Severity Scale from baseline, at Month 15 and at 
Month 24, based on 7-standard field stereo colour fundus photography, as assessed by the 
masked CRC 
• 
Progression from NPDR at baseline to PDR (at least ETDRS level 61) at Month 15 and at 
Month 24, based on 7-standard field stereo colour fundus photography, as assessed by the 
masked CRC 
• 
Improvement of ≥ 2 steps on the ETDRS Severity Scale from baseline, at Month 15 and at 
Month 24, based on 7-standard field stereo colour fundus photography, as assessed by the 
masked CRC 


• 
Neovascularisation as compared to baseline, at Month 15 and at Month 24, based on 
7-standard field stereo colour fundus photography, as assessed by the masked CRC 
• 
Development or progression of macular oedema as compared to baseline, at each study visit, 
based on SD-OCT, as assessed by the masked CRC 
• 
BCVA change from baseline at each study visit 
• 
Total PVD at each study visit, confirmed on both B-scan ultrasound and SD-OCT (6mm), as 
assessed by the masked B-scan expert reader and the masked CRC, respectively 
• 
Total PVD by the Month 3 visit, based on widefield SD-OCT, as assessed by the masked 
CRC, in a subset of sites where this is available 
• 
Vitreous / pre-retinal haemorrhage by Month 24, based on 7-standard field stereo colour 
fundus photography, as assessed by the masked CRC 
• 
Development of iris neovascularisation as compared to baseline, at each study visit, based on 
slit lamp examination 
• 
PRP treatment by the Month 15 visit 
• 
Anti-VEGF treatment by the Month 15 visit 
• 
Vitrectomy by the Month 15 visit 
Safety 
Principal Safety Endpoint: 
• 
Ocular TEAEs in the study eye 
Safety will be further assessed through reported TEAEs, full ophthalmic examination, BCVA 
assessment, assessment of colour vision (in a subset of sites where the Roth 28 Colour Test is 
available), SD-OCT, ffERG (at sites where this is available, in approximately 25% of the subjects) 
and assessment of immunogenicity 
Statistical Methods: 
Determination of Sample Size 
One hundred and fifteen (115) subjects (46 subjects in each of the ocriplasmin arms and 23 subjects 
in the sham arm) will provide 80% power to detect a significant difference in total PVD rate by the 
Month 3 visit, for the comparison of sham to each of the ocriplasmin arms at a 2-sided alpha level of 
0.05, assuming total PVD is achieved in 5% and 40% of the subjects in the sham and ocriplasmin 
arms, respectively. The sample size takes into account a drop-out rate of 10% by the Month 3 visit 
In order to protect the alpha level to 0.05, a hierarchical testing procedure will be used. Ocriplasmin 
0.125mg will be first compared to sham. If the p-value of this first comparison is found < 0.05, then 
ocriplasmin 0.0625mg will be compared to sham 
Statistical Analyses 
Primary Efficacy Analysis: 
• 
The proportion of subjects with total PVD by the Month 3 visit will be calculated in each 
treatment arm with corresponding 95% confidence interval (CI), stratified for NPDR severity 
at baseline. The adjusted differences in proportions between sham and each of the 
ocriplasmin arms will be calculated with its corresponding 95% CI and tested using the 
Cochran-Mantel-Haenszel test. In addition, the effect of treatment on the proportion of 
subjects with total PVD will be computed using a logistic regression with effects for 
treatment and NPDR severity at baseline 


Principal Safety Analyses: 
• 
The proportion of subjects with ocular TEAEs in the study eye at any time during the study 
will be calculated in each treatment arm with corresponding 95% CI 
• 
The proportion of subjects with a loss of ≥ 15 ETDRS letters at any time during the study and 
between Day 0 and Day 7 after each injection will be calculated in each treatment arm with 
corresponding 95% CI 
Sequence of Analyses 
• 
While the Sponsor is masked to the individual treatment assignments, the data analyses for 
the DMC meetings will be performed by an unmasked, independent external statistician. The 
independent external statistician will maintain secure custody of unmasked or partially 
unmasked data  
• 
The analysis of the primary endpoint will be performed by an unmasked, independent, 
external statistician when all subjects have completed the Month 3 visit (Visit 8). The 
independent external statistician will maintain secure custody of unmasked or partially 
unmasked data  
• 
The analysis of the exploratory efficacy and the safety endpoints up to the Month 15 visit will 
be performed when all subjects have completed the Month 15 visit (Visit 10)  
• 
An additional analysis will be performed when all data is available, after the database lock 


TABLE OF CONTENTS 
1. 
BACKGROUND INFORMATION ............................................................. 22 
1.1. 
Introduction ................................................................................................... 22 
1.1.1. 
Diabetic Retinopathy .................................................................................... 22 
1.1.2. 
Current Treatment Options ........................................................................... 22 
1.2. 
Test Product .................................................................................................. 23 
1.3. 
Preclinical / Clinical Data ............................................................................. 24 
1.3.1. 
Preclinical Data ............................................................................................. 24 
1.3.2. 
Clinical Data ................................................................................................. 24 
1.4. 
Study Rationale ............................................................................................. 25 
1.4.1. 
Rationale for the Study ................................................................................. 25 
1.4.2. 
Rationale for the Dose and the Injection Regimen ....................................... 25 
1.4.2.1. 
Rationale for the Dose .................................................................................. 25 
1.4.2.2. 
Rationale for the Injection Regimen ............................................................. 26 
1.4.3. 
Rationale for the Use of a Sham Control ...................................................... 26 
1.5. 
Risks / Benefits ............................................................................................. 26 
1.5.1. 
Potential Risks .............................................................................................. 27 
1.5.1.1. 
Potential Risks Related to the Test Product .................................................. 27 
1.5.1.2. 
Potential Risks Related to Other Study Procedures ...................................... 28 
1.5.2. 
Potential Benefits .......................................................................................... 29 
2. 
STUDY OBJECTIVE ................................................................................... 30 
3. 
STUDY DESIGN AND METHODOLOGY................................................ 31 
3.1. 
Study Endpoints ............................................................................................ 31 
3.1.1. 
Efficacy Endpoints ........................................................................................ 31 
3.1.2. 
Safety Endpoints ........................................................................................... 32 
3.2. 
Study Design Overview ................................................................................ 32 
3.3. 
Number of Subjects ...................................................................................... 33 
3.4. 
Data Monitoring Committee ......................................................................... 33 
3.5. 
Treatment Allocation .................................................................................... 34 
3.5.1. 
Treatment Allocation at First Injection ......................................................... 34 
3.5.2. 
Treatment Allocation at Repeat Injection ..................................................... 35 
3.6. 
Masking ........................................................................................................ 35 


3.6.1. 
Masking Procedures ...................................................................................... 35 
3.6.2. 
Emergency Unmasking ................................................................................. 36 
3.6.3. 
Responsibilities Masked / Unmasked Study Staff ........................................ 36 
3.7. 
Study Duration .............................................................................................. 36 
3.8. 
Data Capturing .............................................................................................. 36 
3.9. 
Regulatory and Ethical Considerations ........................................................ 37 
3.10. 
Criteria for Discontinuation of the Study ..................................................... 37 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................ 38 
4.1. 
Study Population ........................................................................................... 38 
4.1.1. 
Inclusion and Exclusion Criteria .................................................................. 38 
4.1.1.1. 
Subject Inclusion Criteria ............................................................................. 38 
4.1.1.2. 
Subject Exclusion Criteria ............................................................................ 38 
4.2. 
Subject Withdrawal Criteria ......................................................................... 40 
4.2.1. 
Withdrawal from Repeat Injection ............................................................... 40 
4.2.2. 
Withdrawal from the Study .......................................................................... 41 
5. 
STUDY OBSERVATIONS AND PROCEDURES ..................................... 42 
5.1. 
Informed Consent ......................................................................................... 42 
5.2. 
Visit 1 - Screening Visit ............................................................................... 42 
5.3. 
Visit 2 –Day 0 ............................................................................................... 43 
5.4. 
Post-injection Phone Call ............................................................................. 44 
5.5. 
Visit 3 - Day 7 ............................................................................................... 44 
5.6. 
Visit 4a – Day 28 .......................................................................................... 45 
5.7. 
Visit 4b – Day 35 .......................................................................................... 45 
5.8. 
Post-injection Phone Call ............................................................................. 45 
5.9. 
Visit 5 –Day 42 ............................................................................................. 46 
5.10. 
Visit 6a – Day 63 .......................................................................................... 46 
5.11. 
Visit 6b – Day 70 .......................................................................................... 46 
5.12. 
Post-injection Phone Call ............................................................................. 46 
5.13. 
Visit 7 – Day 77 ............................................................................................ 46 
5.14. 
Visit 8 – Month 3 (Day 98) ........................................................................... 46 
5.15. 
Visit 9 – Month 9 (Day 270) ......................................................................... 47 
5.16. 
Visit 10 – Month 15 (Day 450) ..................................................................... 48 
5.17. 
Visit 11 – Month 24 (Day 720) / Exit Visit .................................................. 48 


5.18. 
Unscheduled Visits ....................................................................................... 48 
6. 
TREATMENT OF SUBJECTS .................................................................... 49 
6.1. 
Description of Study Drugs .......................................................................... 49 
6.2. 
Storage and Handling of Study Drug ............................................................ 51 
6.2.1. 
Study Drug Kit Storage ................................................................................ 51 
6.2.2. 
Administration Kit Storage ........................................................................... 51 
6.2.3. 
Study Drug Preparation and Administration ................................................ 51 
6.2.3.1. 
Pre-injection Procedures ............................................................................... 51 
6.2.3.2. 
Ocriplasmin 0.0625mg Injection .................................................................. 52 
6.2.3.3. 
Ocriplasmin 0.125mg Injection .................................................................... 53 
6.2.3.4. 
Sham Injection .............................................................................................. 54 
6.2.4. 
Post-Injection Assessment ............................................................................ 54 
6.2.5. 
Study Drug Accountability ........................................................................... 55 
6.3. 
Treatment Compliance .................................................................................. 55 
6.4. 
Concomitant Medications / Treatments / Interventions ................................ 55 
6.4.1. 
Diabetic Retinopathy-related Treatment ....................................................... 56 
6.4.1.1. 
Escape Criteria .............................................................................................. 56 
7. 
ASSESSMENT OF EFFICACY .................................................................. 57 
7.1. 
Efficacy Parameters ...................................................................................... 57 
7.2. 
Methods and Timing for Assessing Efficacy Parameters ............................. 57 
7.2.1. 
B-scan Ultrasound ........................................................................................ 57 
7.2.2. 
SD-OCT (6mm) ............................................................................................ 57 
7.2.3. 
7-Standard Field Stereo Colour Fundus Photography .................................. 57 
7.2.4. 
Slit Lamp Examination ................................................................................. 58 
7.2.5. 
Best Corrected Visual Acuity ....................................................................... 58 
7.2.6. 
Widefield SD-OCT ....................................................................................... 58 
8. 
ASSESSMENT OF SAFETY ....................................................................... 59 
8.1. 
Safety Parameters ......................................................................................... 59 
8.2. 
Methods and Timing for Assessing Safety Parameters ................................ 59 
8.2.1. 
Adverse Events ............................................................................................. 59 
8.2.2. 
Full Ophthalmic Examination ....................................................................... 59 
8.2.3. 
Best Corrected Visual Acuity ....................................................................... 59 
8.2.4. 
Colour Vision (Roth 28-hue) ........................................................................ 59 


8.2.5. 
SD-OCT ........................................................................................................ 59 
8.2.6. 
Full-field ERG .............................................................................................. 59 
8.2.7. 
Immunogenicity ............................................................................................ 60 
8.3. 
Safety Definitions ......................................................................................... 60 
8.3.1. 
Definition of an Adverse Event .................................................................... 60 
8.3.2. 
Definition of a Serious Adverse Event ......................................................... 60 
8.3.3. 
Clarifications ................................................................................................. 61 
8.4. 
Recording of Adverse Events ....................................................................... 62 
8.4.1. 
Adverse Events ............................................................................................. 62 
8.4.1.1. 
Relationship to Study Drug or the Injection Procedure ................................ 62 
8.4.1.2. 
Adverse Event Intensity ................................................................................ 63 
8.4.1.3. 
Adverse Event Outcome ............................................................................... 63 
8.4.1.4. 
Adverse Event Follow-Up ............................................................................ 63 
8.4.2. 
Pregnancy / Prenatal Exposure ..................................................................... 64 
8.5. 
Treatment of Adverse Events ....................................................................... 65 
8.6. 
Reporting Requirements for Serious Adverse Events .................................. 65 
9. 
STATISTICS ................................................................................................ 67 
9.1. 
Determination of Sample Size ...................................................................... 67 
9.2. 
Subject Analysis Sets .................................................................................... 67 
9.2.1. 
Safety Analysis Set ....................................................................................... 67 
9.2.2. 
Full Analysis Set ........................................................................................... 67 
9.2.3. 
Per Protocol Set ............................................................................................ 67 
9.3. 
Statistical Methods ........................................................................................ 67 
9.3.1. 
Significance .................................................................................................. 68 
9.3.2. 
Procedure for Accounting for Missing, Unused and Spurious Data ............ 68 
9.4. 
Analysis of Subject Disposition, Demographics and Baseline Characteristics
 ...................................................................................................................... 68 
9.5. 
Analysis of Efficacy ..................................................................................... 68 
9.5.1. 
Primary Efficacy Analysis ............................................................................ 68 
9.5.2. 
Exploratory Efficacy Analyses ..................................................................... 68 
9.6. 
Analysis of Safety ......................................................................................... 69 
9.6.1. 
Principal Safety Analyses ............................................................................. 69 
9.6.2. 
Other Safety Analyses .................................................................................. 69 


9.7. 
Sequence of Analyses ................................................................................... 69 
10. 
DATA VERIFICATION AND DIRECT ACCESS TO SOURCE 
DOCUMENTATION ................................................................................... 71 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE ........................... 72 
12. 
DATA HANDLING AND RECORD KEEPING ........................................ 73 
12.1. 
Source documents ......................................................................................... 73 
12.2. 
Electronic Case Report Forms ...................................................................... 73 
12.3. 
Data Review .................................................................................................. 73 
12.4. 
Retention of Records .................................................................................... 73 
13. 
FINANCE AND INSURANCE ................................................................... 75 
13.1. 
Finance .......................................................................................................... 75 
13.2. 
Insurance ....................................................................................................... 75 
14. 
PUBLICATION POLICY AND FINAL REPORT ..................................... 76 
15. 
LIST OF REFERENCES .............................................................................. 77 
16. 
APPENDICES .............................................................................................. 79 
APPENDIX 1. PROTOCOL TABLES ......................................................................... 79 
APPENDIX 2. POST-INJECTION PHONE CALL SCRIPT ...................................... 85 
 
LIST OF TABLES 
Table 1: 
Contact Information ........................................................................................ 2 
Table 2: 
Persons Authorised to Sign Protocol and Amendments ................................. 3 
Table 3: 
List of Abbreviations .................................................................................... 19 
Table 4: 
Glossary of Terms ......................................................................................... 21 
Table 5: 
Study Drugs .................................................................................................. 49 
Table 6: 
Study Plan / Flowchart.................................................................................. 79 
Table 7: 
Study Visit Intervals ..................................................................................... 83 
Table 8: 
Responsibilities Masked and Unmasked Study Staff and Need for 
Certification .................................................................................................. 84 
 
LIST OF FIGURES 
Figure 1: 
Study Design Overview ................................................................................ 32 


LIST OF ABBREVIATIONS 
The following abbreviations are used in this study protocol. 
Table 3: 
List of Abbreviations 
AE 
Adverse Event 
AMD 
Age-related Macular Degeneration 
Anti-VEGF 
Vascular Endothelial Growth Factor 
APE 
Autologous Plasmin Enzyme 
BCVA 
Best Corrected Visual Acuity 
°C 
Degrees Celsius 
CI 
Confidence Interval 
CI-DME 
Centre-Involved Diabetic Macular Oedema 
CRC 
Central Reading Centre 
CRO 
Contract Research Organisation 
CST 
Central Subfield Thickness 
CSR 
Clinical Study Report 
DMC 
Data Monitoring Committee 
DME 
Diabetic Macular Oedema 
DNA 
Deoxyribonucleic Acid 
DR 
Diabetic Retinopathy 
eCRF 
Electronic Case Report Form 
ETDRS 
International Clinical Diabetic Retinopathy Disease Severity 
Scale 
°F 
Degrees Fahrenheit 
ffERG 
Full-field electroretinogram 
G 
Gauge 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HbA1c 
Glycated Haemoglobin 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 


IS / OS 
Inner Segment / Outer Segment 
IXRS 
Interactive Voice / Web Response System 
kDa 
Kilodalton 
LOCF 
Last-Observation-Carried-Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
µg 
Microgram 
Mg 
Milligram 
mL 
Millilitre 
µm 
Micrometer 
Mw 
Molecular Weight 
NaCl 
Sodium Chloride 
NPDR 
Non-Proliferative Diabetic Retinopathy 
OC 
Observed Case 
OCT 
Optical Coherence Tomography 
PDR 
Proliferative Diabetic Retinopathy 
PRP 
Pan-Retinal Photocoagulation 
PT 
Preferred Term 
PVD 
Posterior Vitreous Detachment 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD-OCT 
Spectral Domain Optical Coherence Tomography 
SmPC 
Summary of Product Characteristics 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TEAE 
Treatment-Emergent Adverse Event 
US 
United States 
USPI 
United States Package Insert 
VMA 
Vitreomacular Adhesion 
VMT 
Vitreomacular Traction 
WHO 
World Health Organization 


GLOSSARY OF TERMS 
The following specialist terms are used in this study protocol. 
Table 4: 
Glossary of Terms 
Adequate contraception 
Adequate methods of birth control include intrauterine device, oral, 
implanted or injected contraceptives, and barrier methods with 
spermicide 
Eligible 
Qualified for enrolment into the study based upon strict adherence to 
inclusion / exclusion criteria 
Foveal ischemia 
Foveal ischemia is defined as evidence of disrupted foveal avascular 
zone 
Study drug 
Test product, placebo or comparator being tested or used as a 
reference in the clinical study 
Masking 
A procedure in which one or more parties in the study are kept 
unaware of the treatment assignment in order to reduce the risk of 
biased study outcomes. In a double-masked study, the subject, the 
Investigator and Sponsor staff who are involved in clinical evaluation 
of the subjects and the review or analysis of data are all unaware of 
the treatment assignment 
Principal Investigator 
The Investigator who leads the study conduct at an individual site. 
Every site has a Principal Investigator 
Study Treatment 
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or placebo / sham 
intended to be administered to a subject, identified by a unique 
number, according to the study randomisation or treatment allocation 
Test product 
The ThromboGenics compound being used in the study 
Subject 
Term used throughout the protocol to denote an individual who 
participates in the clinical study, either in one of the ocriplasmin 
arms or in the sham arm 


1. 
BACKGROUND INFORMATION 
1.1. 
Introduction 
1.1.1. 
Diabetic Retinopathy 
According to the World Health Organization (WHO), in 2014, 9% of adults 18 years and older 
had diabetes (WHO, 2015). In the United States (US), an estimated 3 out of 5 people with 
diabetes have one or more of the complications associated with the disease (American 
Association of Clinical Endocrinologists, 2007). Diabetic retinopathy (DR) is one of those 
complications and it is a leading cause of visual disability and blindness among professionally 
active adults (Cunha-Vaz, 1998; Fong et al., 1999). Worldwide, the prevalence rate of 
vision-threatening DR (i.e. proliferative diabetic retinopathy [PDR] and / or diabetic macular 
oedema [DME] – see below) was estimated at 11.72% of the people with diabetes in 2010 
(Yau et al., 2012). Patients with severe stages of DR are reported to have poorer quality of life 
and they utilise more health care resources. 
DR progresses from mild, non-proliferative to more severe, proliferative stages when there is no 
appropriate treatment. The initial, non-proliferative stages of DR are characterised by retinal 
vascular related abnormalities, such as micro-aneurysms, intraretinal haemorrhages, venous 
dilation and cotton-wool spots. As DR progresses, there is a gradual closure of retinal vessels 
that results in impaired perfusion and retinal ischemia. When this progresses beyond certain 
thresholds, severe non-proliferative diabetic retinopathy (NPDR) is diagnosed. The more 
advanced stage, PDR, is characterised by the onset of neovascularisation at the inner surface of 
the retina induced by retinal ischemia. These new vessels are prone to bleed, resulting in vitreous 
haemorrhage. They may also undergo fibrosis and contraction, which may lead to epiretinal 
membrane formation, vitreoretinal traction bands, retinal tears and traction or rhegmatogenous 
retinal detachments. When new vessels are accompanied by vitreous haemorrhage, or when new 
vessels at the optic disc occupy greater than or equal to about ¼ to ⅓ disc area, even in the 
absence of vitreous haemorrhage, PDR is considered high risk. Patients with high risk PDR are 
at high risk of severe vision loss. 
DME is macular oedema arising in patients with DR due to increased retinal vascular 
permeability and is characterised by retinal thickening and / or adjacent hard exudates that either 
involve the centre of the macula or threaten to involve it. DME is an important complication of 
DR and is assessed independently from the DR stage, as it can occur at any stage and follow an 
independent course. 
1.1.2. 
Current Treatment Options 
Good control of blood glucose, blood pressure and blood lipids is important, as it can delay the 
onset of DR and slow its progression.  
Once DR is established and the PDR stage is reached, pan-retinal photocoagulation (PRP) is 
effective in reducing the development of blindness (Cunha-Vaz, 1998). However, some patients 
treated with PRP will still progress to severe vision loss or even complete vision loss resulting 
from persistent or recurrent disease. In addition, PRP treatment may lead to clinically relevant 
complications such as visual field loss or worsening macular oedema (Fong et al., 1999; 
Bailey et al., 1998; Bailey et al., 1999).  


