EVA Nexus Field Observation Study. A Monocentric, Academic Field Observation Study of a Prototype of a New CE-labeled Vitrectomy Device Developed by DORC BV (The Netherlands).
Conditions: Retina Disorder, Vitreous Disorder
Sponsor: Universitaire Ziekenhuizen KU Leuven

 
 
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Clinical Investigation Title: 
EVA Nexus Field Observation Study 
A monocentric, academic field observation study of a prototype of a new CE-labeled 
vitrectomy device developed by DORC BV (The Netherlands). 
 
Clinical Investigation Acronym: EVA Nexus 
 
 
Sponsor 
UZ Leuven 
Principal Investigator 
Prof. dr. Peter Stalmans 
Sponsor Reference Number 
S64913 
Start and end date  
start: April 2021 end date: September 2021 
Version Number and Date 
v2_20210322 - 26 March 2021 
 
 
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone 
other than the Sponsor, the Investigator Team, regulatory authorities, and members of 
the Research Ethics Committee. 

 
 
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CLINICAL INVESTIGATION PLAN AUTHORISATION 
 
Principal Investigator 
Name: Peter Stalmans 
Title: Prof. dr. 
Signature: 
Date: 
Site: UZ Leuven 
Statistician 
Name: Ars Statistica, Jean-Francois Fils 
Title: Medical statistician 
Signature: 
Date: 
Funder 
Name: Pierre Billardon 
Title: CEO DORC BV 
Signature: 
Date: 

 
 
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TABLE OF CONTENTS 
 
 
Contents 
 
Clinical Investigation Title: ........................................................................................................................................ 1 
Clinical Investigation Acronym: EVA Nexus .............................................................................................................. 1 
CLINICAL INVESTIGATION PLAN AUTHORISATION .................................................................................................... 2 
1. 
AMENDMENT HISTORY ............................................................................................................................................. 8 
2. 
LIST OF APPENDICES .................................................................................................................................................. 9 
3. 
ABBREVIATIONS ........................................................................................................................................................ 9 
4. 
CLINICAL INVESTIGATION SUMMARY ..................................................................................................................... 10 
5. 
INTRODUCTION ....................................................................................................................................................... 12 
5.1 
Vitrectomy device ................................................................................................................................................... 12 
1. 
Vitrectome driver. ....................................................................................................................................... 12 
2. 
Aspiration system. ....................................................................................................................................... 12 
3. 
Infusion system. .......................................................................................................................................... 12 
4. 
Light. ............................................................................................................................................................ 13 
5. 
Phaco ultrasound. ....................................................................................................................................... 13 
6. 
Laser module. .............................................................................................................................................. 13 
7. 
Silicone oil injection. ................................................................................................................................... 13 
8. 
Silicone oil extraction. ................................................................................................................................. 14 
9. 
Endodiathermy. ........................................................................................................................................... 14 
5.2 
DORC EVA Nexus device .......................................................................................................................................... 15 
1. Vitrectome ...................................................................................................................................................................... 15 
2. Aspiration system ............................................................................................................................................................ 15 
Vitrectome .......................................................................................................................................................................... 15 
3. Infusion system ............................................................................................................................................................... 15 
4. Light 16 
5. Phaco ultrasound ............................................................................................................................................................ 16 
6. Laser module ................................................................................................................................................................... 16 
7. Silicone oil injection (VFI). ............................................................................................................................................... 16 
8. Silicone oil extraction. ..................................................................................................................................................... 16 
10. Micro Injection .............................................................................................................................................................. 16 
11. Endodiathermy.............................................................................................................................................................. 16 

 
 
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5.3 
Patient safety with the EVA Nexus device .............................................................................................................. 17 
6. 
OBJECTIVES ............................................................................................................................................................. 19 
7. 
CLINICAL INVESTIGATION DESIGN .......................................................................................................................... 21 
7.1 
Trial Design .............................................................................................................................................................. 21 
7.2 
Study Flowchart ...................................................................................................................................................... 21 
8. 
CLINICAL INVESTIGATION POPULATION ................................................................................................................. 22 
8.1. 
Number of participants – sample size analysis ....................................................................................................... 22 
8.2. 
Inclusion criteria ...................................................................................................................................................... 22 
8.3. 
Exclusion criteria ..................................................................................................................................................... 22 
9. 
PARTICIPANT SELECTION AND ENROLMENT ........................................................................................................... 23 
9.1. 
Identifying participants ........................................................................................................................................... 23 
9.2. 
Consenting participants .......................................................................................................................................... 23 
9.3. 
Withdrawal of participants ..................................................................................................................................... 24 
10. 
INVESTIGATIONAL DEVICE ...................................................................................................................................... 25 
10.1. Investigational device details .................................................................................................................................. 25 
10.2. Device manufacturer ............................................................................................................................................... 25 
10.3. Device accountability .............................................................................................................................................. 25 
10.4. Storage conditions .................................................................................................................................................. 25 
10.5. Concomitant Treatments ........................................................................................................................................ 25 
10.6. FAGG Approval ........................................................................................................................................................ 25 
11. 
CLINICAL INVESTIGATION ASSESSMENTS................................................................................................................ 26 
11.1. Subject Characteristics ............................................................................................................................................ 26 
11.2. Clinical investigation assessments .......................................................................................................................... 26 
11.3. Surgical procedure .................................................................................................................................................. 26 
11.4. Safety assessments ................................................................................................................................................. 26 
11.4.1 Adverse events that do not require reporting ........................................................................................................ 26 
12. 
DATA QUALITY ASSURANCE .................................................................................................................................... 27 
12.1. Monitoring, Audit and Inspections ......................................................................................................................... 27 
12.2. Training of staff ....................................................................................................................................................... 27 
12.3. Data Management .................................................................................................................................................. 27 
13. 
STATISTICS ............................................................................................................................................................... 28 
13.1. Description of statistical methods .......................................................................................................................... 28 
13.2. The number of participants ..................................................................................................................................... 28 
13.3. The level of statistical significance .......................................................................................................................... 28 

 
 
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13.4. Criteria for the termination of the clinical investigation ........................................................................................ 28 
13.5. suspension or premature termination of the trial .................................................................................................. 28 
13.6. Procedure for accounting for missing, unused and spurious data ......................................................................... 28 
13.7. Procedures for reporting any deviations from the original statistical plan ............................................................ 29 
13.8. Inclusion in analysis................................................................................................................................................. 29 
14.1 
The clinical investigation management group consists of the following participants: ........................................... 30 
14.2 
Clinical investigation steering committee ............................................................................................................... 33 
14.3 
Data monitoring committee ................................................................................................................................... 33 
14.4 
Monitoring plan ...................................................................................................................................................... 33 
14.5 
Statistical Analysis plan ........................................................................................................................................... 33 
13.13.1. Descriptive statistics ......................................................................................................................... 33 
13.13.2. Inferential statistics .......................................................................................................................... 33 
15. 
GOOD CLINICAL PRACTICE ...................................................................................................................................... 34 
14.1. Declaration of Helsinki ............................................................................................................................................ 34 
14.2. Guidelines for GCP .................................................................................................................................................. 34 
14.3. Ethics review ........................................................................................................................................................... 34 
14.4. Patient Information and Consent Form .................................................................................................................. 34 
14.5. Subject data protection........................................................................................................................................... 34 
14.6. Procedures in case of medical emergency .............................................................................................................. 34 
16. 
CLINICAL INVESTIGATION CONDUCT RESPONSIBILITITES ....................................................................................... 35 
15.1. Clinical investigation plan amendments ................................................................................................................. 35 
15.2. Clinical investigation plan violations, deviations and serious breaches ................................................................. 35 
15.3. End of clinical investigation ..................................................................................................................................... 35 
15.4. Insurance and indemnity......................................................................................................................................... 35 
15.5. Funding ................................................................................................................................................................... 35 
17. 
REPORTING, PUBLICATIONS AND NOTIFICATIONS OF RESULTS ............................................................................. 36 
16.1. Authorship policy .................................................................................................................................................... 36 
16.2. Publication .............................................................................................................................................................. 36 
18. 
REFERENCES ............................................................................................................................................................ 37 
1. 
..................................................................................................................................................................... 37 
18. 
SAFETY REPORTING ................................................................................................................................................. 39 
18.1 
Definitions ............................................................................................................................................................... 39 
18.1.1. Adverse Event (AE) .................................................................................................................................................. 39 
18.1.2. Serious Adverse Event (SAE) ................................................................................................................................... 39 