Multiple studies have demonstrated the benefit of intravitreal anti-vascular endothelial growth 
factor (anti-VEGF) for the treatment of centre-involved DME (CI-DME). At the present time, 
anti-VEGF is the initial treatment choice for CI-DME, with possible subsequent or deferred 
focal / grid laser photocoagulation (American Academy of Ophthalmology Retina/Vitreous 
Panel, 2014). In addition, the corticosteroids Ozurdex® (dexamethasone) and Iluvien® 
(fluocinolone acetonide) have recently been approved for the treatment of DME and the role of 
other corticosteroids in the treatment strategy for patients with DME is currently under 
investigation (American Academy of Ophthalmology Retina/Vitreous Panel, 2014).  
It has been suggested that total posterior vitreous detachment (PVD) can prevent the progression 
of NPDR to PDR. A meta-analysis including 2188 analysable eyes showed that diabetic patients 
with total PVD had a statistically significant lower prevalence of PDR (odds ratio 0.1, 95% 
confidence interval [CI] 0.05-0.18) than patients with no PVD. In the same meta-analysis, 
progression of PDR was significantly associated with no PVD or partial PVD (odd ratio 0.3, 
95% CI 0.09-0.91) (De Smet et al, 2013). This could be explained by total PVD leading to: 
1. Elimination of the scaffold for retinal neovascular outgrowth 
2. Improvement of the oxygen supply to the retina, thereby reducing retinal ischemia, 
production of VEGF, vascular outgrowth and neovascularisation 
Currently, the only method to achieve total PVD is by vitrectomy. However, due to the risk of 
complications, such as recurrent vitreous haemorrhage, retinal tear or detachment, vision loss, 
infectious endophthalmitis and cataract, vitrectomy is only indicated in DR patients who are at 
the high risk PDR stage and who are not amenable to PRP, or in patients with 
macula-threatening vitreomacular traction (VMT) or epiretinal membrane on optical coherence 
tomography (OCT) (American Academy of Ophthalmology Retina/Vitreous Panel, 2014). As 
vitrectomy is only performed in patients who are already at the PDR stage, therapy targeted at 
earlier stages of DR, when the disease process may still be reversible or halted, is urgently 
needed. 
1.2. 
Test Product  
Ocriplasmin, a recombinant human DNA derived protein (Mw 27.2kDa), is a truncated form of 
the human protein, plasmin, with retained protease activity. Ocriplasmin acts on several 
components of the vitreoretinal interface, including laminin, fibronectin and collagen IV and is 
able to induce PVD in a dose- and time-dependent fashion, leaving a clean retinal surface devoid 
of protein debris on electron microscopy (De Smet et al., 2009; Gad Elkareem et al., 2010). 
A single intravitreal injection of JETREA® (ocriplasmin 0.125mg) is approved in the US for the 
treatment of symptomatic vitreomacular adhesion (VMA) and in Europe for the treatment of 
VMT including when associated with macular hole of diameter less than or equal to 400µm. 
In this study, the potential of multiple injections of ocriplasmin 0.0625mg or 0.125mg to safely 
induce total PVD in subjects with moderate to very severe NPDR will be assessed, ultimately 
aiming to reduce the risk of progression to PDR. 


1.3. 
Preclinical / Clinical Data  
1.3.1. 
Preclinical Data 
Please refer to the current Investigator’s Brochure (IB) for a description of the preclinical data. 
1.3.2. 
Clinical Data 
As part of the clinical development programme for ocriplasmin’s initial indication ‘treatment of 
VMT (symptomatic VMA)’, a single intravitreal injection of ocriplasmin has been assessed. 
Subsequent to, or in conjunction with multiple Phase 2 studies, 2 Phase 3 studies (TG-MV-006 
and TG-MV-007) were conducted to support applications for marketing authorisations. As of 
16-Apr-2016, it was estimated that 1638 eyes had been treated with an intravitreal injection of 
ocriplasmin (any dose) in clinical studies, whereas exposure from marketing experience was 
estimated at 23220 eyes. 
The current study is the first of the clinical development programme to support ocriplasmin’s 
new indication ‘to reduce the risk of progression to PDR in patients with NPDR’, assessing the 
effect of up to 3 intravitreal ocriplasmin injections in subjects with NPDR. During the clinical 
development programme supporting the initial indication, there were a limited number of 
subjects who received multiple injections of ocriplasmin 0.125mg as well as a limited number of 
subjects with DR who were treated with ocriplasmin (0.025mg, 0.075mg, 0.125mg or 0.175mg): 
• In the Phase 2 study TG-MV-004, 9 subjects received multiple injections of 
ocriplasmin 0.125mg. In 1 of the cohorts in this study, 15 subjects with VMT were 
assigned to ocriplasmin 0.125mg (n=12) or sham injection (n=3). Five (5) out of 
12 (41.7%) subjects who were assigned to ocriplasmin and 1 out of 3 (33.3%) 
subjects who were assigned to sham injection achieved total PVD by the Day 28 visit. 
The 9 subjects who did not achieve resolution of VMT by the Day 28 visit received 
2 additional open-label injections of ocriplasmin 0.125mg. This led to 7 subjects who 
were assigned to ocriplasmin receiving a total of 3 ocriplasmin injections each, and to 
2 subjects who were assigned to sham injection receiving a total of 2 ocriplasmin 
injections each. At 28 days after the second open-label ocriplasmin injection, 1 out of 
2 subjects who were assigned to sham injection achieved total PVD and none of the 
7 subjects who were assigned to ocriplasmin injection achieved total PVD. All except 
1 of the subjects who received multiple injections of ocriplasmin experienced adverse 
events (AEs), with events occurring both before and after the open label injections. 
With the exception of 1 moderate ocular AE (macular hole) reported after 3 injections 
of ocriplasmin, all ocular events reported after 2 or 3 ocriplasmin injections were mild 
in intensity. The type of the treatment-related AEs reported after 2 or 3 ocriplasmin 
injections were not different from those observed in the total population included in 
the Phase 2 and 3 studies.  
• In order to group data on subjects with DR who were treated with ocriplasmin, a 
pooled analysis has been performed on the treatment-emergent adverse events 
(TEAE) reported for the subjects with DR enrolled in the studies TG-MV-002, 
TG-MV-004, TG-MV-006, TG-MV-007, TG-MV-014 and J-12-075. A total of 
125 subjects with DR were enrolled in these studies, of which 90 received 
ocriplasmin (any dose; 0.025mg, 0.075mg, 0.125mg or 0.175mg) and 62 received 


ocriplasmin 0.125mg. In the subjects who received ocriplasmin 0.125mg, ocular 
treatment-emergent adverse events (ocular TEAEs) in the study eye were reported for 
37 (59.7%) subjects. The most frequently reported TEAEs were eye pain, 
conjunctival haemorrhage, vitreous floaters and retinal haemorrhage. This safety 
profile is not different from that observed in the population included in the 
Phase 2 and 3 studies. 
For a more detailed description of the clinical data, please refer to the current IB. 
1.4. 
Study Rationale  
1.4.1. 
Rationale for the Study 
As described above, it has been suggested that total PVD can prevent the progression of NPDR 
to PDR. This Phase 2 study in diabetic subjects with moderate to very severe NPDR is conducted 
to assess the efficacy and the safety of up to 3 injections of ocriplasmin (0.0625mg or 0.125mg) 
to induce total PVD, in order to reduce the risk of disease progression to PDR. 
1.4.2. 
Rationale for the Dose and the Injection Regimen 
Up to 3 intravitreal injections of ocriplasmin 0.0625mg or 0.125mg will be administered. All 
subjects assigned to an ocriplasmin arm will receive an intravitreal injection of ocriplasmin 
0.0625mg or 0.125mg at Day 0. These subjects will be re-treated with the same dose of 
ocriplasmin at Day 35 and at Day 70 if, by that time, they do not have total PVD on both B-scan 
ultrasound and spectral domain optical coherence tomography (SD-OCT), as assessed by the 
masked B-scan expert reader and the masked central reading centre (CRC), respectively. 
Subjects who have total PVD on both B-scan ultrasound and SD-OCT will receive subsequent 
sham injection(s). 
1.4.2.1. 
Rationale for the Dose 
The evaluation of 2 different ocriplasmin doses (0.0625mg and 0.125mg) will help to inform the 
dose selection for investigation in the Phase 3 studies. 
The dose of 0.125mg will be assessed as this is the dose marketed for treatment of VMT 
(symptomatic VMA). This dose was selected as part of the previous clinical development 
programme supporting ocriplasmin’s initial indication. A single dose of ocriplasmin 0.125mg 
was able to induce VMT release without undue safety findings in 2 separate, dose finding 
clinical studies. Positive results were obtained with this dose in 2 adequate and well-controlled 
Phase 3 studies (TG-MV-006 and TG-MV-007). 
The dose of 0.0625mg will be assessed as preclinical data showed that PVD can be induced with 
ocriplasmin doses of 0.0125 to 0.250mg, with higher doses inducing progressively more 
pronounced PVD. In the dose-ranging studies performed as part of the previous clinical 
development programme, VMT resolution was also observed with a single dose of ocriplasmin 
0.075mg, albeit at a lower rate than what was observed with ocriplasmin 0.125mg. In the current 
study however, up to 3 injections with ocriplasmin will be given, and a lower dose may be 
sufficient to induce total PVD while reducing the number of AEs. 


For a more detailed description of the preclinical and the clinical data, please refer to the current 
IB. 
1.4.2.2. 
Rationale for the Injection Regimen 
In the pivotal Phase 3 studies (TG-MV-006 and TG-MV-007), a single intravitreal injection of 
ocriplasmin 0.125mg led to total PVD in 13.4% of the subjects at Day 28 (62 out of 464 
subjects). In most subjects, a single intravitreal ocriplasmin injection may hence not be sufficient 
to induce total PVD. Repeat administration is expected to increase the total PVD rate. This has 
been observed in a study with the autologous plasmin enzyme (APE) in patients with PDR or 
DME, where a single APE injection led to total PVD in 38% (24 out of 63) of the eyes and 
repeat injection in subjects with no evidence of total PVD at least 1 month after the initial 
injection led to total PVD in 51% (32 out of 63) of the eyes (Diaz-Llopis et al., 2013). In the 
current study, subjects who do not achieve total PVD will therefore receive (an) additional 
ocriplasmin injection(s), with a maximum of 3 injections per subject.  
The time interval between injections has been selected based on the observation that the onset of 
total PVD induced by a single intravitreal injection of ocriplasmin is rapid. In the pivotal Phase 3 
studies (TG-MV-006 and TG-MV-007), 75% of subjects who responded to the treatment, 
responded within 1 week and almost all subjects who responded did so within 1 month. 
Therefore, if a subject has not responded by 1 month after the injection, it is not likely that 
release will occur, justifying repeat injection. 
1.4.3. 
Rationale for the Use of a Sham Control 
As there is currently no non-surgical treatment available to induce total PVD in subjects with 
NPDR, an inactive control will be used. For ethical reasons, sham was chosen over placebo 
given the inherent risks associated with the intravitreal injection procedure, particularly when 
administered repeatedly, including pain, intraocular haemorrhage, infection, transient increase in 
IOP and retinal detachment. Moreover, it has been shown that the majority of subjects receiving 
a sham injection believe that they are receiving a real injection (Glassman et al., 2012). The use 
of a sham control will hence minimise the risks for the subjects in the control arm while 
permitting double masking. 
1.5. 
Risks / Benefits 
This is the first study in which the effect of up to 3 intravitreal injections of ocriplasmin in 
diabetic subjects with moderate to very severe NPDR will be assessed. Based on available 
preclinical and clinical data, it is believed that multiple injections of ocriplasmin will have an 
acceptable safety profile and will have the potential to induce total PVD. Given the measures 
taken to ensure safety of the subjects in this study, the study Sponsor believes that the potential 
benefits of the study outweigh the potential risks, as outlined below. 


1.5.1. 
Potential Risks 
1.5.1.1. 
Potential Risks Related to the Test Product 
Risks of a Single Intravitreal Injection of Ocriplasmin 0.125mg in Subjects with VMT 
(Symptomatic VMA) 
As of 16-Apr-2016, it was estimated that 1638 eyes received an intravitreal injection of 
ocriplasmin (any dose) and 416 eyes received a placebo / sham injection in clinical studies. 
The AEs observed after a single intravitreal injection of ocriplasmin 0.125mg in subjects with 
VMT (symptomatic VMA) mostly occurred within the first week after the injection. The 
majority of these AEs were non-serious, mild to moderate in intensity and resolved within 
2 to 3 weeks without treatment. The most commonly reported AEs were vitreous floaters, eye 
pain, photopsia and chromatopsia, as well as conjunctival haemorrhage resulting from the 
injection procedure. Visual symptoms perceived in the contralateral eye or bilaterally have also 
been reported (such as floaters, flashes). 
With data from the paediatric study TG-MV-009 excluded (16 eyes treated with ocriplasmin and 
8 eyes treated with placebo), 435 serious adverse events (SAEs) have been reported in total in 
clinical trials; 336 of which were reported for subjects treated with ocriplasmin and 99 of which 
were reported for subjects treated with sham or placebo. The most frequently reported SAEs 
were macular hole (108 occurrences; 24.8%), retinal detachment (26 occurrences; 6.0%), visual 
acuity reduced (16 occurrences; 3.7%) and vitreous adhesions (14 occurrences; 3.2%). 
Cumulatively, 15 SAEs with a fatal outcome were reported, all of which were assessed to be 
unrelated to ocriplasmin. 
Please refer to the current IB / the US Package Insert (USPI) / the European Summary of Product 
Characteristics (SmPC) for more detailed information on the risks associated with a single 
intravitreal injection of ocriplasmin in subjects with VMT (symptomatic VMA). 
Risks of Multiple Injections in Subjects with Diabetic Retinopathy 
During the clinical development programme supporting the indication of VMT (symptomatic 
VMA), there were a limited number of subjects who received 2 or 3 injections of ocriplasmin 
0.125mg as well as a limited number of subjects with DR who were treated with ocriplasmin 
(0.025mg, 0.075mg, 0.125mg or 0.175mg). Overall, the risks observed in subjects with DR or 
after repeat injections did not seem to differ from those observed in the population included in 
the Phase 2 and Phase 3 studies (refer also to Section 1.3.2).  
However, there may be undesirable effects that are unknown at this time. 
In order to ensure safety of the subjects in this study, the following measures will be taken: 
• For each subject, AEs will be recorded from the time of providing consent until the 
end of the study (approximately 24 months follow-up from the first injection). At 
each study visit, the study personnel will inquire about AEs, and a full ophthalmic 
examination (including pupillary examination, slit lamp examination, IOP assessment 
and dilated fundus examination), best corrected visual acuity (BCVA) assessment and 
SD-OCT will be performed. In addition, 24-72 hours after each injection visit, there 
will be a scripted post-injection phone call to inquire about AEs and concomitant 


medications / treatments. Based on this phone call, the subject may be invited back 
for an unscheduled study visit.  
• A list of withdrawal criteria from repeat injection has been compiled. If for a subject, 
any of these criteria apply at the time of repeat injection, and it is not possible to 
postpone the repeat injection, within the protocol-specified study visit interval, until 
the event has resolved, he / she should not receive further injection(s). In addition, the 
Investigator may decide not to administer repeat injection(s) at his / her discretion. 
Subjects who are not given repeat injection(s) will continue all other study procedures 
to ensure complete follow-up. 
• In addition to safety follow-up on an individual subject level, a data monitoring 
committee (DMC) will be established to maintain the general safety oversight. The 
DMC will conduct periodic review of safety and efficacy data. In addition, certain 
TEAEs will be escalated to the DMC on an ongoing basis and ad hoc DMC meetings 
may be convened whenever deemed necessary. At any time during the study, the 
DMC will be empowered to make recommendations to the Sponsor on further study 
conduct. 
1.5.1.2. 
Potential Risks Related to Other Study Procedures 
Intravitreal Injection 
The risk of complications from intravitreal injections itself is low. The most common 
complications associated with intravitreal injections are pain, intraocular haemorrhage, infection, 
transient increase in IOP and retinal detachment (Aiello et al, 2004; Avery et al, 2014; 
Jager et al, 2004). The prevalence of endophthalmitis, intraocular haemorrhage and retinal 
detachment after intravitreal injections was estimated at 0.2%, 1.3% and 0.9% per injection, 
respectively in a systematic search of the literature (Jager et al, 2004). Nevertheless, careful 
attention to injection technique and appropriate post-injection monitoring are essential because 
uncommon injection-related complications may be associated with permanent vision loss.  
Antibiotic Eye Drops 
The Investigator may decide at his / her discretion to administer prophylactic topical antibiotics. 
The risks associated with the ocular antibiotic drops are the same as those for oral antibiotics and 
include mild to moderate local allergic reactions characterised by eye redness and itching and 
rare systemic drug reactions including Stevens-Johnson syndrome and / or anaphylaxis. 
Anaesthetic Eye Drops 
Before the intravitreal injection and for some of the ophthalmic assessments, the eye will be 
anaesthetised with anaesthetic drops. Allergic reactions to anaesthetic eye drops are rare, but 
include itching, lid swelling and eye redness. Another risk associated with these drops is 
scratching of the cornea due to rubbing of the numbed eye. Subjects should therefore be 
instructed not to rub their eyes until the anaesthetic wears off (about 15 minutes).  


Pupil Dilation 
For some of the ophthalmic examinations, the pupils will be dilated. The pupils will remain 
dilated for at least 4-6 hours. This may result in light sensitivity and blurred vision (especially for 
near tasks). Subjects should be told to bring sunglasses to the study visits and to not drive while 
their pupils are dilated. Allergic reactions are rare but include lid swelling and eye redness. The 
procedures themselves do not pose any risks to the subjects. 
Tonometry 
Tonometry (IOP measurement) carries a small risk for corneal scratching (abrasion), which 
usually heals without treatment within a few days. 
Fluorescein Angiography 
Fluorescein will be injected in the systemic circulation, which may cause pain at the injection 
site and which carries a small risk of bleeding, bruising and / or infection at the injection site. 
Other side effects may include nausea, vomiting, gastrointestinal distress, headache, syncope and 
hypotension. In addition, the fluorescein may lead to temporary, limited darkening of the skin 
and urine, subsiding within a few hours.  
In very rare cases, a severe allergic reaction can occur, which can cause breathing problems and 
exceptionally lead to death. For this reason, people with a history of drug reaction or allergy will 
be carefully monitored.  
Full-Field ERG 
The full-field ERG (ffERG) test requires an electrode to be placed onto the surface of the eye 
along the lower eyelid, in contact with the tear film and cornea, which may cause irritation and a 
slight foreign-body sensation while it is in place. 
Blood Draw 
Blood draw carries a small risk of pain, excessive bleeding, fainting or light-headedness, 
haematoma under the skin at the site of the needle insertion, and a rare risk of infection. 
1.5.2. 
Potential Benefits 
This is the first study in which the efficacy and safety of up to 3 intravitreal injections of 
ocriplasmin in diabetic subjects with moderate to very severe NPDR will be assessed, and there 
may not be any direct benefit for the study participants. 
An indirect benefit of study participation is that this study may contribute to the development of 
a drug that reduces the risk of disease progression to PDR. In addition, this study may realise 
overall advancement of medical and scientific knowledge that may benefit future patients. In 
addition, subjects will be closely followed up for DR progression while being in the study. 


2. 
STUDY OBJECTIVE 
• To assess the efficacy and safety of up to 3 intravitreal injections of ocriplasmin 
(0.0625mg or 0.125mg), in subjects with moderate to very severe NPDR, to induce 
total PVD in order to reduce the risk of disease progression to PDR 


3. 
STUDY DESIGN AND METHODOLOGY 
3.1. 
Study Endpoints 
3.1.1. 
Efficacy Endpoints 
Primary Efficacy Endpoint 
• Total PVD by the Month 3 visit, confirmed on both B-scan ultrasound and SD-OCT 
(6mm), as assessed by the masked B-scan expert reader and the masked CRC, 
respectively 
Exploratory Efficacy Endpoints 
• A ≥ 2-step progression on the International Clinical Diabetic Retinopathy Disease 
Severity Scale (ETDRS Severity Scale) from baseline, at Month 15 and at Month 24, 
based on 7-standard field stereo colour fundus photography, as assessed by the 
masked CRC 
• Progression from NPDR at baseline to PDR (at least ETDRS level 61) at Month 15 
and at Month 24, based on 7-standard field stereo colour fundus photography, as 
assessed by the masked CRC 
• Improvement of ≥ 2 steps on the ETDRS Severity Scale from baseline, at Month 15 
and at Month 24, based on 7-standard field stereo colour fundus photography, as 
assessed by the masked CRC 
• Neovascularisation as compared to baseline, at Month 15 and at Month 24, based on 
7-standard field stereo colour fundus photography, as assessed by the masked CRC 
• Development or progression of macular oedema as compared to baseline, at each 
study visit, based on SD-OCT, as assessed by the masked CRC 
• BCVA change from baseline at each study visit 
• Total PVD at each study visit, confirmed on both B-scan ultrasound and SD-OCT 
(6mm), as assessed by the masked B-scan expert reader and the masked CRC, 
respectively 
• Total PVD by the Month 3 visit, based on widefield SD-OCT, as assessed by the 
masked CRC, in a subset of sites where this is available 
• Vitreous / pre-retinal haemorrhage by Month 24, based on 7-standard field stereo 
colour fundus photography, as assessed by the masked CRC 
• Development of iris neovascularisation as compared to baseline, at each study visit, 
based on slit lamp examination 
• PRP treatment by the Month 15 visit 
• Anti-VEGF treatment by the Month 15 visit 
• Vitrectomy by the Month 15 visit 


3.1.2. 
Safety Endpoints 
Principal Safety Endpoint 
• Ocular TEAEs in the study eye 
Other Safety Endpoints 
Safety will be further assessed through reported TEAEs, full ophthalmic examination, BCVA 
assessment, assessment of colour vision (in a subset of sites where the Roth 28 Colour Test is 
available), SD-OCT, ffERG (at sites where this is available, in approximately 25% of the 
subjects) and assessment of immunogenicity. 
3.2. 
Study Design Overview 
Figure 1: 
Study Design Overview 
 
• Study design. Multi-centre, randomised, sham-controlled, double-masked, 
Phase 2 clinical study with 3 parallel treatment arms 
• Study arms and treatments. 
− Ocriplasmin 0.0625mg arm. Approximately 46 subjects will receive up to 
3 intravitreal injections of ocriplasmin 0.0625mg, approximately 1 month apart. 
All subjects assigned to this arm will receive an intravitreal injection of 
ocriplasmin 0.0625mg at Day 0. These subjects will be re-treated with 
ocriplasmin 0.0625mg at Day 35 and at Day 70 if, by that time, they have not 
achieved total PVD on both B-scan ultrasound and SD-OCT, as assessed by the 
masked B-scan expert reader and the masked CRC, respectively. Subjects who 
have total PVD on both B-scan ultrasound and SD-OCT will receive subsequent 
sham injection(s) in place of ocriplasmin injection(s). 


− Ocriplasmin 0.125mg arm. Approximately 46 subjects will receive up to 
3 intravitreal injections of ocriplasmin 0.125mg, approximately 1 month apart. All 
subjects assigned to this arm will receive an intravitreal injection of ocriplasmin 
0.125mg at Day 0. These subjects will be re-treated with ocriplasmin 0.125mg at 
Day 35 and at Day 70 if, by that time, have not achieved total PVD on both 
B-scan ultrasound and SD-OCT, as assessed by the masked B-scan expert reader 
and the masked CRC, respectively. Subjects who have total PVD on both B-scan 
ultrasound and SD-OCT will receive subsequent sham injection(s) in place of 
ocriplasmin injection(s) 
− Sham arm. Approximately 23 subjects will receive 3 sham injections, 
approximately 1 month apart. All subjects assigned to this arm will receive a 
sham injection at Day 0, Day 35 and Day 70 
• Test product, dose and mode of administration. Up to 3 intravitreal injections of 
ocriplasmin 0.0625mg or ocriplasmin 0.125mg 
• Reference therapy (comparator), dose and mode of administration. 3 sham 
injections 
• Treatment allocation. Eligible subjects will be sequentially assigned according to a 
computer-generated randomisation list to the ocriplasmin 0.0625mg arm, the 
ocriplasmin 0.125mg arm or the sham arm in a 2:2:1 allocation ratio. Randomisation 
will be stratified by baseline NPDR severity (moderate and moderately severe, i.e. 
ETDRS Level 43A-47D vs. severe and very severe NPDR, i.e. ETDRS Level 53A-E). 
It is expected that more subjects with moderate and moderately severe than with 
severe and very severe NPDR will be enrolled, as a reflection of the natural 
population. Therefore, enrolment in the moderate and moderately severe NPDR 
stratum may become capped in the course of the study 
• Study duration. For each subject enrolled, the study duration will be approximately 
24 months from the first injection 
3.3. 
Number of Subjects 
Approximately 115 subjects are planned to be enrolled (approximately 46 in each ocriplasmin 
arm and 23 in the sham arm). For a detailed description of the sample size determination, refer to 
Section 9.1. 
3.4. 
Data Monitoring Committee 
In order to maintain a general safety oversight and to monitor the risk / benefit balance, a DMC 
will be established for this study.  
From the time the first subject is injected until the last subject completed the Month 3 visit 
(Visit 8), the following TEAEs will be escalated to the DMC on an ongoing basis: 
• Lens subluxation 
• Iso-electric ffERG 


• Clinically significant increased intraocular inflammation after repeat (2nd or 3rd) 
injection 
• BCVA decrease ≥ 15 letters from baseline, without evidence of resolution or 
stabilisation within 24 hours 
• Foveal detachment or worsening of a foveal detachment 
• Any other event at the discretion of the Sponsor 
The DMC will conduct periodic reviews at the following pre-defined timepoints: 
• After approximately 20% of the subjects completed the Month 2 visit (Visit 6b) 
• After approximately 50% of the subjects completed the Month 3 visit (Visit 8) 
• After all subjects completed the Month 3 visit (Visit 8) 
• After all subjects completed the Month 15 visit (Visit 10) 
In addition, ad hoc DMC meetings may be organised. 
The DMC will be empowered to make recommendations to the Sponsor on further study 
conduct. Such recommendations include continuing or terminating the study or modifications to 
the study. Another recommendation may be temporary suspension of enrolment and / or study 
treatment until some uncertainty is resolved. 
The DMC responsibilities and procedures will be documented in the DMC Charter.  
3.5. 
Treatment Allocation 
3.5.1. 
Treatment Allocation at First Injection 
The target is to enrol approximately 115 eligible subjects who will be sequentially assigned, 
according to a computer-generated randomisation list, to the ocriplasmin 0.0625mg arm, the 
ocriplasmin 0.125mg arm or the sham arm in a 2:2:1 allocation ratio (approximately 46 subjects 
in each ocriplasmin arm and approximately 23 subjects in the sham arm).  
Randomisation will be stratified by baseline NPDR severity (moderate and moderately severe 
NPDR, i.e. ETDRS Level 43A-47D vs. severe and very severe NPDR, i.e. ETDRS 
Level 53A-E). It is expected that more subjects with moderate and moderately severe than with 
severe and very severe NPDR will be enrolled, as a reflection of the natural population. 
Therefore, enrolment in the moderate and moderately severe NPDR stratum may become capped 
in the course of the study. 
Allocation of eligible subjects to a treatment arm will be performed through an interactive 
voice / web response system (IXRS). The unmasked treating investigator / designee will access 
the system to obtain the subject’s treatment allocation and the treatment number for the first 
injection. The assigned treatment number will be loaded automatically by IXRS into the 
subject’s electronic case report form (eCRF). 


3.5.2. 
Treatment Allocation at Repeat Injection 
For subjects assigned to the ocriplasmin arms, the treatment allocation at repeat injection will 
depend on their total PVD status, as assessed on B-scan ultrasound and SD-OCT by the masked 
B-scan expert reader and the masked CRC, respectively. Once the total PVD status has been 
assessed, treatment allocation for repeat injection can occur. 
For each injection subsequent to the first one, the unmasked treating investigator / designee will 
access IXRS to obtain the treatment number for the subsequent injection. The assigned treatment 
number will automatically be loaded by IXRS into the subject’s eCRF. 
3.6. 
Masking 
3.6.1. 
Masking Procedures 
The study will be conducted in a double-masked manner up to the Month 15 analysis. As of the 
Month 15 analysis, the Sponsor will be unmasked, while the masking will be kept for the B-scan 
expert reader, the CRCs, the masked study staff and the subjects up to the end of the study.  
In order to maintain the masking, the following measures will be taken: 
• Study staff. In order to maintain the masking, 2 teams of study staff will be 
identified. One (1) team will be masked while the other will be unmasked. The 
unmasked team will include an unmasked treating investigator who will be 
performing the (sham) injections and will ensure immediate follow-up of the subject 
after injection (1-hour post-injection assessment). For an overview of the 
responsibilities of the masked and the unmasked study staff, refer to Table 8 
• Drug kits. Each carton will contain a single vial (ocriplasmin or sham). The carton 
and the vial label will be masked. However, as ocriplasmin vials will have a different 
appearance than sham vials, it is important that drug kits are opened by unmasked 
study personnel only. The vials will have a peel-off label, which will be put in the 
accountability log  
• Administration kits. The carton label will be masked. As there will be 2 different 
types of administration kits, it is important that the kits are opened by unmasked 
study personnel only. All administration kits will contain 2 syringes, 2 needles 
19-gauge (19G) and 1 needle 30-gauge (30G). Some administration kits will also 
contain an ampoule of sodium chloride (NaCl) 9mg/mL (0.9%), whereas others will 
not. The administration kits will have a peel-off label, which will be put in the 
accountability log  
• Injection procedures. In order to maintain the subject masked, injection procedures 
will, as much as possible, be the same for the ocriplasmin and sham injections. 
Pre-injection procedures will be identical for ocriplasmin and sham injections, 
including antisepsis and use of topical anaesthesia. Study drug preparation will not be 
identical for ocriplasmin and sham injections and should be done outside of the 
subject’s view. A sterile drape may be used to cover the subject’s fellow eye and the 
subject will be asked to direct his / her gaze away at all times. Subjects in the sham 
arm will not receive an actual injection (no penetration of the globe will occur). For 


the sham injection, no needle will be attached to the syringe. The unmasked treating 
investigator will press the hub of the syringe firmly against the sclera / conjunctiva 
and slowly depress the plunger to mimic the test product injection procedure 
• B-scan expert reader and CRCs. The B-scan expert reader, the CRC readers and, 
where applicable, the adjudicators at the CRCs will be masked to the treatment 
assignment 
• Immunogenicity assessment. The laboratory in charge of the immunogenicity assay 
will be masked to the treatment assignment 
3.6.2. 
Emergency Unmasking 
Unmasking of a subject’s individual treatment assignment should occur only in the case of a 
medical emergency, or in the event of a serious medical condition, when knowledge of the 
treatment is essential for the clinical management or welfare of the subject, as judged by the 
Investigator. 
In order to unmask a subject’s individual treatment assignment, the masked Investigator will 
need to access IXRS using the Investigator-specific access code to obtain the subject’s treatment 
assignment. When IXRS is not available, please refer to the IXRS user guide for instructions. 
The Investigator has the option of contacting the Sponsor Medical Expert if he / she needs 
medical advice or needs support to perform the unmasking.  
For practical details about emergency unmasking, please refer to the study-specific manuals. 
3.6.3. 
Responsibilities Masked / Unmasked Study Staff 
Refer to Table 8 for an overview of the responsibilities of the masked and the unmasked study 
staff.  
3.7. 
Study Duration 
For each subject enrolled, the study duration will be approximately 24 months from the 
first injection. 
The end of the study is defined as the last visit of the last subject. 
3.8. 
Data Capturing 
Data will be collected via eCRFs. 
At each site, subject numbers will be assigned sequentially to subjects who have consented to 
participate in the study. Data obtained for each subject will be identified with the subject 
number. Subject names will not be collected. 
For subjects who do not meet the eligibility criteria, the minimum information that will be 
captured is the following: date of screening, subject number, procedures completed and reason 
for screening failure. 


3.9. 
Regulatory and Ethical Considerations 
The study will be conducted in accordance with all applicable regulatory requirements. 
This study will be conducted in compliance with the protocol approved by the relevant 
Independent Ethics Committee (IEC) / Institutional Review Board (IRB) and according to the 
Principles of the International Conference of Harmonisation (ICH) guidelines for Good Clinical 
Practice (GCP) E6(R1). In addition, it will be conducted in accordance with all local, federal 
and / or regional regulatory requirements and the principles which have their origin in the 
Declaration of Helsinki.  
The Sponsor will obtain favourable opinion / approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
initiating the study in that country. 
Protocol waivers or exemptions are not allowed unless necessary to eliminate apparent 
immediate hazards to the subject. This should not normally arise in the context of inclusion / 
exclusion criteria, since the subject is not yet fully included in the study at that point in time. 
Adherence to the study design requirements, including those specified in the study plan / 
flowchart, the study visit intervals and the responsibilities of masked and unmasked study staff 
and need for certification (refer to Table 6, Table 7 and Table 8), are essential and required for 
study conduct. 
3.10. 
Criteria for Discontinuation of the Study 
The study may be terminated at all sites or at selected sites, or modified at any time by the 
Sponsor or on the acceptance of DMC recommendation. Reasons for termination or modification 
may include, but are not restricted to, the following: 
1. The incidence or severity of AEs indicates a potential health hazard to subjects 
2. The risks are found to outweigh the potential benefits 
3. Data indicate that an inappropriate dose regimen is being used in the study 
4. The Sponsor decides that the indication under examination will no longer be pursued 
5. The Regulatory Authority demands that the study be terminated 
6. Termination of the study by the IEC / IRB 
7. Investigator fails to comply with the protocol or GCP guidelines 
8. Unsatisfactory enrolment of subjects 
9. Issues related to quality or quantity of data 


4. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1. 
Study Population 
Diabetic subjects with moderate to very severe NPDR (ETDRS Levels 43A-53E), who do not 
have total PVD. 
4.1.1. 
Inclusion and Exclusion Criteria 
Subjects can have only 1 eye treated as part of this study. For eligible subjects where both eyes 
are eligible for injection, the eye with the more advanced NPDR stage (as determined by the 
CRC) will be selected as the study eye. 
4.1.1.1. 
Subject Inclusion Criteria 
A subject must meet all of the following inclusion criteria in order to be enrolled in the study:  
• Male or female aged 18 years or older 
• BCVA of 65 letters read or greater (Snellen equivalent of 20/50 or better) in the study 
eye 
• BCVA of 20 letters read or greater (Snellen equivalent of 20/400 or better) in the 
fellow eye 
• Clear ocular media for adequate fundus imaging in the study eye 
• HbA1c ≤ 12%, as assessed by the central laboratory 
• Moderate to very severe NPDR as per ETDRS Severity Scale (Levels 43A-53E), 
based on 7-standard field stereo colour fundus photograph, as assessed by the CRC 
• Central subfield thickness (CST) of ≤ 340µm on Spectralis SD-OCT or ≤3 20µm on 
non-Spectralis SD-OCT in the study eye, as assessed by the CRC, with or without 
mild CI-DME (mild CI-DME is defined as cysts or intraretinal fluid in the central 
subfield on SD-OCT that in the Investigator’s opinion will not require treatment with 
an anti-VEGF for at least up to 3 months after randomisation) 
• No evidence of total PVD in the study eye, based on both B-scan ultrasound and 
SD-OCT, as assessed by the B-scan expert reader and the CRC, respectively 
• Written informed consent obtained from the subject prior to screening procedures 
4.1.1.2. 
Subject Exclusion Criteria 
If a subject has any of the following criteria, the subject cannot be enrolled in the study: 
• History of or current ocular condition in the study eye that may interfere with the 
assessment of the progression to PDR (e.g. VMT, exudative age-related macular 
degeneration [AMD], retinal vein occlusion [branch or central vein], uveitis, angioid 
streaks, histoplasmosis, toxoplasmosis, rhegmatogenous retinal detachment, retinal 
tear, fibrovascular proliferation, lattice degeneration, macular hole, ocular tumours) 