 
 
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18.1.3. Adverse Device Effect (ADE) ................................................................................................................................... 39 
18.1.4. Serious Adverse Device Effect (SADE) ..................................................................................................................... 39 
18.1.5. Unanticipated Serious Adverse Device Effect (USADE) ........................................................................................... 39 
18.1.6. Device Deficiency (DD) ............................................................................................................................................ 40 
18.2 
Adverse Events that do not require reporting ........................................................................................................ 40 
18.3 
Recording and reporting of Adverse Events............................................................................................................ 40 
18.3.1 Assessment ............................................................................................................................................................. 41 
• 
Severity: ...................................................................................................................................................... 41 
• 
Causality1: ................................................................................................................................................... 41 
18.3.2 Timelines for reporting ........................................................................................................................................... 42 
18.3.3 Follow-up ................................................................................................................................................................ 43 
18.3.4 Pregnancy ........................................................................................................... Fout! Bladwijzer niet gedefinieerd. 
18.3.5 Death 43 
18.4 
Recording and reporting of Device Deficiencies ..................................................................................................... 43 
Each Device Deficiency must be documented by the Investigator in the source documents and reported to the 
Sponsor on a Device Deficiency form (Appendix B). ............................................................................... 43 
18.5 
Reporting requirements to Ethics Committee’s (EC’s) and Competent Authorities (CA’s) ..................................... 44 
18.5.1 Sponsor’s reporting of Serious Adverse Events and Device Deficiencies ............................................................... 44 
18.6 Annual reporting ......................................................................................................................................................... 44 
 

 
 
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This CIP describes the EVA Nexus clinical investigation and provides information about 
procedures for entering participants. Every care was taken in its drafting, but corrections 
or amendments may be necessary. 
This clinical investigation will adhere to the principles outlined in the ISO 14155:2011. It 
will be conducted in compliance with the CIP, the Data Protection Act and other regulatory 
requirements as appropriate. 

 
 
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1. AMENDMENT HISTORY 
 
 
Amendment 
No. 
CIP 
Version No. 
Date 
Issued 
Author(s) of 
Changes 
Details of Changes 

 
 
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2. LIST OF APPENDICES 
 
 
Appendix A 
List of intra-operative complications 
Appendix B 
List of device issues not leading to (S)AE 
Appendix C 
Case Report Form (S)AEs reporting 
Appendix D 
Device deficiency Form 
Appendix E  
Informed Consent Form 
 
3. ABBREVIATIONS 
 
 
AE 
Adverse Event 
AR 
Adverse Reaction 
BCVA 
best-corrected visual acuity 
CA 
Competent Authorities 
CIP 
Clinical Investigation Plan 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
EC 
Ethics Committee (see REC) 
EMR 
Electronical Medical Record 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
IB 
Investigator Brochure 
ICF
Informed Consent Form 
ICH 
International Conference of Harmonization 
IRB 
Independent Review Board 
Log MAR 
logarithm of the minimal angle of resolution 
PI 
Principle Investigator 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 

 
 
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4. CLINICAL INVESTIGATION SUMMARY 
 
 
Title 
EVA Nexus Field Observation Study 
Reference Number 
(Acronym) 
EVA Nexus 
Clinical Phase 
Non applicable 
Objectives 
To perform a field observation study using the newly developed EVA
Nexus vitrectomy device. 
Endpoints 
Primary endpoint: determine the safety and effectiveness of the 
device. 
Design 
Investigator-initiated, mono-center, academic, prospective, 
observational case study 
Data Collection 
Total duration of study for each patient will be 2 days (from surgery 
date to last follow-up day) 
See Study Flow Chart 7.3 
Planned Clinical 
investigation Period 
Q2-Q3 2021 
Clinical investigation 
population 
Patients that are scheduled for intra-ocular surgery regardless of the
indication: 
• 
Vitrectomy surgery 
• 
Cataract surgery 
• 
Vitrectomy combined with cataract surgery 
Number of Participants 
Up to 250, inclusion period of three months.  
Inclusion/Exclusion 
Criteria 
Inclusion criteria 
• Patients that are scheduled for intra-ocular surgery regardless of 
the indication: 
• Vitrectomy surgery 
• Cataract surgery 
• Vitrectomy combined with cataract surgery  
• In case of (combined) vitrectomy: primary or repeat vitrectomy 
• General or retrobulbar anesthesia, the latter can be combined with
sedation 
• Patients aged ≥ 18 years 
Exclusion criteria 
• Patients aged < 18 years 
Device Name 
EVA Nexus (CE-labeled device) 
Principle Intended Use 
The device is intended to be used during ophthalmic surgery. 

 
 
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Manufacturer Name 
DORC B.V.  

 
 
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5. INTRODUCTION 
 
5.1 Vitrectomy device 
In certain disorders of the retina and the vitreous a vitrectomy study can be performed.  
For vitrectomy surgery, a surgical device is used, called “vitrectomy device”. Such device 
integrates many functions: 
1. Vitrectome driver. 
A vitrectome is a small device which is inserted in the eye to remove the vitreous gel. 
The vitrectome has a hollow blunt-ended hollow shaft with a side opening at the distal 
tip. An inner hollow metal tube is moved back-and-forth over this opening, creating a 
guillotine-like cutting effect on the vitreous gel. At slower speeds, the vitrectome will 
take larger bites out the vitreous gel, hence inducing a quicker removal of the vitreous. 
At higher speeds, the vitrectome takes smaller bites, which is a safer approach when 
working close to the retina. The cutting speed is controlled by the vitrectomy machine 
using a foot pedal. Most of the vitrectomes are driven pneumatically, although some 
electrically driven versions have existed in the past. 
Till about 15 years ago, the diameter of the vitrectome was 20G (1 mm), after that a 
switch happened to mostly 23G (0,6) and 25G (0,5) diameter instruments. Since a few 
years, vitrectomy instruments in 27G (0,35 mm) are available. However, this very 
small size has its limitations, hence is only used in less complicated surgeries. 
The DORC EVA drives a pneumatic vitrectome with a maximum of 8.000 cycles per 
minute. 
 
2. Aspiration system. 
This is required to remove liquid from the eye. Several pump systems exist, with 
different ways to displace fluid: 
-Vacuum pumps generate a vacuum, which is controlled by the surgeon using the foot 
switch of the device. The amount of fluid displacement is dependent on the amount of 
vacuum, and on the amount of resistance in the tubing system and instrument inside 
the eye. Vacuum pumps can respond quickly and can generate a large flow, but lack 
control to keep the fluid displacement steady when the surgeon is operating in 
conditions with variable resistance. An example is when working close to the vitreous 
base at the retinal periphery: the tip of the vitrectome will move in and out of the 
vitreous, resulting in high variability of the flow and risk of aspiration the retinal tissue. 
A typical example of a vacuum system is a venturi-pump, which is used in most of the 
vitrectomy devices presently available. 
-Flow pumps displace a required amount of fluid, and only build up vacuum secondary 
to this fluid displacement. In conditions with low resistance, there is little or no vacuum-
buildup. Most flow pumps are less powerful than vacuum pumps, but can provide a 
better control of the flow. This increases safety when working close to the retina. 
A typical example of a flow pump system is a peristaltic pump. Although such pump is 
popular in cataract surgery, it is only used for vitrectomy surgery in conjunction with 
a vacuum pump. 
Our present vitrectomy machine in the UZLeuven (DORC EVA) has a piston-pump which 
can be steered to perform as a vacuum system or as a flow system. This unique feature 
allows the surgeon to choose the best suitable mode for each individual step of the 
surgery. 
 
3. Infusion system. 
Since vitreous is removed from the eye, an infusion system must be present to maintain 
the eye pressure. There are two infusion systems used for vitrectomy surgery: 
-Gravity system: the infusion bottle (or bag) is suspended on a telescopic infusion pole. 

 
 
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The pole can be extended using the vitrectomy machine to a higher or lower height, 
which increases the pressure at which the infusion liquid is driven towards the eye. The 
disadvantage of such system is that the infusion pole movement has its speed limits, 
which can be a problem when a fast pressure change is required in the eye (such as in 
case of hemorrhage). 
 