• Significant ocular trauma in the study eye within 6 months prior to screening 
(including corneo-scleral laceration, lens subluxation, cryo-retinopexy) 
• Corneal, lenticular, or ocular media abnormalities in the study eye that preclude 
observation with the slit lamp or accurate readings with a tonometer 
• Presence of epiretinal membrane in the study eye, based on SD-OCT, as assessed by 
the CRC 
• Presence of foveal ischemia in the study eye, based on fluorescein angiograph, as 
assessed by the CRC 
Refer to the Glossary of Terms for the definition of foveal ischemia 
• Presence of pre-retinal or vitreous haemorrhage in the study eye 
• Presence of iris or angle neovascularisation in the study eye 
• Any active ocular / intraocular infection or inflammation in either eye (e.g. 
blepharitis, infectious conjunctivitis, keratitis, scleritis, endophthalmitis, uveitis) 
• Uncontrolled glaucoma in the study eye (uncontrolled glaucoma is defined as IOP 
≥ 26mmHg in spite of treatment with anti-glaucoma medication) 
• More than 8D high myopia in the study eye  
• Aphakic study eye 
• Previous treatments / procedures as follows: 
Treatment / Procedure In the Study Eye 
Excluded Period prior to Randomisation 
Vitrectomy 
Any time 
PRP 
Any time 
Intraocular surgery 
4 months 
Focal / grid laser photocoagulation 
3 months 
Intravitreal anti-VEGF 
1 month 
Topical ocular steroids 
1 month 
Intravitreal and peri-ocular steroids  
4 months 
Steroid implants 
Any time 
• Uncontrolled hypertension in the opinion of the Investigator (e.g. systolic blood 
pressure > 160mmHg or diastolic blood pressure > 100mmHg for at least 30 days 
prior to screening despite antihypertensive treatment, or any finding in the 
Investigator’s opinion suggesting hypertensive retinopathy) 
• Pseudoexfoliation, Marfan’s syndrome, phacodonesis or any other finding in the 
Investigator’s opinion suggesting lens / zonular instability 
• Current use of or possible need for systemic medications known to be toxic to the 
lens, retina or optic nerve, including Deferoxamine, Chloroquine / 
hydroxychloroquine (Plaquenil), Tamoxifen, Phenothiazines and Ethambutol 


• Known hypersensitivity to ocriplasmin, its excipients or any of the medications that 
will be used for study procedures (e.g. fluorescein, antibiotics, anaesthetic eye drops, 
eye drops for pupil dilation) 
• Pregnant or lactating female, or female of child-bearing potential not utilising an 
adequate form of contraception, or male of reproductive potential not utilising 
contraception (where 1 method is barrier at the minimum) 
Refer to the Glossary of Terms for the definition of adequate contraception 
• Previous ocriplasmin injection in the study eye 
• History and / or current evidence of a systemic medical condition or any other reason 
that may, in the Investigator’s opinion, preclude adherence to the scheduled study 
visits / assessments and safe participation in the study 
• Concurrent participation in another clinical study, at any time during the entire study 
period, in which the subject has been or will be exposed to an investigational or a 
non-investigational product (pharmaceutical product or device) 
• Use of any investigational, non-registered or off-label product within 30 days prior to 
screening, or planned use during the entire study period 
4.2. 
Subject Withdrawal Criteria 
Withdrawals will not be replaced. 
4.2.1. 
Withdrawal from Repeat Injection 
A withdrawal from repeat injection refers to any subject who does not receive repeat injection(s) 
(ocriplasmin or sham). Subjects withdrawn from repeat injection(s) should not be withdrawn 
from the study and, apart from repeat injection-related procedures, should continue all scheduled 
study visits and procedures until the end of the study to ensure complete follow-up. 
The following events should be assessed at Visit 4a (Day 28) and Visit 6a (Day 63), before 
repeat injection. If any of these events apply, no further injection(s) should be given. For events 
that are deemed to be temporary, the injection can be postponed, if this is feasible within the 
protocol-specified study visit interval (refer to Table 7). 
• Severe intraocular inflammation associated with previous injection 
• Active intraocular inflammation or infection in either eye at the time of repeat 
injection 
• Any signs or symptoms of lens subluxation associated with previous injection 
• Any condition associated with previous injection requiring surgical treatment (e.g. 
new macular hole, worsening of existing macular hole, retinal tear, retinal 
detachment, IOP increase) 
• Persistent presence of subretinal fluid or inner segment / outer segment (IS / OS) 
junction changes with functional impairment, associated with previous injection, at 
the time of repeat injection 


• Persistent complaint of dim vision, dark adaptation problems or impaired night 
vision, or afferent pupillary defect, associated with previous injection, at the time of 
repeat injection 
• BCVA decrease ≥ 15 letters from baseline or BCVA worse than 20/400, in the study 
eye, at the time of repeat injection 
• Significant ocular trauma in the study eye at the time of repeat injection 
• Any other intraocular injection since previous study injection 
• Pregnancy 
• Subject’s individual treatment assignment has been unmasked (emergency 
unmasking, refer to Section 3.6.2) 
In addition, subjects may be withdrawn from repeat injection at any time at the discretion of the 
Investigator (e.g. based on significant abnormalities on ophthalmic examination or functional test 
associated with previous injection not listed above).  
If a subject withdraws / is withdrawn from repeat injection, information relative to the 
withdrawal will be documented in the subject’s medical record and in the eCRF. The 
Investigator will document whether the decision to withdraw from repeat injection was made by 
the subject himself / herself or by the Investigator, as well as the reason for withdrawal. 
4.2.2. 
Withdrawal from the Study 
Subjects may withdraw from the study at any time for any reason without jeopardy or prejudice 
or compromising their clinical care. However, every effort should be made to adhere to as many 
study assessments as possible. If a subject indicates that he / she wishes to withdraw from the 
study, whenever possible, the subject should be seen by the Investigator and the procedures for 
the Exit Visit should be performed. The Investigator also has the right to withdraw subjects from 
the study in the event of intercurrent illness, AEs, protocol violations and administrative or other 
reasons. Data for all visits to the point of withdrawal must be recorded in the subject’s medical 
record and in the eCRF.  
The data to be collected for subjects who withdraw from the study should include: 
• Date of withdrawal 
• Reason for withdrawal 
• Data on assessments conducted (if possible) as part of the Exit Visit as described in 
Section 5.17  
• Data on any AEs present at withdrawal 
If withdrawal is a result of an SAE / death or pregnancy, an SAE Form or Pregnancy / Prenatal 
Exposure Form will also have to be completed, respectively. The Investigator will follow 
subjects who are withdrawn from the study as a result of an (S)AE until the event has resolved, 
subsided, stabilised, or until the event is otherwise explained, or the subject is lost to follow-up 
(refer to Section 8.4.1.4). The Investigator will follow-up and document the outcome of the 
pregnancy for pregnant women who are withdrawn from the study (refer to Section 8.4.2). 


5. 
STUDY OBSERVATIONS AND PROCEDURES 
There will be a total of 13 scheduled study visits in this study, including a screening visit, 
3 injection visits and a follow-up period of 24 months from the first injection visit. 24-72 hours 
after each injection visit, there will be a scripted post-injection phone call to inquire about AEs 
and concomitant medications / treatments. Based on this phone call, the subject may be invited 
back for an unscheduled study visit. Additional unscheduled study visits can be conducted at any 
time during the study, if deemed necessary. 
Refer to Table 6 for an overview of the study procedures per scheduled study contact and to 
Table 7 for an overview of the timing and the intervals between those study contacts. Refer to 
Table 8 for an overview of which study procedures should be done by masked and the unmasked 
study staff and for which study procedures certification is needed. A more detailed description of 
the study procedures and the names and addresses of the CRCs and the clinical laboratories are 
provided in the study-specific manuals. 
5.1. 
Informed Consent  
Subjects are required to provide signed and dated informed consent prior to participation in the 
study.  
Before signing the Informed Consent Form, the Investigator or designee will explain the nature, 
purpose, risks and benefits associated with the study and ensure that the subject is given full and 
adequate written information. Subjects must be informed that they are free to discontinue their 
participation in the study at any time. Subjects should be given the opportunity to ask questions 
and be allowed time to consider the information provided. If a subject agrees to participate in the 
study, he / she should sign the Informed Consent Form to indicate that he / she understands all 
aspects of the study. The Investigator will provide the subject with a copy of the Subject 
Information Sheet / Informed Consent Form. 
5.2. 
Visit 1 - Screening Visit 
At the screening visit, the subject’s eligibility for study participation will be determined by 
checking all in- and exclusion criteria as specified in Section 4.1.1. It is advised to do eligibility 
assessment in the order presented below. If a subject fails 1 of the in- / exclusion criteria, the 
subject will be a screening failure and no further assessments will be done (note that certain 
inclusion / exclusion criteria will be confirmed by the B-scan expert reader / the CRC, or the 
central laboratory). The eligibility assessment will entail the following evaluations: 
1. Demography (year of birth, gender, race [except in countries where Regulatory 
Authorities / IEC / IRB do not permit to collection of race]) 
2. Medical history, including concomitant medications / treatments / interventions (refer to 
Section 6.4) 
3. Ocular history 
4. Blood pressure 
5. BCVA (ETDRS) - both eyes 
6. B-scan ultrasound – potential study eye(s) * 


7. Full ophthalmic examination – both eyes 
8. 7-standard field stereo colour fundus photography – potential study eye(s) * 
9. SD-OCT (6mm) – potential study eye(s) * 
10. Fluorescein angiography – potential study eye(s) * 
11. Blood sampling for serum pregnancy test (for women of childbearing potential only) 
Refer to the study-specific manuals for instructions on the collection, processing, storage 
and shipping of blood samples 
12. Blood sampling for HbA1c 
Refer to the study-specific manuals for instructions on the collection, processing, storage 
and shipping of blood samples 
13. (S)AE monitoring (refer to Section 8.4) 
* These examinations need to be performed in potential study eye(s) only. If 1 of the subject’s 
eyes is excluded based on an eligibility criterion that does not need confirmation by the B-scan 
expert reader or the CRC, these examinations do not need to be performed for that eye. If both 
eyes potentially qualify as the study eye, these examinations need to be performed for both eyes. 
For screening failures due to reasons that are expected to be temporary, and for subjects for 
whom eligibility cannot be timely determined due to a problem with one of the eligibility 
assessments (e.g. ungradable B-scan ultrasound), 1 re-screening visit can be organised. The 
re-screening visit should be scheduled at least 28 days after the 1st screening visit. Subjects who 
are re-screened will be given a new subject number and need to have all screening procedures 
repeated (including signing of a new Informed Consent Form).  
For eligible subjects, all information must be recorded in the subject’s eCRF. For subjects who 
do not meet the eligibility criteria, the minimum information to be recorded in the eCRF will be 
the following: date of screening, subject number, procedures completed and reason for screening 
failure. 
5.3. 
Visit 2 –Day 0 
The following procedures will be performed: 
• Urine pregnancy test (for women of childbearing potential only) 
Pregnant women will not be eligible for study participation 
• Blood sampling for immunogenicity assessment 
Refer to the study-specific manuals for instructions on the collection, processing, 
storage and shipping of blood samples 
• BCVA (ETDRS) –both eyes 
• Colour vision (Roth 28-hue) – study eye only (only at sites where the Roth 28 Colour 
Test is available) 
Not needed for subjects > 80 years of age or with a diagnosis of dyschromatopsia at 
baseline 
• Full ophthalmic examination – study eye only 


• SD-OCT (widefield) – study eye only (only at sites where this is available) 
• ffERG – both eyes (in approximately 25% of the subjects, at sites where this is 
available) 
• Treatment number allocation (refer to Section 3.5.1) 
Randomisation can only occur after confirmation of eligibility by the B-scan expert 
reader and the CRC 
•  Study treatment 
• Post-injection assessment (IOP measurement and indirect ophthalmic examination) 
The post-injection assessment should be performed by the unmasked treating 
investigator as many times as needed at his / her discretion but at least once within 
60 minutes after the injection to exclude central retinal artery non-perfusion or other 
complications 
• Record concomitant medications / treatments / interventions (refer to Section 6.4) 
• (S)AE monitoring (refer to Section 8.4) 
All information must be recorded in the subject’s eCRF. 
5.4. 
Post-injection Phone Call 
The masked Investigator / designee will make a scripted phone call to each subject 24-72 hours 
after the injection visit. Based on this phone call, the subject may be invited back for an 
unscheduled study visit as per the masked Investigator’s clinical judgement. 
For the phone script, please refer to Appendix 2. 
5.5. 
Visit 3 - Day 7 
The following procedures will be performed: 
• BCVA (ETDRS) –both eyes 
• Colour vision (Roth 28-hue) – study eye only (only at sites where the Roth 28 Colour 
Test is available) 
Not needed for subjects > 80 years of age or with a diagnosis of dyschromatopsia at 
baseline 
• Full ophthalmic examination – study eye only 
• SD-OCT (6mm) – study eye only 
• Record concomitant medications / treatments / interventions (refer to Section 6.4) 
• (S)AE monitoring (refer to Section 8.4) 
All information must be recorded in the subject’s eCRF. 


5.6. 
Visit 4a – Day 28 
The following procedures will be performed: 
• Urine pregnancy test (for women of childbearing potential only) 
• BCVA (ETDRS) –both eyes 
• Colour vision (Roth 28-hue) – study eye only (only at sites where the Roth 28 Colour 
Test is available) 
Not needed for subjects > 80 years of age or with a diagnosis of dyschromatopsia at 
baseline 
• B-scan ultrasound – study eye only 
• Full ophthalmic examination – study eye only 
• SD-OCT (6mm) – study eye only 
• SD-OCT (widefield) – study eye only (only at sites where this is available). 
• Assess list of events that lead to withdrawal from repeat injection (refer to 
Section 4.2.1) 
• Record concomitant medications / treatments / interventions (refer to Section 6.4)  
• (S)AE monitoring (refer to Section 8.4)  
All information must be recorded in the subject’s eCRF. 
5.7. 
Visit 4b – Day 35 
The following procedures will be performed: 
• Treatment number allocation for repeat injection (refer to Section 3.5.2) 
•  Study treatment 
• Post-injection assessment (IOP measurement and indirect ophthalmic examination) 
The post-injection assessment should be performed by the unmasked treating 
investigator as many times as needed at his / her discretion but at least once within 
60 minutes after the injection to exclude central retinal artery non-perfusion or other 
complications 
• Record concomitant medications / treatments / interventions (refer to Section 6.4)  
• (S)AE monitoring (refer to Section 8.4)  
All information must be recorded in the subject’s eCRF. 
5.8. 
Post-injection Phone Call 
Refer to Section 5.4. 


5.9. 
Visit 5 –Day 42 
The procedures to be performed at Visit 5 (Day 42) are the same as those to be performed at 
Visit 3 (Day 7). Refer to Section 5.5 for the description of the study procedures at this visit. 
5.10. 
Visit 6a – Day 63 
The procedures to be performed at Visit 6a (Day 63) are the same as those to be performed at 
Visit 4a (Day 28). Refer to Section 5.6 for the description of the study procedures at this visit. 
5.11. 
Visit 6b – Day 70 
The procedures to be performed at Visit 6b (Day 70) are the same as those to be performed at 
Visit 4b (Day 35). Refer to Section 5.7 for the description of the study procedures at this visit. 
5.12. 
Post-injection Phone Call 
Refer to Section 5.4. 
5.13. 
Visit 7 – Day 77 
The following procedures will be performed: 
• BCVA (ETDRS) –both eyes 
• Colour vision (Roth 28-hue) – study eye only (only at sites where the Roth 28 Colour 
Test is available) 
Not needed for subjects > 80 years of age or with a diagnosis of dyschromatopsia at 
baseline 
• B-scan ultrasound – study eye only 
• Full ophthalmic examination – study eye only 
• SD-OCT (6mm) – study eye only 
• Record concomitant medications / treatments / interventions (refer to Section 6.4) 
• (S)AE monitoring (refer to Section 8.4) 
All information must be recorded in the subject’s eCRF. 
5.14. 
Visit 8 – Month 3 (Day 98) 
The following procedures will be performed: 
• Blood pressure 
• Blood sampling for HbA1c 
Refer to the study-specific manuals for instructions on the collection, processing, 
storage and shipping of blood samples 
• Blood sampling for immunogenicity assessment 
Refer to the study-specific manuals for instructions on the collection, processing, 
storage and shipping of blood samples 


• BCVA (ETDRS) – both eyes 
• Colour vision (Roth 28-hue) – study eye only (only at sites where the Roth 28 Colour 
Test is available) 
Not needed for subjects > 80 years of age or with a diagnosis of dyschromatopsia at 
baseline 
• B-scan ultrasound – study eye only 
• Full ophthalmic examination – both eyes 
• 7-standard field stereo colour fundus photography – study eye only (only if the 
Investigator suspects that the subject has progressed to PDR) 
• SD-OCT (6mm) – study eye only 
• SD-OCT (widefield) – study eye only (only at sites where this is available). 
• ffERG – both eyes (in approximately 25% of the subjects, at sites where this is 
available) 
• Record concomitant medications / treatments / interventions (refer to Section 6.4)  
• (S)AE monitoring (refer to Section 8.4) 
All information must be recorded in the subject’s eCRF. 
5.15. 
Visit 9 – Month 9 (Day 270) 
The following procedures will be performed: 
• Blood pressure 
• Blood sampling for HbA1c 
Refer to the study-specific manuals for instructions on the collection, processing, 
storage and shipping of blood samples 
• BCVA (ETDRS) – both eyes 
• Colour vision (Roth 28-hue) – study eye only (only at sites where the Roth 28 Colour 
Test is available) 
Not needed for subjects > 80 years of age or with a diagnosis of dyschromatopsia at 
baseline 
• B-scan ultrasound – study eye only 
• Full ophthalmic examination – both eyes 
• 7-standard field stereo colour fundus photography – study eye only (only if the 
Investigator suspects that the subject has progressed to PDR) 
• SD-OCT (6mm) – study eye only 
• Record concomitant medications / treatments / interventions (refer to Section 6.4) 
• (S)AE monitoring (refer to Section 8.4) 


All information must be recorded in the subject’s eCRF. 
5.16. 
Visit 10 – Month 15 (Day 450) 
The following procedures will be performed: 
• Blood pressure 
• Blood sampling for HbA1c 
Refer to the study-specific manuals for instructions on the collection, processing, 
storage and shipping of blood samples 
• BCVA (ETDRS) – both eyes 
• Colour vision (Roth 28-hue) – study eye only (only at sites where the Roth 28 Colour 
Test is available) 
Not needed for subjects > 80 years of age or with a diagnosis of dyschromatopsia at 
baseline 
• B-scan ultrasound – study eye only 
• Full ophthalmic examination – both eyes 
• 7-standard field stereo colour fundus photography – study eye only 
• SD-OCT (6mm) – study eye only 
• ffERG – both eyes (only for subjects with expert-defined ffERG abnormalities at the 
previous assessment) 
• Record concomitant medications / treatments / interventions (refer to Section 6.4)  
• (S)AE monitoring (refer to Section 8.4) 
All information must be recorded in the subject’s eCRF. 
5.17. 
Visit 11 – Month 24 (Day 720) / Exit Visit 
The procedures to be performed at Visit 11 (Month 24) are the same as those to be performed at 
Visit 10 (Month 15). Refer to Section 5.16 for the description of the study procedures at this 
visit. 
5.18. 
Unscheduled Visits 
Unscheduled visits can be conducted at any time during the study (e.g. based on scripted 
post-injection phone call).  
For each unscheduled visit, the following information must be recorded in the subject’s eCRF: 
• Reason for visit 
• Procedures performed and results obtained 
• Concomitant medications / treatments / interventions (refer to Section 6.4) 
• (S)AEs (refer to Section 8.4) 


 
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6. 
TREATMENT OF SUBJECTS 
6.1. 
Description of Study Drugs 
Table 5: 
Study Drugs 
Study Drug 
Ocriplasmin 0.0625mg 
Ocriplasmin 0.125mg 
Sham 
Study Drug 
Components 
ocriplasmin 
0.5mg/0.2mL 
Sodium chloride 
(NaCl) 9mg/mL 
(0.9%)  
ocriplasmin 
0.5mg/0.2mL 
Sodium chloride 
(NaCl) 9mg/mL 
(0.9%) 
- 
Formulation 
Active Substance 
ocriplasmin 
0.5mg/0.2mL 
Excipients 
Mannitol  
Citric acid 
Sodium hydroxide 
(NaOH) for pH 
adjustment 
Water for injection 
NaCl 9mg/mL (0.9%) 
Active Substance 
ocriplasmin 
0.5mg/0.2mL 
Excipients 
Mannitol  
Citric acid 
Sodium hydroxide 
(NaOH) for pH 
adjustment 
Water for injection 
NaCl 9mg/mL (0.9%) 
- 
Presentation 
Clear and colourless 
solution 
Clear and colourless 
solution 
Clear and colourless 
solution 
Clear and colourless 
solution 
- 
Volume for 
dilution 
0.2mL 
0.6mL 
0.2mL 
0.2mL 
- 
Volume to be 
administered 
0.1mL 
0.1mL 
- 


 
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Table 5: 
Study Drugs (Continued) 
Study Drug 
Ocriplasmin 0.0625mg 
Ocriplasmin 0.125mg 
Sham 
Route of 
Administration 
Intravitreal injection 
Intravitreal injection 
Sham injection 
Dosing Schedule 
• 
Up to 3 injections for subjects in the 
ocriplasmin 0.0625mg arm, administered at 
Day 0, Day 35 and Day 70 
• 
Up to 3 injections for subjects in the 
ocriplasmin 0.125mg arm, administered at 
Day 0, Day 35 and Day 70a 
• 
3 sham injections for subjects in the sham 
arm, administered at Day 0, Day 35 and 
Day 70  
• 
Up to 2 sham injections for subjects in the 
ocriplasmin arms, administered at Day 35 
and / or Day 70a 
a All subjects assigned to the ocriplasmin arms will receive an intravitreal injection of ocriplasmin 0.0625mg or 0.125mg at Day 0. These subjects will be re-treated with the 
same dose of ocriplasmin at Day 35 and at Day 70 if, at that time, they do not have total PVD on both B-scan ultrasound and SD-OCT, as assessed by the masked B-scan 
expert reader and the masked CRC, respectively. Subjects who have total PVD on both B scan ultrasound and SD-OCT will receive subsequent sham injection(s) in place 
of ocriplasmin injection(s) 


 
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Ocriplasmin is supplied in a single use, glass (type I glass) vial containing 0.5mg ocriplasmin in 
0.2mL solution (2.5mg/mL). Ocriplasmin vials are packed in carton boxes, each of which 
contains a single vial. Vials are closed with a chlorobutyl rubber stopper and a polypropylene 
flip-off cap. 
NaCl (0.9%) is supplied in a single use ampoule containing 5mL NaCl 9mg/mL (0.9%). 
Sham is supplied as an empty glass (type I glass) vial. Sham vials are packed in carton boxes, 
each of which contains a single vial. Vials are closed with a chlorobutyl rubber stopper and a 
polypropylene flip-off cap. 
All vials and cartons are labelled and packed in accordance with current ICH guidelines on Good 
Manufacturing Practice (GMP) and GCP E6(R1). 
6.2. 
Storage and Handling of Study Drug 
6.2.1. 
Study Drug Kit Storage 
Study drug kits should be stored protected from light at -20°C±5°C (-4°F±9°F) in a temperature 
controlled, secure facility with limited access.  
If temperature excursions are noted, this must be reported immediately to the CRO, who works 
on behalf of the Sponsor. Study drug subject to a temperature excursion should be immediately 
quarantined under the indicated storage conditions, until further instructions from the CRO.  
After Thawing 
Once thawed, the study drug should be diluted and used immediately. Do not refreeze a vial once 
it has been thawed. 
After Opening / Dilution 
From a microbiological point of view, the study drug must be used immediately after 
opening / dilution.  
6.2.2. 
Administration Kit Storage 
Administration kits should be stored at ambient temperature.  
6.2.3. 
Study Drug Preparation and Administration 
The unmasked treating investigator / designee will prepare the injections. The unmasked treating 
investigator will administer the injections (ocriplasmin 0.0625mg, ocriplasmin 0.125mg and 
sham). 
In addition to the procedures described below, added safety measures in adherence to specific 
institutional policies associated with intravitreal injections will be used. Also refer to 
(Avery et al., 2014) for a guideline on intravitreal injection technique and monitoring. 
6.2.3.1. 
Pre-injection Procedures 
Pre-injection procedures will be implemented to minimise the risk of potential AEs associated 
with intravitreal injections.  


 
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The pre-injection procedures, including injection tray assembly and anaesthetic preparation, will 
be performed under controlled aseptic conditions. This will include surgical hand disinfection, 
sterile gloves and disinfection of the periocular skin, eyelid and ocular surface (i.e. cleansed with 
povidone-iodine).  
Adequate anaesthesia should be administered prior to the injection as per local clinical practice 
and in line with the JETREA USPI / SmPC. A prophylactic topical antibiotic may be 
administered at the discretion of the unmasked treating investigator. 
6.2.3.2. 
Ocriplasmin 0.0625mg Injection 
Study drug preparation will be done outside of the subject’s view. In addition, a sterile drape 
may be used to cover the fellow eye and the subject will be instructed to direct his / her gaze 
away at all times. It is recommended to follow the guidelines published by Avery et al on 
intravitreal injections (Avery et al., 2014). The injection should be carried out under aseptic 
conditions, which includes the use of surgical hand disinfection, sterile gloves, a surgical mask, a 
sterile drape and a sterile eyelid speculum (or equivalent). 
1. Remove the drug kit from the freezer and allow to thaw at room temperature (takes about 
2 minutes) 
2. Once completely thawed, remove the protective polypropylene flip-off cap from the 
ocriplasmin vial and discard the flip-off cap immediately 
3. Disinfect the top of the ocriplasmin vial with an alcohol wipe 
4. Disinfect the top of the NaCl (0.9%) ampoule with an alcohol wipe. Twist off the head of 
the ampoule to decapsulate. Insert the syringe cone into the ampoule and withdraw 
NaCl (0.9%). Detach the syringe from the ampoule and attach 1 of the 19G needles. 
Carefully expel the air and excess NaCl (0.9%) from the syringe and adjust the volume to 
the 0.6mL mark 
5. Add 0.6mL NaCl (0.9%) into the ocriplasmin vial. Discard the needle and the syringe 
6. Swirl the vial 
7. Visually inspect the vial for particulate matter. Only a clear, colourless solution without 
visible particles should be used 
8. Using aseptic technique, withdraw all of the solution using the other 19G needle (slightly 
incline the vial to ease withdrawal) and discard the needle after withdrawal of the vial 
contents. Do not use this needle for the intravitreal injection 
9. Replace the needle with the sterile 30G injection needle, carefully expel the air and 
excess drug from the syringe and adjust the volume to the 0.1mL mark on the syringe 
(corresponding to 0.0625mg ocriplasmin) 
10. Inject 0.1mL of the solution into the mid-vitreous: 
a. The injection should be made through the pars plana in the inferotemporal quadrant 
3.5-4mm posterior to the limbus 
b. The needle should be inserted at least 6mm towards the centre of the eye avoiding the 
horizontal meridian 


 
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c. Use a moderately slow injection technique in order to allow the test product to enter 
the vitreous 
11. Slowly remove the needle and use a sterile cotton-tip applicator to prevent reflux of both 
the test product and the vitreous 
12. Discard the syringe and the needle immediately after the injection 
13. Put the NaCl (0.9%) ampoule back in its administration kit carton and the ocriplasmin 
vial in its study drug kit carton. Seal both cartons and store securely for drug 
accountability 
6.2.3.3. 
Ocriplasmin 0.125mg Injection 
Study drug preparation will be done outside of the subject’s view. In addition, a sterile drape 
may be used to cover the fellow eye and the subject will be instructed to direct his / her gaze 
away at all times. It is recommended to follow the guidelines published by Avery et al on 
intravitreal injections (Avery et al., 2014). The injection should be carried out under aseptic 
conditions, which includes the use of surgical hand disinfection, sterile gloves, a surgical mask, a 
sterile drape and a sterile eyelid speculum (or equivalent). 
1. Remove the drug kit from the freezer and allow to thaw at room temperature (takes about 
2 minutes) 
2. Once completely thawed, remove the protective polypropylene flip-off cap from the 
ocriplasmin vial and discard the flip-off cap immediately 
3. Disinfect the top of the ocriplasmin vial with an alcohol wipe 
4. Disinfect the top of the NaCl (0.9%) ampoule with an alcohol wipe. Twist off the head of 
the ampoule to decapsulate. Insert the syringe cone into the ampoule and withdraw 
NaCl (0.9%). Detach the syringe from the ampoule and attach 1 of the 19G needles. 
Carefully expel the air and excess NaCl (0.9%) from the syringe and adjust the volume to 
the 0.2mL mark  
5. Add 0.2mL NaCl (0.9%) into the ocriplasmin vial. Discard the needle and the syringe 
6. Swirl the vial 
7. Visually inspect the vial for particulate matter. Only a clear, colourless solution without 
visible particles should be used 
8. Using aseptic technique, withdraw all of the solution using 1 of the 19G needles (slightly 
incline the vial to ease withdrawal) and discard the needle after withdrawal of the vial 
contents. Do not use this needle for the intravitreal injection 
9. Replace the needle with the sterile 30G injection needle, carefully expel the air and 
excess drug from the syringe and adjust the volume to the 0.1mL mark on the syringe 
(corresponding to 0.125mg ocriplasmin) 
10. Inject 0.1mL of the solution into the mid-vitreous: 
a. The injection should be made through the pars plana in the inferotemporal quadrant 
3.5-4mm posterior to the limbus 


 
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b. The needle should be inserted at least 6mm towards the centre of the eye avoiding the 
horizontal meridian 
c. Use a moderately slow injection technique in order to allow the test product to enter 
the vitreous 
11. Slowly remove the needle and use a sterile cotton-tip applicator to prevent reflux of both 
the test product and the vitreous 
12. Discard the syringe and the needle immediately after the injection 
13. Put the NaCl (0.9%) ampoule back in its administration kit carton and the ocriplasmin 
vial back in its study drug kit carton. Seal both cartons and store securely for drug 
accountability 
6.2.3.4. 
Sham Injection 
Study drug preparation will be done outside of the subject’s view. In addition, a sterile drape 
may be used to cover the fellow eye and the subject will be instructed to direct his / her gaze 
away at all times. It is recommended to follow the guidelines published by Avery et al on 
intravitreal injections (Avery et al., 2014). The injection should be carried out under aseptic 
conditions, which includes the use of surgical hand disinfection, sterile gloves, a surgical mask, a 
sterile drape and a sterile eyelid speculum (or equivalent). 
1. Remove the drug kit from the freezer and allow to attain room temperature (leave at room 
temperature for at least 2 minutes for masking reasons) 
2. Remove the protective polypropylene flip-off cap from the sham vial and discard the flip-
off cap immediately 
3. Disinfect the top of the sham vial with an alcohol wipe 
4. Using aseptic technique, mimic solution withdrawal using 1 of the 19G needles (slightly 
incline the vial to ease withdrawal) and discard the needle after 
5. Adjust the dose volume to the 0.1mL mark on the syringe 
6. Press the hub of the syringe firmly against the sclera / conjunctiva and slowly depress the 
plunger to mimic an actual injection procedure 
7. Discard the syringe immediately after the sham injection. Also discard the unused 
syringe, 30G and 19G needles 
8. Put the sham vial back in the study drug kit carton. Seal the study drug kit carton and the 
empty drug administration kit carton and store both cartons securely for drug 
accountability 
6.2.4. 
Post-Injection Assessment 
During the 1-hour period after injection (ocriplasmin or sham), the subject should be monitored 
for elevated IOP. Elevated IOP may occur when the central retinal artery remains closed for 
approximately 2 minutes, if the subject reports no light perception. The following will be done: 
1. Visualise the optic nerve head to verify reperfusion of the central retinal artery in the 
immediate post-injection period 


 
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2. Monitor IOP with tonometry 
3. Increased IOP may warrant treatment (e.g. anterior chamber paracentesis). However, 
transient graying or obscuration of vision following injection is expected and does not 
need to be treated 
Verify that the retina is attached and that there is no haemorrhage. 
Instruct subjects that they should avoid rubbing their eye. Also instruct subjects to report any 
symptoms suggestive of infection, bleeding, retinal break or tear, increased IOP or lens 
subluxation without delay (e.g. eye pain, worsening eye redness, severely blurred or decreased 
vision, increased sensitivity to light, floaters, fluctuation of vision, double vision, headache, 
halos around light, nausea and vomiting). 
6.2.5. 
Study Drug Accountability 
A full accountability record must be maintained. The unmasked treating investigator / designee 
(e.g. study nurse, study coordinator or pharmacist) will be responsible for recording the receipt, 
administration and return of all supplies using the supplied forms. 
Unused study drug and administration kits must be stored securely. Used study drug kits 
(containing used ocriplasmin or sham vials) and used administration kits (containing the used 
NaCl [0.9%] ampoule where applicable) must be sealed and stored securely. An unmasked study 
monitor will visit the site periodically to check inventories and ensure that IXRS assigned 
treatments have correctly been administered and that all unused supplies remain intact or 
quarantined. 
After study treatment is completed for all subjects, and upon request from the Sponsor, all used 
and unused study drug and administration kits must be reconciled by the unmasked study 
monitor and returned to the Sponsor or its representative, together with the drug return form and 
a copy of the accountability form. 
Under no circumstances will the Investigator allow the study drug to be used in any manner other 
than directed by this protocol. 
6.3. 
Treatment Compliance 
As the treatment is not dispensed to the subject, but administered by the unmasked treating 
investigator, no procedures for monitoring subject treatment compliance are required. 
6.4. 
Concomitant Medications / Treatments / Interventions 
At each study visit, the Investigator should question the subject about any medications / 
treatments / interventions taken / received by the subject. All concomitant medications / 
treatments / interventions should be recorded in the subject’s eCRF. 


 
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6.4.1. 
Diabetic Retinopathy-related Treatment 
6.4.1.1. 
Escape Criteria 
• Subjects may be treated with PRP following the confirmation of progression from 
NPDR to PDR, as assessed by the masked CRC.  
No minimum time interval between study treatment and PRP needs to be considered. 
• Subjects may be treated with an anti-VEGF treatment following the confirmation of 
development of CI-DME with CST of ≥ 340µm on Spectralis SD-OCT or ≥ 320µm 
on non-Spectralis SD-OCT, or an increase of 50µm from baseline in CST, based on 
SD-OCT, as assessed by the masked CRC.  
There are no clinical data on concomitant use of ocriplasmin with anti-VEGF 
treatment, however, as ocriplasmin is a proteolytic enzyme with serine protease 
activity which could be present in the eye for several days after intravitreal injection, 
administration in close temporal association with other medicinal products in the 
same eye may affect the activity of both medicinal products and is therefore not 
recommended. A minimum time of 7 days between study treatment and anti-VEGF 
injection is therefore required. 


 
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7. 
ASSESSMENT OF EFFICACY 
7.1. 
Efficacy Parameters 
Refer to Section 3.1.1 for the efficacy endpoints. 
7.2. 
Methods and Timing for Assessing Efficacy Parameters 
Refer to Table 8 for an overview of which study procedures should be done by masked and the 
unmasked study staff and for which study procedures certification is needed. 
7.2.1. 
B-scan Ultrasound 
B-scan ultrasounds will be used to assess total PVD. The images will be submitted to and 
evaluated by the B-scan expert reader. 
B-scan ultrasounds will be taken for all subjects: 
• At Visit 1 (screening visit) for potential study eye(s)  
If 1 of the subject’s eyes is excluded based on an eligibility criterion that does not 
need confirmation by the B-scan expert reader or the CRC, no B-scan ultrasound 
needs to be performed for that eye. If both eyes potentially qualify as the study eye, 
B-scan ultrasounds need to be taken for both eyes 
• At Visit 4a (Day 28), Visit 6a (Day 63), Visit 7 (Day 77), Visit 8 (Month 3), 
Visit 9 (Month 9), Visit 10 (Month 15) and Visit 11 (Month 24) / the Exit Visit for 
the study eye 
7.2.2. 
SD-OCT (6mm) 
6mm SD-OCTs will be used for assessment of efficacy (total PVD, macular oedema) and safety. 
The images will be submitted to and evaluated by the masked CRC. 
6mm SD-OCT imaging will be performed for all subjects: 
• At Visit 1 (screening visit) for potential study eye(s)  
If 1 of the subject’s eyes is excluded based on an eligibility criterion that does not 
need confirmation by the B-scan expert reader or the CRC, no SD-OCT needs to be 
taken for that eye. If both eyes potentially qualify as the study eye, SD-OCT imaging 
needs to be performed for both eyes 
• At each scheduled study visit, with the exception of Visit 2 (Day 0) and the repeat 
injection visits (Visit 4b [Day 35] and Visit 6b [Day 70]), for the study eye  
7.2.3. 
7-Standard Field Stereo Colour Fundus Photography 
7-standard field stereo colour fundus photography will be used to assess DR stage, 
neovascularisation and vitreous / pre-retinal haemorrhage. The images will be submitted to and 
evaluated by the masked CRC. 