-Air system: using a spike, air is blown into the infusion bottle. A higher air pressure 
will increase the force at which liquid is driving towards the eye. Such system can 
respond more quickly to required pressure changes. Our present vitrectomy machine 
in the UZLeuven (DORC EVA) has this type of infusion system.  
A logistical side-effect of such air-driven system is that the infusion liquid connected to 
the eye must be packaged in glass bottles, since plastic bags or plastic bottles have an 
inherent flexibility which would cause unwanted hysteresis.  
-In case of combined phaco-vitrectomy, both infusion in the anterior and in the 
posterior eye segment is required. Since our present vitrectomy device (DORC EVA) 
only has a single infusion line, the tubing needs to be reconnected from the phaco 
handpiece on the posterior segment infusion canula halfway the surgery.  
 
4. Light. 
A powerful light source is required to illuminate the inside of the globe during surgery. 
For this purpose, a PMMA fiber is connected to the light source of the vitrectomy 
machine and guided into the eye. 
Historically, a halogen light source was used. About 15 years ago, more powerful Xenon 
light sources became available and are still present in many vitrectomy devices. More 
recently, LED light sources became more popular. Also our present vitrectomy device 
(DORC EVA) is equipped with an LED light source.  
Increasing light output is required when using ultra-small gauge surgery (27G), since 
the diameter of the light fiber is extremely thin. However, care must be taken by the 
surgeon to avoid light toxicity when the light source is held too close to the same area 
of the retina for too long. Retinal damage due to light toxicity after vitrectomy can have 
a major effect on the visual acuity of the patient. 
In most light sources for vitrectomy surgery, the light is filtered, eliminating more 
bluish wavelengths to increase its safety. 
 
5. Phaco ultrasound. 
To remove an opacified lens from the eye (cataract), the lens needs to be emulsified 
in the eye. For this purpose, a small needle is used that is oscillating on an ultrasonic 
frequency. These oscillations emulsify the lens material, after which can be aspirated 
(using the aspiration system of the device). The DORC EVA has an analog driver board 
and operates at a frequency of 40 kHz. 
 
6. Laser module. 
To reattach the retina in case of retinal detachment, laser coagulates need to be placed 
around the breaks in the retina. For this purpose, a vitrectomy machine has a built-in 
laser module. A glass fiber is used to guide the laser light into the eye on the retina. 
Using the foot switch of the device, laser coagulates can be directed towards the 
desired location on the retina. The DORC EVA uses a 532 nm endo laser which has 
been the standard for ophthalmic use.  
 
7. Silicone oil injection. 
Not infrequently, the eye needs to be filled with silicone oil during surgery for retinal 
detachment. For this purpose, a system is present that drives the silicone oil from a 
(glass) syringe into the eye. The DORC EVA can drive (pre) filled syringes of silicon oil 
with a pressure up to 6 bars. 

 
 
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8. Silicone oil extraction. 
For removal of the silicone oil, a system is present that generates a high vacuum to 
remove the viscous oil from the eye through a small opening. The DORC EVA generates 
a vacuum up to 660 mmHg to remove the silicon oil. 
 
9. Endodiathermy. 
In case a hemorrhage occurs inside or outside of the eye, a diathermy probe can be 
connected to the vitrectomy device to coagulate the bleeding vessel 
The DORC EVA operates at frequency of 1 Mhz to create the coagulation.  
 
 
 

 
 
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5.2 DORC EVA Nexus device 
For the safety of the patient, the need for a performant vitrectomy device is essential.  
In our center, we have been using the DORC EVA vitrectomy machine since 2012. DORC 
will release a novel version of this surgical platform, named the EVA Nexus.  
This new device has several improved features compared to the present DORC EVA.  
 
1. Vitrectome 
Both EVA and EVA NEXUS provide vitrectomy. The cut speed range of EVA NEXUS, 10.000 
cycles per minute,  is broader than that of EVA. A higher cut speed is generally accepted 
as a clinical benefit, without addition of new risk.   
2. Aspiration system 
The aspiration system of the EVA NEXUS is the same with one additional feature. 
EVA NEXUS has an additional proportional controlled backflush. 
 
The aspiration system in the DORC EVA was designed to be used with 23G/25G vitrectomy 
instruments. However, 27G vitrectomy is become more mainstream each year 1-5. This 
feature should increase the safety during surgery when performing vitreous removal very 
close to the retina, also known as “vitreous base shaving”. 
3. Vitrectome 
The maximum cut-speed of the EVA Nexus vitrectome is 20 000 cycles per minute, which 
is almost twice the current speed of the DORC EVA device. As explained above, this 
increased cut rate will also contribute to a safer removal of the vitreous close to the retina. 
To maximize surgical ergonomy, the hand piece of the vitrectomy is now covered with a 
dampening sleeve, which reduces the amount of vibration for the surgeon holding the 
vitrectome during the surgery.  
4. Infusion system 
 
Our present vitrectomy device generates a desired amount of pressure in the infusion 
bottle (by changing the bottle height of by injection of air in the bottle), but there is no 
control over the actual amount of liquid that is infused in the eye. This can cause danger 
in two directions: 
-In some circumstances, the infusion flow will be too high, which impedes normal arterial 
perfusion of the eye, which can create ischemic damage in the eye. Such vitrectomy- 
related vascular damage is not infrequently described in the literature 6. 
-In other circumstances, the aspiration of liquid can be higher than the infusion flow, hence 
the eye pressure can become too low, which can cause hemorrhage or even collapse of 
the eye. 
The EVA Nexus system has an active infusion system, which constantly provides a stable 
infusion to the eye and a stable intra-ocular pressure during surgery. Hence, it features 
automated control of the intra-ocular pressure during anterior and posterior segment 
surgery. 

 
 
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The fixed and gravity modes are both pressure controlled and can be regarded similar 
technology with the same functional result. The eIOP mode in EVA NEXUS supports the 
surgeon to maintain the IOP by maintaining the Irrigation/Aspiration balance  (regulated 
by the pump system to get precise Intra Ocular Pressure control), where in EVA Intra 
Ocular Pressure is a result of the surgeon controlled settings of the system.  
The EVA Nexus has twin irrigation lines, which omits the need to switch the infusion 
halfway the surgery in case of combined phaco-vitrectomy 
Another, logistical implication is that the infusion liquid used during cataract surgery or 
vitrectomy surgery must not be packaged anymore in a glass bottle, since the DORC EVA 
Nexus actively aspirates the infusion liquid from the container. Therefore, less expensive 
packages of infusion liquid can be used (fluid bags or plastic bottles). 
 
5. Light 
The system had a LED-powered light source, with filtered output to eliminate the shorter 
light wavelengths that induce light toxicity during prolonged exposure to the retina. This 
is the same light source as in the present DORC EVA device. 
6. Phaco ultrasound 
The phaco handpiece that fits to EVA Nexus is the same CE-labeled commercial handpiece 
already used on our present surgical device.  
Although the design is somewhat different, both EVA and EVA NEXUS use similar principles 
of operation to drive the phaco handpiece for emulsification or fragmentation of the lens. 
All performance requirements are the same.   
 
7. Laser module 
The EVA Nexus has a built-in 532 nm diode-laser. This is the same laser module as used 
in our present vitrectomy device.  
 
8. Silicone oil injection (VFI). 
There are no differences between the EVA and EVA NEXUS for silicone oil injection. 
 
9. Silicone oil extraction. 
There are no differences between the EVA and EVA NEXUS for silicone oil extraction. 
 
10. Micro Injection 
In addition to the EVA the EVA NEXUS has a Micro Injection functionality, which is basically 
the same functionality as VFI, in a smaller and more precise volume dosing. The VFI 
function can be set in the range 0-6 bar, with step size 0,5 bar. The MI function can be 
set in the range 0-2 bar, with step size of 0,1 bar.  
 