 
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7-standard field stereo colour fundus photographs will be taken for all subjects: 
• At Visit 1 (screening visit) for potential study eye(s)  
If 1 of the subject’s eyes is excluded based on an eligibility criterion that does not 
need confirmation by the B-scan expert reader or the CRC, no 7-standard field stereo 
colour fundus photograph need to be taken for that eye. If both eyes potentially 
qualify as the study eye, 7-standard field stereo colour photographs need to be taken 
for both eyes 
• At Visit 10 (Month 15) and at Visit 11 (Month 24) / the Exit Visit for the study eye 
In addition, 7-standard field stereo colour fundus photographs will be taken for subjects that the 
Investigator suspects progressed to PDR: 
• At Visit 8 (Month 3) and at Visit 9 (Month 9) 
7.2.4. 
Slit Lamp Examination 
Slit lamp examination will be performed for all subjects: 
• At Visit 1 (screening visit), Visit 8 (Month 3), Visit 9 (Month 9), Visit 10 (Month 15) 
and at Visit 11 (Month 24) / the Exit Visit for both eyes 
• At Visit 2 (Day 0), Visit 3 (Day 7), Visit 4a (Day 28), Visit 5 (Day 42), 
Visit 6a (Day 63) and at Visit 7 (Day 77) for the study eye 
7.2.5. 
Best Corrected Visual Acuity 
BCVA will be reported as the number of letters read correctly by the subject on the ETDRS 
chart. 
BCVA will be assessed for all subjects: 
• At each scheduled study visit, with the exception of the repeat injection visits 
(Visit 4b [Day 35] and Visit 6b [Day 70]), for both eyes 
7.2.6. 
Widefield SD-OCT 
Widefield SD-OCT will be used for exploratory assessment of total PVD. The images will be 
submitted to and evaluated by the masked CRC. 
Widefield SD-OCT imaging will be performed in a subset of subjects, enrolled at sites where this 
is available: 
• At Visit 2 (Day 0), Visit 4a (Day 28), Visit 6a (Day 63) and Visit 8 (Month 3) for the 
study eye 


 
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8. 
ASSESSMENT OF SAFETY 
8.1. 
Safety Parameters 
Refer to Section 3.1.2 for the safety endpoints. 
8.2. 
Methods and Timing for Assessing Safety Parameters 
Refer to Table 8 for an overview of which study procedures should be done by masked and the 
unmasked study staff and for which study procedures certification is needed. 
8.2.1. 
Adverse Events 
All AEs must be recorded from the time of providing consent until the end of the study for all 
subjects.  
8.2.2. 
Full Ophthalmic Examination 
A full ophthalmic examination (pupillary examination, slit lamp examination, IOP assessment 
and dilated fundus examination) will be performed for all subjects: 
• At Visit 1 (screening visit), Visit 8 (Month 3), Visit 9 (Month 9), Visit 10 (Month 15) 
and at Visit 11 (Month 24) / the Exit Visit for both eyes 
• At Visit 2 (Day 0), Visit 3 (Day 7), Visit 4a (Day 28), Visit 5 (Day 42), Visit 6a 
(Day 63) and at Visit 7 (Day 77) for the study eye 
8.2.3. 
Best Corrected Visual Acuity 
BCVA will be both a measure of efficacy and safety. Refer to Section 7.2.5 for more information 
on the method and timing of BCVA measurement. 
8.2.4. 
Colour Vision (Roth 28-hue) 
Hue discrimination ability will be assessed by the Roth 28 Colour Test. 
The Roth 28-hue colour vision test will be performed in a subset of subjects, enrolled at sites 
where the Roth 28 Colour Test is available, and who are ≤ 80 years of age and do not have a 
diagnosis of dyschromatopsia at baseline:  
• At each scheduled study visit, with the exception of Visit 1 (screening) and the repeat 
injection visits (Visit 4b [Day 35] and Visit 6b [Day 70]), for the study eye 
8.2.5. 
SD-OCT 
SD-OCTs will be used both as a measure of efficacy and safety. Refer to Section 7.2.2 and 
Section 7.2.6 for more information on the timing of SD-OCT imaging. 
8.2.6. 
Full-field ERG 
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ffERG will be performed for approximately 25% of the subjects, enrolled at sites where this is 
available: 
• At Visit 2 (Day 0) and Visit 8 (Month 3) for both eyes 
In addition, ffERG will be performed for subjects with expert-defined ffERG abnormalities: 
• At Visit 10 (Month 15) for both eyes - for subjects with expert-defined ffERG 
abnormalities at Visit 8 (Month 3) 
• At Visit 11 (Month 24) / the Exit Visit for both eyes - for subjects with expert-
defined ffERG abnormalities at Visit 10 (Month 15) 
8.2.7. 
Immunogenicity 
An immunogenicity assay will be performed to assess whether multiple injections of ocriplasmin 
0.0625mg or 0.125mg induce an immune response. Blood samples for assessment of 
immunogenicity will be sent to the central laboratory for immunogenicity testing. 
Blood samples for immunogenicity assessment will be taken from all subjects: 
• At baseline (Visit 2 [Day 0]) and at Visit 8 (Month 3) 
8.3. 
Safety Definitions 
8.3.1. 
Definition of an Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment.  
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) product. 
8.3.2. 
Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening 
NOTE: The term "life-threatening" refers to an event in which the patient was at risk 
of death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe 
• Requires in-patient hospitalisation or prolongation of existing hospitalisation 
• Results in persistent or significant disability / incapacity 
• Is a congenital abnormality / birth defect 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered SAEs, such as important medical events that might not be immediately 


 
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life-threatening or result in death or hospitalisation but might jeopardise the patient or might 
require intervention to prevent one of the other outcomes listed above.  
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, neoplasms or convulsions that do not result in hospitalisation. 
8.3.3. 
Clarifications 
Hospitalisation 
Hospitalisation for elective treatment of a pre-existing condition (i.e. a condition present prior to 
the subject’s signature of the informed consent) that did not worsen during the study is not 
considered an (S)AE. Complications that occur during hospitalisation are AEs. If a complication 
prolongs hospitalisation, or meets any of the other SAE criteria, the complication is an SAE. 
Pre-existing Conditions, Including DR 
Pre-existing conditions (i.e. conditions present or detected at the start of the study) which worsen 
during the study, exacerbation of a pre-existing illness or an increase in frequency or intensity of 
a pre-existing episodic event or condition are (S)AEs. Anticipated day-to-day fluctuations of 
pre-existing condition(s) that do not worsen with respect to baseline are not (S)AEs. 
Worsening or progression of DR is considered to be a “lack of efficacy” or “failure of expected 
pharmacological action” per se and is already recorded in the efficacy data and therefore does 
not need to be reported as an (S)AE. However, the signs and symptoms and / or clinical sequelae 
resulting from the lack of efficacy may be reported as an (S)AE if considered by the Investigator 
to fulfil the definition of an (S)AE. 
Medical or Surgical Procedures 
Medical or surgical procedures (e.g. endoscopy, colonoscopy) are not (S)AEs; the condition that 
leads to the procedure is an (S)AE.  
In case of elective medical or surgical procedures, or pre-study planned medical or surgical 
procedures for pre-existing conditions (i.e. a condition present prior to the subject’s signature of 
the informed consent) that did not worsen during the study, the condition that leads to the 
procedure does not need to be reported as an (S)AE. 
Death 
Death is not an SAE; the condition that leads to death is an SAE. 
Abnormal Laboratory Values 
In the absence of diagnosis, abnormal laboratory values that are judged by the Investigator to be 
clinically significant must be recorded as an (S)AE. Clinically significant abnormal laboratory 
findings that are present at baseline and significantly worsen following the start of the study will 
also be reported as an (S)AE. However, clinically significant abnormal laboratory findings that 
are associated with DR, unless judged by the Investigator as more severe than expected for the 
subject’s condition, or that are present or detected at the start of the study and do not worsen, will 
not be reported as (S)AEs. 


 
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8.4. 
Recording of Adverse Events 
8.4.1. 
Adverse Events 
Adverse Events (Non-serious and Serious) 
(S)AEs occurring from the time of providing consent until the end of the study (Visit 11 – 
Month 24 / Exit Visit) must be recorded in the subject’s eCRF.  
(S)AEs observed during the 1-hour post-injection assessment should be recorded by the 
unmasked treating investigator / designee in the unmasked AE pages of the eCRF. If such an 
(S)AE is ongoing after the post-injection assessment, it will be followed up in a masked manner 
by the masked Investigator. All other (S)AEs should be recorded by the masked Investigator / 
designee in the masked AE pages of the eCRF.  
In order to escalate relevant TEAEs in a timely manner to the DMC (refer to Section 3.4), all 
(S)AEs need to be recorded in the eCRF within 24 hours after receipt or awareness of the 
information. 
The (S)AE term should be reported in standard medical terminology when possible. For each 
(S)AE, the Investigator will assess and record the date of onset, date of resolution, intensity, 
causality, action taken, seriousness, outcome (if applicable), and whether or not it led to 
withdrawal from the study.  
When possible, signs and symptoms indicating a common underlying pathology should be 
documented as one comprehensive event with an overall diagnosis. If a diagnosis cannot be 
made initially, the main signs and symptoms should be documented and updated with a diagnosis 
when available.  
Serious Adverse Events 
The unmasked treating investigator / masked Investigator shall report SAEs immediately, and 
no later than 24 hours after receipt or awareness of the information, by completing the SAE 
Form in the subject’s eCRF. The SAE Form should be completed as thoroughly as possible and 
verified with the corresponding source documents. It is very important that the Investigator 
provides an assessment of the relationship to the study drug or the injection procedure at the time 
of the initial SAE report. The eCRF system will automatically send the information to the 
Sponsor for processing. 
If the eCRF system cannot be used for any reason, the Investigator shall submit the completed 
SAE Form by email or fax to the Sponsor (email: pharmacovigilance@thrombogenics.com; 
fax: + 1 8775274503), within the same timeframe. The data should be entered in the eCRF as 
soon as the system becomes available again. 
8.4.1.1. 
Relationship to Study Drug or the Injection Procedure 
For each (S)AE, the unmasked treating investigator / masked Investigator must determine 
whether the event is related to the study drug or the injection procedure. To do so, the 
Investigator shall determine whether, in his / her medical judgment, there is a reasonable 
possibility that the event may have been caused by the study drug or the injection procedure, as 
defined below. 


 
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Related 
• There is reasonable probability that the (S)AE may have been caused by the study 
drug or the injection procedure; the (S)AE follows a reasonable temporal sequence 
from study treatment and the (S)AE cannot be reasonably explained by the subject's 
clinical status or other factors (e.g. disease under study, concurrent disease[s], and 
concomitant medications) 
Unrelated 
• There is no reasonable probability that the (S)AE has been caused by the study drug 
or the injection procedure; the (S)AE does not follow a reasonable sequence from 
study treatment, or can be reasonably explained by the subject’s clinical status or 
other factors (e.g. disease under study, concurrent disease[s], and concomitant 
medications) 
8.4.1.2. 
Adverse Event Intensity 
The unmasked treating investigator / masked Investigator shall assess and record the intensity of 
the (S)AE according to the following scale: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities)  
• Severe (incapacitating, with inability to perform normal activities)  
An AE that is assessed as ‘Severe’ should not be confused with an SAE. ‘Severe’ is part of a 
scale used for rating the intensity of an event. An event is defined as ‘Serious’ when it meets 1 of 
the pre-defined outcomes as described in Section 8.3.2. A severe AE can be of relatively minor 
medical significance / non-serious (e.g. severe itching). Similarly, an SAE can be of mild 
intensity (e.g. mild chest pain). 
For AEs that change in intensity, the start and stop date of each intensity should be recorded. 
8.4.1.3. 
Adverse Event Outcome 
At the time of reporting the outcome of an AE, it must be recorded as ongoing, resolved, or 
resolved with sequelae / death. 
8.4.1.4. 
Adverse Event Follow-Up  
Non-Serious Adverse Events 
The masked Investigator will follow subjects from the study who are withdrawn from the study 
as a result of an AE until the event has resolved, subsided, stabilised, or until the event is 
otherwise explained, or the subject is lost to follow-up. 
Other AEs will be followed until the subject has recovered or the subject’s participation in the 
study is complete. 


 
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Serious Adverse Events 
The Sponsor or delegated Pharmacovigilance Service Provider will follow-up SAE reports to 
completion. Investigators are expected to provide the additional information required for 
complete assessment and documentation of the SAE reports in a timely manner. 
When more information becomes available, the masked Investigator must update the SAE Form 
in the subject’s eCRF. The eCRF system will automatically send the follow-up report to the 
Sponsor for processing.  
If the eCRF system cannot be used for any reason, the Investigator shall submit the follow-up 
report by email or fax to the Sponsor (email: pharmacovigilance@thrombogenics.com; 
fax: + 1 8775274503), within the same timeframe. The data should be entered in the eCRF as 
soon as the system becomes available again. 
Copies of hospital reports, autopsy reports and other documents should be provided if they are 
relevant to the evaluation of the SAE.  
SAEs should be followed-up until the event has resolved, subsided, stabilised, or until the event 
is otherwise explained, or the subject is lost to follow-up. 
If the Investigator learns of any SAE at any time after a subject has completed the study, and 
he / she considers the event to be possibly related to the study drug or the injection procedure, 
he / she will notify the Sponsor by emailing or by faxing (email: 
pharmacovigilance@thrombogenics.com; fax: + 1 8775274503). 
Screening Failures 
For screening failures, only (S)AEs related to participation at the screening visit will be 
followed-up as described in the sections above. 
8.4.2. 
Pregnancy / Prenatal Exposure 
Pregnancies will be recorded from the time of providing consent until the end of the study 
(Visit 11 – Month 24 / Exit Visit). 
Subjects with reproductive potential, whether male or female, must agree to use contraception 
for the duration of the study. The Investigator should counsel subjects with regard to the possible 
untoward effects on the foetus. 
Female subjects of childbearing potential will need to have a negative pregnancy test at Visit 1 
(Screening) and at Visit 2 (Day 0). In addition, a urine pregnancy test will be taken at each repeat 
injection visit and for any woman of childbearing potential who missed 1 period at any time 
during the study. Female subjects who are pregnant at the time of repeat injection must not 
receive further injection(s). Pregnant subjects should not be withdrawn from the study, but 
should be asked to continue with all scheduled study visits and procedures until the end of the 
study to ensure complete follow-up.  
Pregnancy occurring in a female subject or in the partner of a male subject should be reported 
immediately to the Investigator. The Investigator should report pregnancies immediately to the 
Sponsor by using the Pregnancy / Prenatal Exposure Form in the eCRF (for study subjects) or via 
email or fax (email: pharmacovigilance@thrombogenics.com; fax: + 1 8775274503) (for 


 
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pregnant partners). The eCRF system will automatically send the form to the Sponsor for 
processing. If the eCRF system cannot be used for any reason, the Investigator shall submit the 
Pregnancy / Prenatal Exposure report by email or fax to the Sponsor (email: 
pharmacovigilance@thrombogenics.com; fax: + 1 8775274503). The data should be entered in 
the eCRF as soon as the system becomes available again. 
In case of a pregnancy in the partner of a male subject, the Investigator should obtain written 
informed consent from the pregnant partner prior to obtaining information about the pregnancy. 
The Investigator will provide the pregnant partner with a copy of the Pregnant Partner 
Information Sheet / Informed Consent Form. 
Pregnancies should be monitored until conclusion. The outcome of all pregnancies (spontaneous 
miscarriage, elective termination, normal birth or congenital abnormality) must be followed up 
and documented via the Pregnancy Follow-up Form, even for subjects withdrawn from the study 
or who completed the study.  
Pregnancy in itself is not regarded as an AE unless there is a suspicion that the study drug may 
have interfered with the effectiveness of a contraceptive medication. If there is an adverse 
condition associated with the pregnancy, the adverse condition is recorded on the AE eCRF 
page, but not the pregnancy itself. If an adverse condition as a result of pregnancy is considered 
serious, an SAE Form must be completed. All reports of congenital abnormalities / birth defects 
in the offspring of study participants are SAEs. Spontaneous miscarriages should also be 
reported and handled as SAEs. 
Screening Failures 
Subjects who are pregnant before study drug administration (and who will hence be screening 
failures) will not be followed up. 
8.5. 
Treatment of Adverse Events 
Treatment of any AE is at the sole discretion of the Investigator and according to current good 
medical practice. The treatment / procedure should be recorded in the eCRF. 
8.6. 
Reporting Requirements for Serious Adverse Events 
In accordance with ICH GCP, the Sponsor is responsible for the ongoing safety evaluation of an 
investigational medicinal product under clinical investigation. As such, the Sponsor is 
responsible for prompt notification to all concerned Investigators, IECs / IRBs and Regulatory 
Authorities of findings that could adversely affect the health of the subjects, impact the conduct 
of the study or alter the authorisation to continue the study. 
The Sponsor or delegated Pharmacovigilance Service Provider will submit Suspected 
Unexpected Serious Adverse Reactions (SUSARs) to the Regulatory Authorities in an expedited 
manner as follows:  
• Fatal or life-threatening SUSARs – as soon as possible but no later than 7 calendar 
days after the Sponsor’s first knowledge of the minimum criteria for expedited 
reporting 


 
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• Non-fatal and non-life-threatening SUSARs – as soon as possible but no later than 
15 calendar days after the Sponsor’s first knowledge of the minimum criteria for 
expedited reporting 
• Relevant follow-up information for fatal or life-threatening SUSARs – within an 
additional 8 calendar days 
Where required by IEC / IRB procedure, it is the Principal Investigator’s responsibility to notify 
the IEC / IRB of all SUSARs / SAEs that occur at his / her site. 
SUSARs that have arisen in other clinical studies of the same sponsor and with the same study 
drug and that could have consequences for the safety of the subjects involved in the clinical 
study that was assessed by the concerned IEC / IRB will be reported in accordance with the 
requirements of the concerned IEC / IRB.  