10. Endodiathermy. 
Although the design is somewhat different, both EVA and EVA NEXUS use similar 
principles of operations to drive the diathermy handpiece to coagulate tissue 
 
 

 
 
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5.3 Patient safety with the EVA Nexus device 
This field observation study will be performed to obtain more information on the safety 
and daily use of the EVA Nexus device in routine phaco/vitrectomy surgery. This 
information can lead to small adjustments to the device to further fine tune a safe device 
which can be used by other surgeons.  
During a vitrectomy surgery, the surgeon removes the vitreous gel. This is done using a 
mini-guillotine of half millimeter diameter (or even less in 27G surgery) that is inserted in 
the eye. Meanwhile, an infusion fluid is injected in the eye. Sufficient fluid irrigation is 
mandatory to avoid a drop in the eye pressure which can lead to retinal or choroidal 
hemorrhage. On the other hand, it must be avoided to have the eye pressure elevate too 
high, since this can block the arterial blood supply which can lead to permanent damage 
of the eyesight of the patient.   
The EVA Nexus device has an automated system, which allows better control of the eye 
pressure during the surgery compared to existing vitrectomy technology.  
Another novel feature on this device is the improvement of the guillotine itself. The faster 
the guillotine can go backwards and forwards, the safer the surgery can be performed. 
The EVA Nexus device can keep up to a speed of 20000 cuts per minute, whereas in even 
the most performant devices the speed is limited to 16000 cuts per minute. 
Often vitrectomy is combined with lens surgery. The removal of the lens is nowadays done 
using a device that emulsifies the lens with ultrasonic waves. This technique is called 
“phaco-emulsification”, which has been the golden standard in cataract surgery for more 
than 20 years. The hand-held phaco-emulsification probe connected to the EVA Nexus is 
the same probe as used on our present DORC EVA device, but the internal steering is 
redesigned to allow better fine-tuning of the surgical settings according to the preferences 
of the surgeon. 
Besides the EVA Nexus itself, several of the disposable supplies of this surgical platform 
were optimized: 
• 
Newly designed phaco needles improve anterior chamber stability during cataract 
surgery.  
• 
The instrument cannulas used during vitrectomy were redesigned. The smaller 
outside part occupies less space hence will allow more movement of the eye during 
the surgery. 
• 
The infusion line can connect to the infusion canula without the need to remove its 
sealing cap. This reduces the amount of surgical movements and allows better 
surgical flexibility when the infusion needs to be switched to another instrument 
cannula during surgery.  
• 
The infusion line locks onto the infusion canula, reducing the incidence of a 
commonly occurring issue that the infusion line disconnects from the cannula 
during the surgery. 
After brought under anesthesia, the patients is draped while the vitrectomy device is being 
prepared. This involves connecting of all the surgical supplies (see above) and priming of 
the device. This whole procedure takes 10-20 minutes, depending on the complexity of 

 
 
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the case.The packaging of the surgical supplies was reworked (reduction in the amount of 
packaging materials) and the infusion giving set has been simplified significantly for the 
EVA Nexus platform. This should shorten the total surgical time.  
Surgical issues and/or (S)AE’s that are related to the surgical device will always be 
observed either during the surgery or during the postoperative visit on day one. Late-
onset complications such as proliferative vitreoretinopathy, retinal detachment etc. are 
considered non-related to the surgical device. Hence, in this study, data acquisition is 
terminated after the postoperative visit on day one, although the patient will have further 
postoperative follow-up according the standard of care.  
 
 
 
 

 
 
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6. OBJECTIVES 
The primary objective and primary parameters are shown in the table below: 
 
The main purpose of this 
study is to evaluate the intra-
operative safety of a new 
surgical device. 
Therefore, having no idea of the percentage of 
patients 
having 
complications, 
we 
make 
the 
hypothesis that minimum 5% of the patients will have 
complications. In order to make sure that we have at 
least 10 patients with complications, we plan recruit 
250 patients in total in order to get at least 10 
complications with EVA Nexus.  
For this purpose, typical surgical parameters will be 
recorded during vitrectomy surgery: 
• Surgical indication 
• If combined phaco-surgery is performed: amount 
of phaco power used 
• Staining dyes (if used) 
• Amount of laser coagulates (if used) 
• Type of tamponade left in the eye: BSS+ liquid, air 
bubble, air, gas (type + concentration) or silicone 
oil (type)  
 
Specific adverse events that may occur during 
(phaco)vitrectomy will be recorded to assess the 
surgical safety 15-18: see list in Appendix A.  
This AE reporting is already present in the surgical 
report (KWS-Formasa) used for daily vitrectomy 
surgery using the DORC EVA device. The occurrence 
of these AE’s during surgeries using the EVA Nexus 
will be compared to historical data retrieved from 
surgeries using the DORC EVA platform. 
 
Device issues that caused some hindering during the 
surgery but that do not lead to an (S)AE, such as error 
messages/warnings that did occur, malfunctioning of 
supplies that required replacement etc. will be 
recorded.  
See Appendix B for a full list, which is already part of 
our 
present 
surgical 
report 
(KWS-Formasa).  
The occurrence of these issues during surgeries using 
the EVA Nexus will be compared to historical data 
retrieved from surgeries using the DORC EVA 
platform.  
 
 
 

 
 
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The secondary objective and secondary parameters are shown in the table below: 
 
Secondary objective 
Secondary parameters 
To evaluate the possible 
reduction of total surgical time.  
The time that was required to prepare the EVA Nexus 
will be recorded (connecting of supplies + priming). 
During the study period, this time will also be 
recorded during surgeries performed with the DORC 
EVA device for comparison.  
To evaluate possible (S)AE that 
may be related to the use of the 
surgical platform.  
Rarely, adverse events that are related to the 
surgery may only become visible the day after the 
surgery. 
A 
typical 
example 
is 
a 
choroidal 
hemorrhage, which is related to variations in intra-
ocular pressure during the surgery. 
Hence, standard as in the standard-of care, a 
postoperative check of the eye at the day after the 
surgery will be performed to determine the presence 
of such AE’s.  
 
 
To evaluate the impact of usage 
of the EVA NEXUS on the 
surgical parameters used during 
the procedure  
The surgical parameters include a range of data 
collected on the following: 
Aspiration 
Irrigation / Infusion 
BSS Usage 
Vitrectomy 
Ultrasound  
Illumination 
Diathermy 
Micro-injection 
Silicone oil injection / extraction  
Laser 

 
 
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7. CLINICAL INVESTIGATION DESIGN 
 
7.1 Trial Design 
Investigator-initiated, academic, mono-center, prospective, field observation study using 
a novel CE-labeled surgical platform.  
 
The study will be terminated after a time period of three months. A maximum of 250 
patients will be enrolled. The study will consist of 3 patient visits. Study follow-up is 1 day 
after the date of the vitrectomy surgery. 
During surgery, intra-operative complications and issues will be recorded for safety 
assessment: see list in previous paragraph.  
Typical postoperative follow-up after vitrectomy includes the clinical tests to assess that 
normal postoperative outcome is present, without the presence of adverse events. 
Hence, the same clinical data will be collected in the study patients as in patients 
undergoing the standard-of-care. 
 
This field observation study is conducted to obtain information about the complication rate 
of the EVA Nexus system which will be compared with the incidence of these complications 
occurring is surgeries performed using our present DORC EVA platform. 15-18  
7.2 Study Flowchart 
 
 
 
Preop (inclusion) 
Surgery 
Postop day 1 
Vitrectomy 
 
X 
Visual acuity 
X 
 
X 
Eye pressure 
X 
 
X 
Biomicroscopy 
X 
 
X 
Ophthalmoscopy 
X 
 
X 
OCT 
X1 
 
 
Ultrasound 
X2 
 
X2 
Adverse events 
X3 
 
X 
Surgical summary  
 
X 
 
 
 
X1 if required, depending on indication for surgery, e.g.: macular pucker, macular hole, 
vitreomacular traction, … 
X2 if required, depending on indication for surgery, e.g.: vitreous hemorrhage 
X3 any pre-operative clinical condition that is known to affect the incidence of (S)AE’s 
during surgery (e.g. zonular dehiscence, tamsulosine medication, axial length, …) 
 

 
 
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8. CLINICAL INVESTIGATION POPULATION 
 
8.1. 
Number of participants – sample size analysis 
With a complication rate ranging from 5% up to 30% in previous studies, we have no a 
priori about the complication rate of the EVA Nexus system. We therefore consider a rather 
conservative hypothesis and expect to have around 5% of complications with the EVA 
Nexus system. We plan recruit 250 patients in total in order to get at least 10 complications 
with EVA Nexus. The estimated enrolment time is 6 months. 
 
8.2. 
Inclusion criteria 
• 
Patients that are scheduled for vitrectomy surgery, cataract surgery or combined 
surgery, regardless of the indication 
• 
Primary or repeat vitrectomy 
• 
General or local anesthesia, or combination 
• 
Patients Aged ≥ 18 years 
8.3. 
Exclusion criteria 
• 
Patients aged < 18 years old 

 
 
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9. PARTICIPANT SELECTION AND ENROLMENT 
 
9.1. 
Identifying participants 
 
The trial will be initiated only after the device manufacturer (DORC B.V.) has received a 
CE-label for both the surgical device (EVA Nexus) and its surgical supplies. Hence, no 
FAGG application will be necessary for this study.  
Since no experimental device is used in this field observation study, the patient is not 
asked for permission to have the surgery done using this device, but approval is needed 
from the patient to use his/hers EMR data for a clinical trial. Patients that are not asked 
for study participation could also undergo surgery with the EVA Nexus device, since it 
will be fully approved for clinical used at the time of the study.  
Hence, it is important to emphasize that whether the patient is included in trial has in no 
way any influence on the clinical care: the surgery might be performed with the same 
device, and the same clinical data will be recorded before, during and after the surgery. 
There are no supplementary study visits, nor is any specific study-related clinical or 
technical examination performed.  
 
Patients will be asked for permission for inclusion in the study on the evening of the day 
of the surgery. After finishing all surgeries, the surgeon always does a round in the one-
night-stay department to see the patients that were operated that day. During that post-
operative patient briefing, the surgeon will ask the patient for inclusion in the trial and to 
sign the informed consent. 
This ‘approval after surgery’ instead of asking before the surgery had several advantages: 
• Although the patients follow exactly the same clinical path as in the standard-of-care 
(including the device used for the surgery), it is very disturbing for a patient to hear 
pre-operatively that he/she will be included in a clinical study. Patients usually do not 
understand that only the use of their EMR for a study also requires their informed 
consent and signature. Rather, patients that are asked for such approval before the 
surgery will experience more stress because they may (incorrectly) believe some 
experimental therapy is being done.  
• The surgeon will not know in advance whether a patient will be included in the study. 
Indeed, when asked after the surgery, a patient may or may not give their consent for 
participation.  
Hence, neither the decision to perform the surgery nor the scheduling of the surgery 
will be influenced by participation in the trial, further eliminating any possibility that 
participation in the trial may influence the clinical care of the patient.  
However, in theory, a surgeon may decide not to ask permission for study participation 
in patients that have more surgical risk. For example: high myopia, very small eye size, 
previous ocular trauma etc. all make the surgery more prone for adverse events. 
Therefore, in this study, the investigator will ask ALL patients that were operated that 
day for their approval to participate in the trial and keep an (pseudonymized ) list of how 
many patients refused participation This way, this theoretical bias in patient selection is 
also omitted.  
In case a patient prefers not to have their EMR used for this field observation study, the 
further clinical tract remains unaltered.  
9.2. 
Consenting participants 
Patients that are underwent phaco and/or vitrectomy surgery will be given the 
informed consent and will be asked to participate in the clinical trial.  

 
 
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Following Ethic Committee (EC) approval and before any investigation related procedure, 
potential participant must personally sign and date the latest approved version of the 
informed consent form before the EMR is used for this study. 
 
Written and verbal versions of the participant information and Informed consent will be 
presented to the participants detailing no less than: the exact nature of the clinical 
investigation; the implications and constraints of the clinical investigation plan; the known 
side effects and any risks involved in taking part (if present). It will be clearly stated that 
the participant is free to withdraw from the clinical investigation at any time for any reason 
without prejudice to future care, and with no obligation to give the reason for withdrawal. 
 
The participant will be allowed as much time as wished to consider the information, and 
the opportunity to question the Investigator, their GP or other independent parties to 
decide whether they will participate in the clinical investigation. Written Informed Consent 
will then be obtained by means of participant dated signature and dated signature of the 
person who presented and obtained the informed consent. The person who obtained the 
consent must be suitably qualified and experienced, and have been authorized to do so 
by the Coordinating/Principal Investigator. A copy of the signed Informed Consent will be 
given to the participants. The original signed form will be retained at the clinical 
investigation site. 
 
In case of updates of the participant information and Informed consent the participant 
must personally sign and date the latest approved version of the informed consent form 
before any further clinical investigation specific procedures are performed. 
 
For this clinical trial, signature for approval from the patient will be obtained at the 
evening of the day of the surgery (see above). 
9.3. 
Withdrawal of participants 
Subjects are free to discontinue participation in the investigation at any time, and without 
prejudice to further treatment. Subjects who discontinue the investigation should always 
be asked about the reason(s) for their discontinuation and about the presence of any 
Adverse Event/Adverse Device Effect or Device Deficiency and, if possible, be assessed 
by an investigator. Adverse Event/Adverse Device Effect should be followed up. 
 
Subjects may be withdrawn from investigation treatment and assessments at any time. 
 
Incorrectly enrolled subjects will be withdrawn from further investigation treatment and 
assessments. A subject may, however, continue the investigation under special 
circumstances (i.e. if continuation of investigation treatment or follow-up actions are 
necessary for the subject’s safety and well-being, or if only a follow-up period remains, 
and the continuation of the investigation is not expected to be associated with any risk 
or discomfort for the subject) 

 
 
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10. 
INVESTIGATIONAL DEVICE 
 
10.1. Investigational device details 
The device used for this clinical trial and its supplies will have a CE-label. Hence, no FAGG 
approval will be requested to use the device for this trial.  
10.2. Device manufacturer 
Manufacturer of devices included in section 10.1 is DORC BV, Scheijdelveweg 2, 3214 VN 
Zuidland, The Netherlands. 
10.3. Device accountability 
In the hospital, there is a standard procedure for returning faulty products. This procedure 
will be followed, similar to the standard clinical path. 
10.4. Storage conditions 
All disposable supplies used with the device come pre-sterilized and will be used before 
expiration date. The reusable instruments (mainly: phaco handpiece) will be steam- 
sterilized according to the guidelines provided by the manufacturer. 
10.5. Concomitant Treatments 
Before, during and after the surgery, the same medication and antiseptic treatment will 
be applied as in patients following the standard clinical path. This includes: 
• 
Preoperative application of mydriasert to dilate the pupil 
• 
Preoperative antiseptic treatment with betadine 
• 
BSS plus infusion liquid during the surgery 
• 
Intra-operative injection of Mydrane if pupillary dilation is required 
• 
Intra-operative injection of Miostat if pupillary miosis is required 
• 
Injection of parabulbar triamcinolone and clindamycin at the end of the surgery 
• 
Postoperative dexamethasone anti-inflammatory eyedrops 
At the discretion of the investigator, additional medication may be prescribed. 
 
10.6. FAGG Approval 
Not applicable, see 10.1 

 
 
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11. 
CLINICAL INVESTIGATION ASSESSMENTS 
 
11.1. Subject Characteristics 
During vitrectomy surgery, typical surgical parameters will be recorded: 
• Surgical indication 
 
• If combined phaco-surgery is performed: amount of phaco power used 
 
• Staining dyes (if used) 
 
• Amount of laser coagulates (if used) 
 
• Type of tamponade left in the eye: BSS+ liquid, air bubble, air, gas (type + 
concentration) or silicone oil (type) 
 
11.2. Clinical investigation assessments 
Patients that are scheduled for vitrectomy and/or cataract surgery that is commonly 
performed will be included. The preoperative preparation of the patient and the surgery 
itself will not be different from the standard of care. 
Typical postoperative follow-up after vitrectomy includes the clinical tests to assess that 
normal postoperative outcome is present, without the presence of adverse events. 
Hence, the same clinical data will be collected in the study patients as in patients 
undergoing the standard-of-care. 
11.3. Surgical procedure 
The patient will be operated under local anesthesia, local anesthesia with sedation or 
general anesthesia, depending on the surgeon’s and patient’s preferences and general 
status of health. In case of vitrectomy surgery, in case the patient is phakic and over 50 
years old, the surgery will be combined with a cataract surgery (phaco-emulsification) in 
most cases. As in the standard of care, the patients will stay overnight in the hospital after 
the surgery (one-night stay). 
11.4. Safety assessments 
The EVA Nexus device and it supplies are CE certified per Medical Device Directive 
(93/42/EEC) and comply therefore with the safety and performance requirements as stated 
in the Essential Requirements of this directive. Compliance with applicable safety and 
performance standards has been confirmed during extensive testing as part of the 
development process and the associated records are part of the design history file. These 
records are subject to periodic surveillance audits by Notified Body DEKRA.  
 