 
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9. 
STATISTICS 
9.1. 
Determination of Sample Size 
One hundred and fifteen (115) subjects (46 subjects in each of the ocriplasmin arms and 
23 subjects in the sham arm) will provide 80% power to detect a significant difference in total 
PVD rate by the Month 3 visit, for the comparison of sham to each of the ocriplasmin arms at a 
2-sided alpha level of 0.05, assuming total PVD is achieved in 5% and 40% of the subjects in the 
sham and ocriplasmin arms, respectively. The sample size takes into account a drop-out rate of 
10% by the Month 3 visit. 
In order to protect the alpha level to 0.05, a hierarchical testing procedure will be used. 
Ocriplasmin 0.125mg will be first compared to sham. If the p-value of this first comparison is 
found < 0.05, then ocriplasmin 0.0625mg will be compared to sham. 
9.2. 
Subject Analysis Sets 
9.2.1. 
Safety Analysis Set 
The Safety Analysis Set consists of all subjects who received at least 1 dose of study drug. 
Analyses on the Safety Analysis Set will be performed based on treatment actually administered 
at Visit 2 (Day 0). 
9.2.2. 
Full Analysis Set 
The Full Analysis Set consists of all subjects who received at least 1 dose of study drug and for 
whom data of at least 1 post-baseline efficacy assessment is present. Analysis on the Full 
Analysis Set will be based on the assigned randomised treatment. 
9.2.3. 
Per Protocol Set 
The Per Protocol Set consists of a subset of subjects of the Full Analysis Set, excluding those 
subjects with major deviations from the protocol that may substantially affect the results of the 
efficacy analysis. Full details of the criteria leading to exclusion of data from the Per Protocol 
Set will be specified in the statistical analysis plan (SAP). Analysis on the Per Protocol Set will 
be based on the assigned randomised treatment. 
9.3. 
Statistical Methods 
Statistical methodology that will be applied to the study data will be described in detail in the 
SAP to be finalised prior to the Month 3 analysis. Deviations from the SAP will be described in 
the final CSR. 
Descriptive statistics for continuous variables will include the number of subjects with available 
data, mean with its 95% CI (where indicated), standard deviation, median, Q1 and Q3, P05 and 
P95, minimum and maximum. 
Categorical data will be summarised by presenting count and percentage with its 95% CI, where 
indicated. 


 
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9.3.1. 
Significance 
All statistical tests will be performed at the two-sided 5% (α=5%) level of significance unless 
otherwise specified. All p-values, with the exception of the 2 p-values resulting from the 
comparisons of the primary efficacy endpoint, will be considered as supportive and explorative. 
CIs will be two-sided 95%, unless otherwise specified. 
9.3.2. 
Procedure for Accounting for Missing, Unused and Spurious Data 
All reasonable efforts will be made to obtain complete data for all subjects. However, missing 
observations may occur due to subjects lost to follow-up or to noncompliance with required 
assessments. Management of dropouts and missing data will depend on their frequency and the 
nature of the outcome parameter.  
The primary analysis of the efficacy parameters will be performed on the Full Analysis Set using 
the last-observation-carried-forward (LOCF), unless otherwise specified. Sensitivity analysis to 
evaluate the robustness of the data will be performed using alternative imputation method on the 
Full Analysis Set and the Per Protocol Set. 
In the safety analysis, missing data will not be replaced and data analysis will be performed 
based on the Observed Case (OC) imputation method. 
9.4. 
Analysis of Subject Disposition, Demographics and Baseline 
Characteristics 
Subject disposition (including withdrawals), demographics and baseline characteristics and 
withdrawal status will be summarised by treatment arm and overall using descriptive statistics. 
9.5. 
Analysis of Efficacy 
Efficacy analyses will be performed on the Full Analysis Set.  
9.5.1. 
Primary Efficacy Analysis 
The proportion of subjects with total PVD by the Month 3 visit will be calculated in each 
treatment arm with corresponding 95% CI, stratified for NPDR severity at baseline. The adjusted 
differences in proportions between sham and each of the ocriplasmin arms will be calculated 
with its corresponding 95% CI and tested using the Cochran-Mantel-Haenszel test. In addition, 
the effect of treatment on the proportion of subjects with total PVD will be computed using a 
logistic regression with effects for treatment and NPDR severity at baseline. 
9.5.2. 
Exploratory Efficacy Analyses 
The analysis of exploratory dichotomous endpoints will be similar to the methodology used for 
the primary endpoint. For each exploratory endpoint, the proportion of subjects who achieve the 
endpoint at a certain study visit will be calculated in each treatment arm with corresponding 
95% CI, stratified for NPDR severity at baseline. The adjusted differences in proportions 
between sham and each of the ocriplasmin arms will be calculated with their corresponding 95% 
CIs and tested using the Cochran-Mantel-Haenszel test. In addition, the effect of treatment on the 
proportion of subjects who achieve the endpoint will be computed using a logistic regression 
with effects for treatment and NPDR severity at baseline. Mean change from baseline in ETDRS 


 
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letters will be calculated by treatment arms at follow-up visits, stratified for NPDR severity at 
baseline. The adjusted differences in means between treatment arms will be summarised and 
analysed using a PROC GLM model including factors for treatment, BCVA at baseline and 
NPDR severity at baseline. 
9.6. 
Analysis of Safety 
Safety analyses will be performed on the Safety Analysis Set. No formal statistical comparison 
will be performed and no p-value will be calculated. Analyses will be performed irrespective of 
stratum. 
9.6.1. 
Principal Safety Analyses 
The proportion of subjects with ocular TEAEs in the study eye at any time during the study will 
be calculated in each treatment arm with corresponding 95% CI.  
The proportion of subjects with a loss of ≥ 15 ETDRS letters at any time during the study and 
between Day 0 and Day 7 after each injection will be calculated in each treatment arm with 
corresponding 95% CI. 
9.6.2. 
Other Safety Analyses 
Adverse Events 
AEs (ocular, in the study and the non-study eye, and non-ocular) will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Summaries of AEs will use the system organ 
class (SOC) and preferred term (PT) codes, as appropriate. 
AEs will be summarised by treatment arm, SOC and PT. Both the number and percentage of 
subjects who experience the event and the number of events will be summarised.  
TEAEs, study drug-related AEs, AEs leading to withdrawal from the study and SAEs will be 
summarised in a similar manner. AEs will also be tabulated by maximum severity, relationship 
to study treatment, and onset from study treatment. 
Other Safety Assessments 
Descriptive statistics will be calculated by study visit and treatment arm for slit lamp 
examination parameters, IOP, loss of vision in BCVA, Roth 28-hue colour vision status, 
SD-OCT parameters and ffERG assessments. 
Concomitant Medications 
Concomitant medications will be listed by subject and medication name. 
9.7. 
Sequence of Analyses 
• While the Sponsor is masked to the individual treatment assignments, the data 
analyses for the DMC meetings will be performed by an unmasked, independent 
statistician. The independent external statistician will maintain secure custody of 
unmasked data 


 
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• The analysis of the primary endpoint will be performed by an unmasked, 
independent, external statistician when all subjects have completed the Month 3 visit 
(Visit 8). The independent external statistician will maintain secure custody of 
unmasked data 
• The analysis of the exploratory efficacy and the safety endpoints up to the 
Month 15 visit will be performed when all subjects have completed the 
Month 15 visit (Visit 10) 
• An additional analysis will be performed when all data is available, after the database 
lock 


 
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10. 
DATA VERIFICATION AND DIRECT ACCESS TO SOURCE 
DOCUMENTATION  
During the conduct of the study and thereafter until the final clinical study report (CSR) has been 
completed, unmasked / masked study monitors from the CRO, working on behalf of the Sponsor, 
will visit the study site at regular intervals by prior arrangement. During these visits, data 
recorded in the eCRFs and other data related to the study will be reviewed, and any discrepancies 
or omissions will be resolved. The monitors require direct access to appropriate parts of medical 
records relating to the subject’s participation in this study, for the purpose of verifying the data 
provided to the company. The Investigator agrees to allow the study monitors to inspect the drug 
storage area, study drug stocks, drug accountability records, subject charts and study source 
documents, and other records relative to study conduct. 
Other people, working for the CRO, Sponsor, IEC / IRB or Regulatory Authority may also wish, 
by prior arrangement, to have direct access to these records. Direct access, by prior arrangement, 
must also be permitted if an audit is requested by a regulatory authority or the Sponsor. An 
inspection may occur during the study or at any time subsequently until the time that the 
Investigator is informed by the Sponsor that the documentation no longer needs to be stored. 
Monitoring will be performed according to applicable provisions of the CRO’s clinical 
monitoring procedures and in compliance with applicable regulatory requirements. 


 
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11. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Sponsor and people working on behalf of the Sponsor (including the CRO) will implement 
and maintain quality assurance and quality control systems with written SOPs (Sponsor’s 
and / or CRO’s) to ensure that data are generated and recorded in accordance with the protocol. 
The Informed Consent Form will be verified for all subjects enrolled in the study. The monitor 
will verify that all Informed Consent Forms are signed and dated prior to enrolment of the 
subject into the study. 100% of all SAEs, inclusion / exclusion criteria, demographic data and 
efficacy measures will be source verified. In addition, the complete eCRF for a subset of subjects 
will be 100% source verified. The subject source documents will be cross-checked with the 
eCRF and the SAE Forms. Drug accountability will be performed for all subjects in the study. 
To ensure compliance with GCP and applicable regulatory requirements, the Sponsor may 
conduct a quality assurance audit. Additionally, authorised representatives of the Sponsor, a 
Regulatory Authority, an IEC / IRB may visit the site to perform audits or inspections, including 
source data verification. The purpose of a Sponsor audit or inspection is to systematically and 
independently examine all study-related activities and documents to determine whether these 
activities were conducted and data were recorded, analysed, and accurately reported according to 
the protocol, ICH GCP, and any applicable regulatory requirements. The Investigator should 
contact the Sponsor or the CRO immediately if contacted by a Regulatory Authority about an 
inspection. 


 
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12. 
DATA HANDLING AND RECORD KEEPING 
12.1. 
Source documents 
All documents and data relating to the study will be kept in an orderly manner in secure study 
files provided by the CRO. While the study is ongoing, unmasked source documents should be 
stored separately from the masked source documents and all efforts should be made to ensure 
that they cannot be accessed by masked study personnel. 
12.2. 
Electronic Case Report Forms 
eCRFs will be used to collect subject data during the course of the study. eCRFs must be fully 
completed for each subject. 
Each eCRF will consist of: 
• an unmasked part, which will only be accessible and completed by the unmasked 
treating investigator / designee (with the exception of the unmasked AE pages for 
masked follow-up of AEs that start within the 1-hour post-injection period, refer to 
Section 8.4.1 for more information), and 
• a masked part, which will be completed by the masked Investigator / designee 
Access to the eCRFs will be by means of a unique username and password through a secure web 
browser. Changes to the original data entries will trigger a reason for change dialogue box while 
the time, date and name of the user making the change are automatically logged. 
The unmasked treating investigator / masked Investigator is required to sign the unmasked part / 
the masked part of the eCRF, respectively, to verify that he / she has reviewed the recorded data.  
12.3. 
Data Review 
A data manager or monitor working on behalf of the sponsor will review eCRFs for 
completeness and clarity upon entry of data by the Investigator / designee. Missing, incorrect or 
unclear data will be identified by the data manager or the monitor and will need to be 
provided / clarified / corrected by investigational site personnel as necessary throughout the 
study. The CRO / Sponsor Representative may request additional documentation from the 
Investigator such as physician procedure notes or physician written summaries when AEs are 
observed and reported. 
Development of the primary database for the study will be performed by the CRO / Sponsor 
Representative. The CRO / Sponsor Representative will also be responsible for the quality 
control of the database and confirming the overall integrity of the data. 
12.4. 
Retention of Records 
Following closure of the study, the Investigator must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere) in a safe and secure location. The 
records must be easily accessible, when needed (e.g. audit or inspection), and must be available 
for review in conjunction with assessment of the facility, supporting systems, and staff.  


 
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The Sponsor will inform the Investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements. The minimum retention time will meet the strictest 
standard applicable to a particular site, as dictated by ICH GCP, any institutional requirements, 
applicable laws or regulations. 
Study files may be discarded upon written notification by the Sponsor. To avoid error, the 
Investigator should contact the Sponsor before destroying any records or reports pertaining to the 
study to ensure they no longer need to be kept. Other source documents, such as subject’s 
medical records, must be retained for the maximum period of time permitted by the hospital or 
institution and until such time when the Investigator is informed by the Sponsor that there is no 
further need to do so. 
In addition, in accordance with the Investigator Agreement, the Sponsor should be contacted if 
the site’s Principal Investigator plans to leave the site so that appropriate arrangements can be 
made. 


 
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13. 
FINANCE AND INSURANCE 
13.1. 
Finance 
Financial issues are addressed in a separate agreement. 
There are no incentives for subjects for participation in the study. Subjects will be compensated 
for travel expenses only. 
13.2. 
Insurance 
In the event that a subject suffers injury or death directly attributable to participation in this 
study, appropriate treatment and / or compensation will be provided by and / or paid to the 
subject by the Sponsor in accordance with applicable national and international laws and / or 
guidelines.  


 
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14. 
PUBLICATION POLICY AND FINAL REPORT 
The Publication Policy is addressed in a separate agreement. 
During the course of and at the conclusion of the study, after the data are analysed, a CSR will be 
prepared. The Sponsor will provide Investigators with a summary of the results. 
During the course of the study, the Sponsor will designate the CSR signatory Coordinating 
Investigator. 


 
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15. 
LIST OF REFERENCES 
Aiello LP, Brucker AJ, Chang S, Cunningham ET Jr, D'Amico DJ, Flynn HW Jr, Grillone LR, 
Hutcherson S, Liebmann JM, O'Brien TP, Scott IU, Spaide RF, Ta C, Trese MT (2004). 
Evolving guidelines for intravitreous injections. Retina 24 (5 Suppl): S3-19. 
American Academy of Ophthalmology Retina/Vitreous Panel (2014). Preferred Practice Pattern® 
Guideline. Diabetic Retinopathy. San Francisco, CA: American Academy of Ophthalmology. 
American Association of Clinical Endocrinologists (2007). State of diabetes complications in 
America: a comprehensive report issues by the American Association of Clinical 
Endocrinologists. 
http://multivu.prnewswire.com/mnr/AACE/2007/docs/Diabetes_Complications_Report.pdf 
04 August 2015 
Avery RL, Bakri SJ, Blumenkranz MS, Brucker AJ, Cunningham ET Jr, DʼAmico DJ, Dugel 
PU, Flynn HW Jr, Freund KB, Haller JA, Jumper JM, Liebmann JM, McCannel CA, Mieler WF, 
Ta CN, Williams GA (2014). Intravitreal injection technique and monitoring: updated guidelines 
of an expert panel. Retina 34 Suppl 12: S1-S18. 
Bailey CC, Sparrow JM, Grey RH, Cheng H (1998). The National Diabetic Retinopathy Laser 
Treatment Audit. II. Proliferative retinopathy. Eye (Lond) 12 (Pt 1): 77-84. 
Bailey CC, Sparrow JM, Grey RH, Cheng H (1999). The National Diabetic Retinopathy Laser 
Treatment Audit. III. Clinical outcomes. Eye (Lond) 13 (Pt 2): 151-159. 
Cunha-Vaz J (1998). Lowering the risk of visual impairment and blindness. Diabet Med. 15 
(Suppl 4): S47-50. 
De Smet MD, Valmaggia C, Zarranz-Ventura J, Willekens B (2009). Microplasmin: ex vivo 
characterization of its activity in porcine vitreous. Invest Ophthalmol Vis Sci. 50 (2): 814-819. 
De Smet MD, Gad Elkareem AM, Zwinderman AH (2013). The vitreous, the retinal interface in 
ocular health and disease. Ophthalmologica 230 (4): 165-178. 
Diaz-Llopis M, Udaondo P, Millán JM, Arevalo JF (2013). Enzymatic vitrectomy for diabetic 
retinopathy and diabetic macular edema. World J Diabetes 4 (6): 319-323. 
Fong DS, Ferris FL 3rd, Davis MD, Chew EY (1999). Causes of severe visual loss in the early 
treatment diabetic retinopathy study: ETDRS report no. 24. Early Treatment Diabetic 
Retinopathy Study Research Group. Am J Ophthalmol. 127 (2): 137-141. 
Gad Elkareem AM, Willekens B, Vanhove M, Noppen B, Stassen JM, de Smet MD (2010). 
Characterization of a stabilized form of microplasmin for the induction of posterior vitreous 
detachment. Curr Eye Res. 35 (10): 909-915. 
Glassman AR, Stockdale CR, Beck RW, Baker C, Bressler NM; Diabetic Retinopathy Clinical 
Research Network (2012). Evaluation of masking study participants to intravitreal injections in a 
randomized clinical trial. Arch Ophthalmol. 130 (2): 190-194. 
Jager RD1, Aiello LP, Patel SC, Cunningham ET Jr (2004) Risks of intravitreous injection: a 
comprehensive review. Retina 24 (5): 676-698. 


 
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Yau JW, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T, Chen SJ, Dekker JM, 
Fletcher A, Grauslund J, Haffner S, Hamman RF, Ikram MK, Kayama T, Klein BE, Klein R, 
Krishnaiah S, Mayurasakorn K, O'Hare JP, Orchard TJ, Porta M, Rema M, Roy MS, Sharma T, 
Shaw J, Taylor H, Tielsch JM, Varma R, Wang JJ, Wang N, West S, Xu L, Yasuda M, Zhang X, 
Mitchell P, Wong TY; Meta-Analysis for Eye Disease (META-EYE) Study Group (2012). 
Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 35 (3): 556-564. 
World Health Organization (WHO). (2015). Diabetes. Fact sheet N°312. 
http://www.who.int/mediacentre/factsheets/fs312/en/ 21 May 2015. 