11.4.1 Adverse events that do not require reporting 
After vitrectomy, the following transient adverse events are commonly present during the 
first day after surgery, hence will not require reporting: 
• 
Decreased visual acuity compared to preoperative measurement 
• 
Reddish eye 
• 
Moderately and temporarily increased ocular pressure (<35 mmHg) 
• 
Mild to moderate intra-ocular inflammation 
• 
Mild corneal edema In addition see section 18.2. 

 
 
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12. 
DATA QUALITY ASSURANCE 
 
12.1. Monitoring, Audit and Inspections 
Investigator and the institution(s) will permit trial-related monitoring, audits, EC review, 
and regulatory inspections (where appropriate) by providing direct access to source data 
and other documents. 
12.2. Training of staff 
The Principal Investigator will ensure that appropriate training relevant to the investigation 
is given to the medical, nursing and other staff at the site involved and that new 
information of relevance to the performance of this investigation is forwarded to the staff 
involved. 
 
The staff at the investigational site will sign a confirmation document that they are 
trained. 
12.3. Data Management 
 
An eCRF will be created on the RedCap platform. This platform provides all required 
functionality, security and traceability to be compliant with a CRF. To pseudonymize the 
patient data in the eCRF, a separate file containing the list of patients linked to the study 
number will be kept behind the hospital firewall, only accessible by the study personnel 
involved in this trial. 
 
All documents will be stored safely in confidential conditions. On all clinical investigation- 
specific documents, other than the signed consent, the participant will be referred to by 
the clinical investigation participant number/code, not by name. 
 
All clinical investigation documentation will be kept for 25 years from the clinical 
investigation plan defined end of clinical investigation point. When the minimum 
retention period has elapsed, clinical investigation documentation will not be destroyed 
without permission from the sponsor. 

 
 
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13. 
STATISTICS 
 
13.1. Description of statistical methods 
Will be outsourced to a licensed medical statistician (Ars Statistica).  
An pseudonymizedExcel-export will be generated from the eCRF for statistical analysis. 
 
For the primary endpoint (complication rate of the EVA Nexus), a one-sample proportion 
test will be performed to test whether the obtained rate is different from rates found in the 
literature (30%, 15% and 5%).  
For the remaining data (demographics and secondary objectives), group comparisons (no 
complications vs complications) of categorical variables will be analyzed using a Fisher’s 
exact test and group comparisons (no complications vs complications) of continuous 
variables will be performed using the T-test or the Wilcoxon signed rank test, as 
appropriate (=when the normality of the residuals and the equality of the variances are 
met, the T-test will be used, and when the normality of the residuals or the 
homoskedasticity of the variances will not be met, the Wilcoxon signed rank test will be 
used). Last, in order to test a first predictive model, a logistic or Poisson regression, as 
appropriate, with backward selection method will be performed, starting with all variables 
associated with the target with a p-value lower than 0.1. The final model will contain 
variables associated with the outcome with a p-value lower than 0.05. 
 
13.2. The number of participants 
Maximum 250, inclusion time 4 months. 
 
13.3. The level of statistical significance 
For all analyses, the level of significance will be 5% two-sided significant level. 
 
13.4. Criteria for the termination of the clinical investigation 
Clinical investigation will be terminated after the postoperative visit on the day after the 
surgery.   
 
13.5. suspension or premature termination of the trial 
In case of suspension or premature termination of the trial a notification will be sent in 
writing to the CA and EC explaining the reason behind this decision. 
 
13.6. Procedure for accounting for missing, unused and spurious data  
Missing data will be reported with reasons given where available, and the missing data 
pattern will be examined. We will explore the mechanism of missing data (MCAR, MAR) by 
means of the Jamshidian & Jalal’s (2010)’s test for MCAR or logistic regression models for 
MAR which will explore if missingness (i.e. whether the primary outcome is missing or not) 
is related to measured baseline variables.  As indicated by Molenberghs et al. (2008), one 
can never totally exclude a MNAR process, but every MNAR model has a MAR counterpart 
with equal fit.  Therefore, in case of MCAR, MAR or MNAR missing processes, Maximum 
Likelihood (ML) and Multiple Imputation (MI) can be used, using the mice R package for 
the last one (Raghunathan et al., 2001; van Buuren & Oudshoorn, 2000), with a predefined 
seed. Indeed, ML and MI uses all available data in the study, produces unbiased estimates 
of the treatment effect and correct p-values. MI is also a method of choice because it 

 
 
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allows not only to impute missing values on the outcome but also on the covariate (Dziura 
et al., 2013) and is valid for MCAR, MAR and MNAR (Molenberghs et al., 2008).  
 
 
 
13.7. Procedures for reporting any deviations from the original statistical 
plan 
The final statistical plan will be agreed prior to final data lock and prior to any analyses 
taking place. Any deviation thereafter will be reported in the final trial report. 
13.8. Inclusion in analysis 
All patients will be included in the trial. 

 
 
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14. 
Clinical investigation management group and 
parties involved  
14.1 The clinical investigation management group consists of the 
following participants: 
 
Principal Investigator 
Name: Peter Stalmans  
Title: Vitreoretinal surgeon 
Address: 
UZLeuven 
Herestraat 49 
3000 Leuven 
Telephone: 016/ 33 26 60  
Email: oogziekten@uzleuven.be 
Statistician 
Name: Mr. Jean-François Fils, Ars Statistica 
Title: Bio-Statistician 
Address: 
Boulevard des Archers, 40 
1400 Nivelles 
Email: jean-francois.fils@ars-statistica.com 
Clinical investigation Management 
Name: 
Ingeborg 
Vriens 
Title: CRA 
Address: 
Ophthalmology 
UZLeuven E 107 
Herestraat 49 
3000 Leuven 
Telephone: +32 16 34 22 29 
Email: 
ingeborg.vriens@uzleuven.be 

 
 
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Clinical investigation Coordination Centre 
For general queries, supply of clinical investigation documentation, and collection of data,
please contact the Clinical Investigation Coordinator: 
Name: Ingeborg Vriens 
Address: UZ Leuven campus Gasthuisberg – E107 - Herestraat 49, 3000 Leuven 
Telephone: +32 16 34 22 29 
Email: 
ingeborg.vriens@uzleuven.be 

 
 
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Clinical Queries 
Clinical queries should be directed to oogziekten@uzleuven.be who will direct the 
query to the appropriate person 
Investigation site 
Name: UZ Leuven E107 
Address: Herestraat 49, 3000 Leuven 
Telephone: +32 16 33 26 60 
Email: oogziekten@uzleuven.be  
Sponsor 
Name: UZ Leuven 
Address: Herestraat 49, 3000 Leuven 
Telephone: 
Email: oogziekten@uzleuven.be  
Funder 
Name: DORC B.V. 
Address: Scheijdelveweg 2, 3214 VN Zuidland, The Netherlands 
Telephone: +31 6 55 23 91 00 and +31 1 81 74 50 90 
Email: j.burckhardt@dorcglobal.com  

 
 
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14.2 Clinical investigation steering committee 
N/A 
 
14.3 
Data monitoring committee 
N/A 
 
 
14.4 
Monitoring plan 
The study protocol was reviewed by the CTC prior to study approval. In case the CTC 
decides to appoint a monitor for this trial, the monitor will be able to visit the Investigator 
site prior to the start of the clinical investigation and during the course of the clinical 
investigation if required, in accordance with the monitoring plan. In such case, monitoring 
can be performed according to ISO 14155:2011. 
Data will be evaluated for compliance with the clinical investigation plan and accuracy in 
relation to source documents. Following written standard operating procedures, the 
monitors will verify that the clinical investigation is conducted and data are generated, 
documented and reported in compliance with the clinical investigation plan, GCP and the 
applicable regulatory requirements. 
 
14.5 
Statistical Analysis plan 
13.13.1. Descriptive statistics 
 
Summary statistics (Nb observations, minimum, Q25, median, Q75, maximum, standard 
deviation) of the whole studied group will be provided. 
 
13.13.2. Primary outcome 
For the primary endpoint (complication rate of the EVA Nexus), a one-sample proportion 
test will be performed to test whether the obtained rate is different from rates found in the 
literature (30%, 15% and 5%).  
 
 
13.13.3. Inferential statistics 
 
For the primary endpoint (complication rate of the EVA Nexus), a one-sample proportion 
test will be performed to test whether the obtained rate is different from rates found in the 
literature (30%, 15% and 5%).  
For the remaining data (demographics and secondary objectives), group comparisons (no 
complications vs complications) of count variables will be analyzed using a Fisher’s exact 
test and group comparisons (no complications vs complications) of continuous variables 
will be performed using the T-test or the Wilcoxon signed rank test, as appropriate (=when 
the normality of the residuals and the equality of the variances are met, the T-test will be 
used, and when the normality of the residuals or the homoskedasticity of the variances 
will not be met, the Wilcoxon signed rank test will be used). Last, in order to test a first 
predictive model, a logistic or Poisson regression, as appropriate, with backward selection 
method will be performed, starting with all variables associated with the target with a p-
value lower than 0.1. The final model will contain variables associated with the outcome 
with a p-value lower than 0.05. 
 
 
 
 

 
 
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15. 
GOOD CLINICAL PRACTICE 
 
14.1. Declaration of Helsinki 
The Investigator will ensure that this clinical investigation is conducted in full conformity 
with the current revision of the Declaration of Helsinki (last amended October 2000, with 
additional footnotes added 2002 and 2004). 
14.2. Guidelines for GCP 
The Investigator will ensure that this clinical investigation is conducted in full conformity 
with relevant regulations and with the International standard for Good Clinical Practice 
for clinical investigations of medical devices for human subjects (ISO 14155:2011). 
14.3. Ethics review 
The clinical investigation plan, Investigator’s Brochure, Case Report Forms (CRFs), 
informed consent form, participant information sheet and any other documents needed 
for review by an appropriate Ethics Committee (EC) or regulatory authority will be 
submitted to obtain written approval. Any additional requirements imposed by the EC or 
regulatory authority will be followed, if appropriate. The trial will be conducted in 
compliance of the Belgian Law of 7 May 2004 on experiments on the human person. 
 
The Investigator will submit and, where necessary, obtain approval for all amendments 
to the original approved documents. Furthermore, the clinical investigation will not begin 
until the required approval/favorable opinion of the EC or regulatory authority has been 
obtained. 
14.4. Patient Information and Consent Form 
The Principal Investigator will ensure that the subject is given full and adequate oral and 
written information about the nature, purpose, possible risks and benefits of the 
investigation. Subjects must also be notified that they are free to discontinue participation 
in the investigation at any time. The subject should be given the opportunity to ask 
questions and time for consideration. 
 
The subject’s signed informed consent has to be obtained before collecting any 
investigation related procedures. The original must be filed by the Principal Investigator. 
A copy of the Patient Information including the signed Consent Form should be given to 
the subject. If modifications are made according to local requirements, the new version 
must be approved by the EC. 
14.5. Subject data protection 
The clinical investigation staff will ensure that the participants’ anonymity is maintained. 
The participants will be identified only by a sequential ID number on the eCRF. All 
documents will be stored securely and only accessible by clinical investigation staff and 
authorized personnel. The clinical investigation will comply with the Data Protection Act 
which requires data to be pseudonymized as soon as it is practical to do so. 
14.6. Procedures in case of medical emergency 
The Principal Investigator is responsible for ensuring that procedures and expertise are 
available to cope with medical emergencies during the investigation. 

 
 
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16. 
CLINICAL INVESTIGATION CONDUCT RESPONSIBILITITES 
 
15.1. Clinical investigation plan amendments 
Amendments to the clinical investigation plan must be submitted to the Sponsor for 
review before submitting to the appropriate EC and Regulatory Authority for approval. 
 
15.2. Clinical investigation plan violations, deviations and serious 
breaches 
The Clinical investigator will not implement any deviation from the clinical investigation 
plan without agreement from the Sponsor, except where necessary to eliminate an 
immediate hazard to clinical investigation participants. 
In the event that the Clinical investigator needs to deviate from the clinical investigation 
plan, the nature of and reasons for the deviation will be recorded in the CRF and notified 
to the Sponsor. If this necessitates a subsequent clinical investigation plan amendment, 
this will be submitted to the Sponsor for approval and then to the appropriate REC and 
Regulatory Authority for review and approvals as appropriate. It is Sponsor policy that 
waivers to the clinical investigation plan will not be approved. 
In the event that a serious breach of GCP is suspected, this will be reported to the 
Sponsor immediately. 
15.3. End of clinical investigation 
The end of clinical investigation is defined as the last participant’s last visit. 
The investigator and/or the clinical investigation steering committee have the right at 
any time to terminate the clinical investigation for clinical or administrative reasons. 
 
The end of the clinical investigation will be reported to the EC and Regulatory Authority 
within 90 days, or 15 days if the clinical investigation is terminated prematurely. The 
Investigators will inform participants of the premature clinical investigation closure and 
ensure that the appropriate follow up is arranged for all participants involved. 
A summary report of the clinical investigation will be provided to the EC and Regulatory 
Authority within 1 year of the end of the clinical investigation. 
15.4. Insurance and indemnity 
In accordance with the Belgian Law relating to experiments on human persons dated May 
7, 2004, Sponsor shall assume, even without fault, the responsibility of any damages 
incurred by a Study Patient and linked directly or indirectly to the participation to the 
Study, and shall provide compensation therefore through its insurance.” 
15.5. Funding 
This is a monocentric, academic field observation study. A study grant will also be provided 
by DORC BV to cover the administrative and personnel expenses for this study. 
 

 
 
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17. 
REPORTING, PUBLICATIONS AND NOTIFICATIONS OF RESULTS 
 
16.1. Authorship policy 
Ownership of the data arising from this clinical investigation resides with the clinical 
investigation team. On completion of the clinical investigation, the clinical investigation 
data will be analyzed and tabulated, and a clinical investigation report will be prepared in 
accordance with ISO14155:2011. 
16.2. Publication 
The Principal Investigator intents to publish the obtained study data in a specialized journal 
for retinal surgery. The statistician will provide a study report, which will be used as source 
data to write the results section of the manuscript. The publication will also cover 
authorship, acknowledgements (mentioning the grant provider of the trial), and an 
overview of relevant scientific publications. 
Before submitting for publication, the manuscript will be sent to the grant provider, 
allowing the grant provider give feedback on the manuscript within 2 weeks. It is up to 
the Principal Investigator to decide to make any changes to the manuscript based on this 
feedback. 

 
 