 
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16. 
APPENDICES 
APPENDIX 1. PROTOCOL TABLES 
Table 6: 
Study Plan / Flowchart 
Visit Type / Number 
V1 
V2 
Phone 
Call 
V3 
V4a 
V4b 
Phone 
Call 
V5 
V6a 
V6b 
Phone 
Call 
V7 
V8 
V9 
V10 
V11 
/ 
Exit 
Visit 
Study Month as of 
First Injection /  
Study Day as of First 
Injection 
Scree-
ninga 
 
D0 
 
D2b 
 
D7 
 
D28 
M1  
/  
D35 
 
D37b 
 
D42 
 
D63 
M2  
/  
D70 
 
D72b 
 
D77 
M3  
/  
D98 
M9  
/ 
D270 
M15  
/  
D450 
M24  
/  
D720 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography, medical 
and ocular history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood pressure 
measurement 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Pregnancy testc 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Blood sampling for 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Blood sampling for 
immunogenicity 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 


 
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Table 6: 
Study Plan / Flowchart (Continued) 
Visit Type / Number 
V1 
V2 
Phone 
Call 
V3 
V4a 
V4b 
Phone 
Call 
V5 
V6a 
V6b 
Phone 
Call 
V7 
V8 
V9 
V10 
V11 
/ 
Exit 
Visit 
Study Month as of 
First Injection /  
Study Day as of First 
Injection 
Scree-
ninga 
 
D0 
 
D2b 
 
D7 
 
D28 
M1  
/  
D35 
 
D37b 
 
D42 
 
D63 
M2  
/  
D70 
 
D72b 
 
D77 
M3  
/  
D98 
M9  
/ 
D270 
M15  
/  
D450 
M24  
/  
D720 
Ophthalmic assessments: 
• BCVA (ETDRS) 
Xd 
Xd 
 
Xd 
Xd 
 
 
Xd 
Xd 
 
 
Xd 
Xd 
Xd 
Xd 
Xd 
• Colour vision (Roth 
28-hue)e f 
 
X 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
X 
X 
X 
• B-scan ultrasound 
Xg  
 
 
 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
• Full ophthalmic 
examinationh 
Xd 
X 
 
X 
X 
 
 
X 
X 
 
 
X 
Xd 
Xd 
Xd 
Xd 
• 7-standard field stereo 
colour fundus 
photography 
Xg 
 
 
 
 
 
 
 
 
 
 
 
O 
O 
X 
X 
• SD-OCT (6mm)  
Xg 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
X 
X 
X 
• SD-OCT (widefield)f 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
• Fluorescein 
angiography  
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• ffERGi 
 
Xd 
 
 
 
 
 
 
 
 
 
 
Xd 
 
Xd j 
Xd j 


 
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Table 6: 
Study Plan / Flowchart (Continued) 
Visit Type / Number 
V1 
V2 
Phone 
Call 
V3 
V4a 
V4b 
Phone 
Call 
V5 
V6a 
V6b 
Phone 
Call 
V7 
V8 
V9 
V10 
V11 
/ 
Exit 
Visit 
Study Month as of 
First Injection /  
Study Day as of First 
Injection 
Scree-
ninga 
 
D0 
 
D2b 
 
D7 
 
D28 
M1  
/  
D35 
 
D37b 
 
D42 
 
D63 
M2  
/  
D70 
 
D72b 
 
D77 
M3  
/  
D98 
M9  
/ 
D270 
M15  
/  
D450 
M24  
/  
D720 
Assess list of events that 
lead to withdrawal from 
repeat injectionk 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Treatment number 
allocation 
 
Tl 
 
 
 
T 
 
 
 
T 
 
 
 
 
 
 
Study treatment 
 
T 
 
 
 
T 
 
 
 
T 
 
 
 
 
 
 
Post-injection 
assessmentm 
 
T 
 
 
 
T 
 
 
 
T 
 
 
 
 
 
 
Record concomitant 
medications / treatments 
/ interventions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(S)AE monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
V = Visit; D = Day; M = Month 
Procedures indicated by ‘T’ should be performed by the unmasked treating investigator / designee. Procedures indicated by ‘O’ are optional. At Visit 8 
(Month 3) and Visit 9 (Month 9), 7-standard field stereo colour fundus photographs should only be taken if the Investigator suspects that the subject has 
progressed to PDR. Light grey coloured visits indicate injection visits. 
a For screening failures due to reasons that are expected to be temporary, and for subjects for whom eligibility cannot be timely determined due to a problem 
with one of the eligibility assessments (e.g. in case of ungradable B-scan ultrasound), 1 re-screening visit can be organised. The re-screening visit should be 
scheduled at least 28 days after the 1st screening visit 
b The masked Investigator / designee will make a scripted phone call to each subject 24-72 hours after the injection visit. Based on this phone call, the subject 
may be invited back for an unscheduled study visit as per the masked Investigator’s clinical judgement 
c Only for women of childbearing potential. Serum pregnancy test at screening (Visit 1), urine pregnancy test at Visit 4a and Visit 6a. Urine pregnancy testing 
should be repeated in any woman of childbearing potential who missed 1 period 
d Performed in both eyes. Ophthalmic assessments without footnote are performed in the study eye only  
e Not needed for subjects > 80 years of age or with a diagnosis of dyschromatopsia at baseline 


 
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f Only at sites where this is available 
g Performed in potential study eye(s) only. If one of the subject’s eyes is excluded based on an eligibility criterion that does not need confirmation by the B-scan 
expert reader or the CRC, these examinations do not need to be performed for that eye. If both eyes potentially qualify as the study eye, these examinations 
need to be performed for both eyes 
h Full ophthalmic examination including pupillary examination, slit lamp examination, IOP assessment and dilated fundus examination. The same slit lamp 
machine should be used across study visits for a given subject 
i ffERG will be performed at sites where this is available, in approximately 25% of the subjects 
j Only for subjects with expert-defined ffERG abnormalities at the previous assessment 
k Refer to Section 4.2.1 for the list of withdrawal criteria from repeat injection 
l Randomisation can only occur after confirmation of eligibility by the B-scan expert reader, the CRC and the central laboratory 
m Post-injection IOP measurement and indirect ophthalmic examination will be performed by the unmasked treating investigator as many times as needed at his / 
her discretion but at least once within 60 minutes after the injection to exclude central retinal artery non-perfusion or other complications 


 
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Table 7: 
Study Visit Intervals 
Interval 
Optimal Interval 
Allowed Interval 
Visit 1 (Screening) → Visit 2 (Day 0) 
10-14 days 
10-17 days 
Visit 2 → Post-injection Phone Call 
24–48 hours 
24–72 hoursa 
Visit 2 (Day 0) → Visit 3 (Day 7) 
7 days 
7±3 days (4–10 days) 
Visit 2 (Day 0) → Visit 4a (Day 28) 
28 days  
28±3 days (25-31 days) 
Visit 4a (Day 28) → Visit 4b (Day 35) 
7 days 
6-10 days 
Visit 4b (Day 35) → Post-injection Phone Call 
24–48 hours 
24–72 hoursa 
Visit 4b (Day 35) → Visit 5 (Day 42) 
7 days 
7±3 days (4–10 days) 
Visit 4b (Day 35) → Visit 6a (Day 63) 
28 days 
28±3days (25-31 days) 
Visit 6a (Day 63) → Visit 6b (Day 70) 
7 days 
6-10 days 
Visit 6b (Day 70) → Post-injection Phone Call 
24–48 hours 
24–72 hoursa 
Visit 6b (Day 70) → Visit 7 (Day 77) 
7 days 
7±3 days (4–10 days) 
Visit 6b (Day 70) → Visit 8 (Day 98) 
28 days 
28±3days (25-31 days) 
Visit 2 (Day 0) → Visit 9 (Month 9) 
270 days 
270±14 days (256-284 days) 
Visit 2 (Day 0) → Visit 10 (Month 15) 
450 days 
450±14 days (436-464 days) 
Visit 2 (Day 0) → Visit 11 (Month 24) 
720 days 
720±14 days (706-734 days) 
a If an unscheduled post-injection visit falls within the allowed interval for the 7-days post-injection visit (4-10 days 
after injection), the unscheduled post-injection visit and the Day 7 visit will take place on the same day 


 
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Table 8: 
Responsibilities Masked and Unmasked Study Staff and Need for 
Certification 
Study Procedure 
Masked 
Study Staff 
Unmasked 
Study Staff 
Certification 
needed 
Study drug: 
Study drug accountability 
 
X 
 
Injection-related procedures: 
IXRS access 
 
X 
 
(Pre-)injection procedures 
 
X 
 
1-hour post-injection assessment 
 
X 
 
Scripted phone call 24-72 hours after the injection 
X 
 
 
Conduct unscheduled study visit(s) 
X 
 
 
Assess list of events that lead to withdrawal from repeat 
injection 
X 
 
 
AE reporting: 
AEs during 1-hour post-injection assessment 
 
X 
 
All other AEs 
X 
 
 
Ophthalmic assessment: 
BCVA 
X 
 
 
Colour vision (Roth 28-hue) 
X 
 
 
B-scan ultrasound 
X 
 
X 
Full ophthalmic examination 
X 
 
 
7-standard field stereo colour fundus photography 
X 
 
X 
SD-OCT (6mm and widefield) 
X 
 
X 
Fluorescein angiography 
X 
 
X 
ffERG 
X 
 
X 
Other procedures: 
Informed consent 
X 
 
 
Demography, medical and ocular history 
X 
 
 
Blood sampling (serum pregnancy test, HbA1c, 
immunogenicity) 
X 
X 
 
Blood pressure measurement 
X 
 
 
Urine pregnancy test 
X 
X 
 
Record concomitant medications / treatments / interventions 
X 
 
 
 


 
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Protocol Amendment 2 TG-MV-015_28-OCT-2016 
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APPENDIX 2. POST-INJECTION PHONE CALL SCRIPT  
Within 24-72 hours after each injection visit, the masked Investigator (or designee) should call 
the subject to ask about post-injection complaints. During the telephone contact, the Investigator 
(or designee) will determine whether there is a need to bring the subject in for an unscheduled 
study visit. If the subject cannot be reached on the first attempt, the Investigator (or designee) 
must make at least 2 additional attempts to reach the subject. Each attempt should be 
documented in the eCRF with the date and time of the contact noted. 
A successful telephone contact is one in which the Investigator (or designee) has spoken directly 
to the subject and has determined the need for an unscheduled post-injection visit based on the 
answers to the questions outlined below. A telephone contact with someone other than the 
subject does not qualify as a successful telephone contact. 
The following questions should be asked in the order noted.  
Adverse Events 
1. How are you feeling in general? 
2. Do you have any complaints since the injection? 
The Investigator (or designee) should not in any way prompt or probe the subject about 
anything, in particular not about changes in vision. Any complaints (e.g. blurred vision) should 
be recorded in the eCRF as for any AE, with time of onset, severity etc. If the subject has taken a 
concomitant medication for treatment of a complaint (e.g. aspirin for a headache), then the 
medication should be recorded on the eCRF page with the appropriate indication. 
Concomitant Medications 
1. Did you take any NEW medications since the injection? 
2. Did you change any medications you were taking since the injection (did you take more 
or less of the medications? Or stop any medications?) 
The masked Investigator (or designee) should verify that there are no changes to the 
concomitant medications since the last study visit. If there has been a change in any medication 
or an additional medication that was taken, the masked Investigator (or designee) should 
complete all the information as required on the eCRF page for concomitant medications. If there 
is a new medication that has been taken the indication should also be noted on the eCRF page. 
Once the Investigator (or designee) has asked about complaints and concomitant medications, a 
decision should be made as to whether or not the subject should return for an unscheduled 
post-injection visit. 

SAP_001.pdf: 
 
Cover Page 
TG-MV-015_Abbreviated SAP_17-JAN-2019 
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Protocol TG-MV-015 
CONFIDENTIAL 
Abbreviated SAP –Final Analysis 
V1.0 
 
 
 
 
Page 1 of 7 
 
 
ABBREVIATED STATISTICAL ANALYSIS PLAN FOR  
FINAL ANALYSIS 
 
PROTOCOL TITLE: 
A PHASE 2, RANDOMISED, DOUBLE-MASKED, 
SHAM-CONTROLLED, MULTI-CENTRE STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF OCRIPLASMIN 
IN INDUCING TOTAL POSTERIOR VITREOUS DETACHMENT 
(PVD) IN SUBJECTS WITH NON-PROLIFERATIVE DIABETIC 
RETINOPATHY (NPDR) (CIRCLE) 
PROTOCOL NUMBER: 
TG-MV-015 
STUDY PHASE: 
PHASE 2 
EudraCT NUMBER: 
2015-002415-15 
IND NUMBER: 
126449 
SPONSOR: 
THROMBOGENICS NV, GASTON GEENSLAAN 1 
B-3001 LEUVEN, BELGIUM 
FINAL PROTOCOL DATE: 
04-SEP-2015 
AMENDMENT 1 DATE: 
13-OCT-2015 
AMENDMENT 2 DATE: 
28-OCT-2016 
Abbreviated SAP 17Jan2019 
CONFIDENTIAL 
The information contained in this document is CONFIDENTIAL and is the property of ThromboGenics.  Except to the extent 
necessary to obtain informed consent, information may not be disclosed unless such disclosure is required by government 
regulation or state/local customs or law.  No part of it may be transmitted, reproduced, published, or used by anyone without 
the written permission of ThromboGenics.  Persons to whom the information is disclosed must be informed that the 
information is CONFIDENTIAL and may not be further disclosed by them.  
 
 
 


Protocol TG-MV-015 
CONFIDENTIAL 
Abbreviated SAP –Final Analysis 
V1.0 
 
 
 
 
Page 2 of 7 
Table of Contents 
1. 
Background ....................................................................................................................................................... 3 
2. 
Objective ............................................................................................................................................................ 3 
3. 
Conventions for Analysis and Computations ................................................................................................. 3 
4. 
Appendix ........................................................................................................................................................... 7 
4.1. 
Conventions for Imputing Partially Missing and Missing Dates ......................................................... 7 
 
 
 


Protocol TG-MV-015 
CONFIDENTIAL 
Abbreviated SAP –Final Analysis 
V1.0 
 
 
 
 
Page 3 of 7 
1. Background 
This document describes the tables and listings generated for the Final Analysis. The final analysis took 
place after all subjects completed the Month 24 visit (Visit 11). This document is an abbreviated version 
of the original SAP, which also contained mock-up tables and listings. In addition, information which is 
considered of intellectual property nature is not included in this abbreviated version of the SAP.  
2. Objective 
The objective of this document is to define the set of summary tables and individual data listings that will 
support the writing of the clinical study report.  
3. Conventions for Analysis and Computations 
All Treated Subjects Analysis Set 
A single analysis set will be used. The All Treated Subjects analysis set will include subjects who are 
randomized and receive the first injection of study treatment. Subjects will be assigned to the treatment 
they receive at the time of the first injection. 
Baseline Value 
Baseline value is defined as the last non-missing value prior to administration of the first injection of the 
study drug. 
Change from Baseline 
Change from Baseline is calculated as the difference between the value at a considered visit minus the 
Baseline value. Change from Baseline will be missing if either one of the Baseline Value or the value at 
the considered visit is missing. 
Adverse Events 
Adverse events are coded using MedDRA version 18.1. 
If a subject has multiple occurrences of an AE after an injection, the subject is presented only once in the 
respective subject count. Events are counted each time in the event column. Ocular adverse events are 
those that occur in either eye. Events recorded as OU (both eyes) are counted once for the study eye and 
once for the non-study eye, and are counted as 2 separate ocular events. 
Drug related events are events considered by the Investigator with a reasonable possibility that the study 
treatment caused the event or events with a missing relationship. 
Where severity is missing, the adverse event will be assigned to the ‘severe’ category. 


Protocol TG-MV-015 
CONFIDENTIAL 
Abbreviated SAP –Final Analysis 
V1.0 
 
 
 
 
Page 4 of 7 
AEs will be attributed to the closest injection prior to the occurrence of the event. AEs with a start date 
corresponding to the date of one of the injections will be attributed to that particular injection. 
Treatment Emergent Adverse Events 
Treatment Emergent Adverse Events are adverse events with a start date on or post the date of the first 
injection, or a missing start date.  
Concomittant Interventions/Anti-VEGFs  
Concomittant Interventions (including Anti-VEGFs) are interventions with a start date on or post the date 
of the first injection, or a missing start date. 
Imputation of Partially Missing Dates  
The conventions for imputing partially missing dates are provided in the appendix of this document. 
Age Computation 
The Date of Birth (DOB) will be imputed to 01JULYYYY where YYYY correspond to the year of birth. 
The following SAS code will be used for calculating age. 
floor((intck('month',DOB,first injection date) - (day(first injection date) < day(DOB))) / 12) 
By Visit Layout 
In tables summarizing data ‘By Visit’, post-injection 2 and 3 visits will be presented on 2 rows. The first 
row will be labelled ‘Day/Month xx, Post-Injection 2/3’ and will present data of subjects with 2 or 3 
injections, respectively. The second row will be labelled ‘Day/Month xx, Missing Repeat Injection(s)’ 
and will present data of subjects who did not receive the complete set of repeat injections.  
 
Early Termination Visit 
The Early Termination visit corresponds to the last visit attended by subjects who discontinue from the 
study. Early Termination visits will be re-coded when possible. The related data will be summarized in 
the corresponding re-coded visit and in a visit named ‘Early Termination’. For example, if a subject 
discontinues with its last visit being the Day 28 visit, then the corresponding data will appear in the line 
‘Day 28, Post-Injection 1’ and in the line ‘Early Termination’ of the summary tables.  
Unscheduled Visit 
Unscheduled visits will not appear in the summary tables, but in the listings. 
 
Summary Statistics 
Descriptive statistics for continuous variables and calculated change from baseline variables will include:  
• number of subjects with available data  
• mean and standard deviation  
• median  
• minimum and maximum 


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Abbreviated SAP –Final Analysis 
V1.0 
 
 
 
 
Page 5 of 7 
• 95% CI for mean, where indicated. 
Categorical data and shift from baseline will be summarized by presenting:  
• count  
• percentage (where the denominator is based on the total number of subjects in the treatment 
group or overall, unless otherwise stated in the table footnotes)  
• 95% CI for the proportion (Clopper-Pearson method), where indicated.  
Protocol Deviations 
Deviations from the protocol will be documented on an ongoing basis by the study monitors and project 
managers throughout the study. Protocol deviations are recorded outside the clinical database and will be 
reviewed by ThromboGenics during the course of the study, prior to database lock. 
Missing Data 
Missing data will not be replaced (unless otherwise specified), and data analysis will be performed based 
on the observed cases (OC) principle. 
Subgroup Analysis 
No subgroup analyses, nor analysis per center, will be performed. 
Sensitivity Analysis 
No sensitivity analyses will be performed. 
Changes in Planned Analyses from the Protocol 
The early stopping of the subject enrolment has led to the following changes to the analyses planned in 
the protocol. 
A single analysis dataset will be used instead of the 3 listed in the protocol. 
The first and third quartiles, and 5th and 95th percentiles will not be included in the summary statistics 
of continuous variables. 
No statistical testing will be performed. 
The last-observation-carried-forward method for data imputation will not be used, and no sensitivity 
analysis will be performed. 
The stratification variable, NPDR severity, will not be taken into account in any summary statistics.  
The following exploratory endpoints will not be summarized:  
• A ≥ 2-step progression on the ETDRS Severity Scale from baseline, at Month 15 and at 
Month 24, based on 7-standard field stereo colour fundus photography, as assessed by the 
masked CRC 


Protocol TG-MV-015 
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Abbreviated SAP –Final Analysis 
V1.0 
 
 
 
 
Page 6 of 7 
• Improvement of ≥ 2 steps on the ETDRS Severity Scale from baseline, at Month 15 and at 
Month 24, based on 7-standard field stereo colour fundus photography, as assessed by the 
masked CRC 
• Neovascularisation as compared to baseline, at Month 15 and at Month 24, based on 7 standard 
field stereo colour fundus photography, as assessed by the masked CRC 
• Vitreous / pre-retinal haemorrhage by Month 24, based on 7-standard field stereo colour fundus 
photography, as assessed by the masked CRC 
• Development of iris neovascularisation as compared to baseline, at each study visit, based on slit 
lamp examination 
 


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CONFIDENTIAL 
Abbreviated SAP –Final Analysis 
V1.0 
 
 
 
 
Page 7 of 7 
4. Appendix 
4.1. Conventions for Imputing Partially Missing and Missing Dates 
Partially missing and missing dates will be imputed using the following rules when used for calculating 
day intervals (actual data will be presented in the listings). 
For start dates, the following rules will be used: 
- 
Missing day and month/year present: if the month and year are the same as the month and year of 
the first injection then impute with the date of the first injection; otherwise, impute with the first 
day of the month 
- 
Missing day and month, and year present: if the year is the same as the year of the first injection 
then impute with the date of the first injection; otherwise, impute with the first day of the year 
- 
If missing date, then no imputation 
For end dates, the following rules will be used: 
- 
Missing day and month/year present: if the month and year are the same as the month and year of 
the first injection then impute with the date of the first injection; otherwise, impute with the last 
day of the month 
- 
Missing day and month, and year present: if the year is the same as the year of the first injection 
then impute with the date of the first injection; otherwise, impute with the last day of the year 
- 
If missing date, then no imputation