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18. 
REFERENCES 
 
1. Comparative study of 27-gauge vs 25-gauge vitrectomy for epiretinal membrane. 
Mitsui K, Kogo J, Takeda H, Shiono A, Sasaki H, Munemasa Y, Kitaoka Y, Takagi H. 
Eye (Lond). 2016 Apr;30(4):538-44. 
2. Retrospective Comparison of 27-Gauge and 25-Gauge Microincision Vitrectomy 
Surgery with Silicone Oil for the Treatment of Primary Rhegmatogenous Retinal 
Detachment. Li J, Zhao B, Liu S, Li F, Dong W, Zhong J. J Ophthalmol. 2018. 
3. Surgical outcomes of 27-gauge and 25-gauge vitrectomy day surgery for 
proliferative diabetic retinopathy. Naruse Z, Shimada H, Mori R. Int Ophthalmol. 
2018. 
4. Comparison of 25- and 27-Gauge Pars Plana Vitrectomy in Repairing Primary 
Rhegmatogenous Retinal Detachment. Otsuka K, Imai H, Fujii A, Miki A, Tagami M, 
Azumi A, Nakamura M. J Ophthalmol. 2018 
5. Outcomes of transconjunctival sutureless 27-gauge vitrectomy for vitreoretinal 
diseases. Li J, Liu SM, Dong WT, Li F, Zhou CH, Xu XD, Zhong J. Int J Ophthalmol. 
2018 
6. Dziura, J. D., Post, L. A., Zhao, Q., Fu, Z. & Peduzzi, P. (2013). Strategies for Dealing 
with Missing Data in Clinical Trials: From Design to Analysis. Yale Journal of Biology 
and Medicine, 88, 343-358. 
7. Jamshidian, M. & Jalal, S. (2010). Tests of Homoscedasticity, Normality, and Missing 
Completely at Random for Incomplete Multivariate Data. Psychometrika, 75(4), 
649–674. 
8. Molenberghs, G., Beunckens, C., Sotto, C. & Kenward, M. G. (2008). Every Missing 
Not at Random Model Has Got a Missing at Random Counterpart with Equal Fit. 
Journal of the Royal Statistical Society:  
Series B (Statistical Methodology), 70 (2), 371-388. 
9. Raghunathan TE, Lepkowski JM, Van Hoewyk J, Solenberger P (2001). A Multivariate 
Technique for Multiply Imputing Missing Values Using a Sequence of Regression 
Models." Survey Methodology, 27(1), 85{95. 
10. van Buuren S, Oudshoorn CGM (2000). Multivariate Imputation by Chained 
Equations: MICE V1.0 User's Manual." TNO Report PG/VGZ/00.038, TNO Preventie 
en Gezond- 
heid, 
Leiden. 
http://www.stefvanbuuren.nl/publications/MICE%20V1.0%20Manual% 
  
20TNO00038%202000.pdf. 
11. Pars plana vitrectomy for vitreomacular traction syndrome: a systematic review and 
metaanalysis of safety and efficacy. Jackson TL, Nicod E, Angelis A, Grimaccia F, 
Prevost AT, Simpson AR, Kanavos P. Retina. 2013 Nov-Dec;33(10):2012-7 
12. United Kingdom National Ophthalmology Database Study of Vitreoretinal Surgery 
Report 3, Retinal Detachment. Timothy L. Jackson, PhD, FRCOphth, Paul H.J. 
Donachie, MSc, Ahmed Sallam, PhD, FRCOphth, 
John M. Sparrow, DPhil, FRCOphth, Robert L. Johnston, FRCOphth. Ophthalmology 
2014;121:643-648 
13. The Royal College of Ophthalmologists’ National Ophthalmology Database Study of 
Vitreoretinal Surgery Report 6, Diabetic Vitrectomy. Timothy L. Jackson, PhD, 
FRCOphth; Robert L. Johnston, FRCOphth; Paul H. J. Donachie, MSc; TomH. 
Williamson, MD, FRCOphth; John M. Sparrow, DPhil, FRCOphth; David H.W. Steel, 
FRCOphth. JAMA Ophthalmol. 2016;134(1):79-85. doi:10.100 
14. United Kingdom National Ophthalmology Database Study of Vitreoretinal Surgery: 
Report 2, Macular Hole. Timothy L. Jackson, PhD, FRCOphth, Paul H. J. Donachie, 
MSc, John M. Sparrow, DPhil, FRCOphth, Robert L. Johnston, FRCOphth. 
Ophthalmology 2013;120:629–634 
15. The Royal College of Ophthalmologists’ National Ophthalmology database study of 
vitreoretinal surgery report 4, epiretinal membrane. Timothy l. Jackson, phd, 

 
 
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frcophth, Paul h.j. Donachie, msc, Tom h. Williamson, md, frcophth, John m. 
Sparrow, dphil, frcophth, Robert l. Johnston, frcophth. Retina 35:1615–1621, 2015 
 
This list is open to changes. 

 
 
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18. 
SAFETY REPORTING 
 
18.1 Definitions 
The definitions and reporting requirements adopted in this Clinical Investigation Plan (CIP) 
are based on the ISO 14155:2011 standard and the MEDDEV 2.7/3 – rev 3 guideline. 
 
18.1.1. 
Adverse Event (AE) 
An AE is any untoward medical occurrence, unintended disease or injury or any untoward 
clinical signs (including an abnormal laboratory finding) in subjects, users or other persons 
whether or not related to the investigational medical device. 
 
Note 1: This definition includes events related to the investigational medical device or the 
comparator. 
Note 2: This definition includes events related to the procedures involved. 
Note 3: For users or other persons, this definition is restricted to events related to 
investigational medical devices. 
 
18.1.2. 
Serious Adverse Event (SAE) 
A SAE is an adverse event that: 
 
a) led to death, 
b) led to serious deterioration in health of the subject, that either resulted in: 
- a life-threatening illness or injury, or 
- a permanent impairment of a body structure or a body function, or 
- requires in-patient hospitalization or prolongation of existing hospitalization, or 
- in medical or surgical intervention to prevent life threatening illness or injury or 
permanent impairment to a body structure or a body function, 
c) led to fetal distress, fetal death or a congenital abnormality or birth defect. 
 
Note: Planned hospitalization for pre-existing condition, or a procedure required by the 
CIP, without a serious deterioration in health, is not considered a serious adverse event. 
 
18.1.3. 
Adverse Device Effect (ADE) 
An ADE is an adverse event related to the use of an investigational medical device. 
 
Note 1: This includes any adverse event resulting from insufficiencies or inadequacies in 
the instructions for use, the deployment, the implantation, the installation, the operation, 
or any malfunction of the investigational medical device. 
Note 2: This includes any event that is a result of a use error or intentional misuse of the 
investigational medical device. 
 
18.1.4. 
Serious Adverse Device Effect (SADE) 
A SADE is an adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event. 
 
18.1.5. 
Unanticipated Serious Adverse Device Effect (USADE) 
An USADE is a serious adverse device effect which by its nature, incidence, severity or 
outcome has not been identified in the current version of the risk analysis report. 
Note: An anticipated serious adverse device effect (ASADE) is an effect which by its nature, 
incidence, severity or outcome has been identified in the risk analysis report. 

 
 
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18.1.6. 
Device Deficiency (DD) 
A DD is an inadequacy of an investigational medical device with respect to its identity, 
quality, durability, reliability, safety or performance. 
 
Note: This may include malfunctions, use errors, and inadequate labelling. 
 
 
18.2 Adverse Events that do not require reporting 
In general, the following should not be reported as AEs: 
 
• 
Pre-existing conditions, including those found as a result of screening (these should 
be reported as medical history or concomitant illness. 
• 
Pre-planned procedures, unless the condition for which the procedure was planned 
has worsened from the first trial-related activity after the subject has signed the 
informed consent. 
 
The following events are commonly observed and are therefore not considered as adverse 
events for the purpose of the trial: 
• 
Decreased visual acuity compared to preoperative measurement 
• 
Reddish eye 
• 
Moderately and temporarily increased ocular pressure (<35 mmHg) 
• 
Mild to moderate intra-ocular inflammation 
• 
Mild corneal edema 
All these event will be recorded in the patient’s medical notes according to routine practice. 
The following events not to be considered as SAEs are: 
• 
Pre-planned hospitalizations unless the condition for which the hospitalization was 
planned has worsened from the first trial-related activity after the subject has 
signed the informed consent. 
• 
Hospitalization as part of a standard procedure for protocol therapy administration. 
However, hospitalization or prolonged hospitalization for a complication of therapy 
administration will be reported as an SAE. 
• 
Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE. 
18.3 Recording and reporting of Adverse Events 
Investigators will seek information on AEs during each patient contact. All events, whether 
reported by the patient or noted by trial staff, will be recorded in the patient’s medical 
record and in the (e)CRF within a reasonable time after becoming aware. If available, the 
diagnosis should be reported on the AE form, rather than the individual signs or symptoms. 
If no diagnosis is available, the Investigator should record each sign and symptom as 
individual AEs using separate AE forms. 
The following minimum information will be recorded for each AE: 
- AE description 
 
- start and stop date of the AE 
 
- severity 

 
 
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- seriousness 
- causality assessment to the Investigational Medical Device (IMD) and/or study 
procedures 
- outcome 
For more information see Appendix A, B and C. 
18.3.1 
Assessment 
All AEs must be evaluated by an Investigator as to: 
 
• 
Seriousness: whether the AE is an SAE. See above for the seriousness criteria. 
 
• 
Severity: 
o 
Severity must be evaluated by an Investigator according to the following 
definitions: 
 
Mild – no or transient symptoms, no interference with the subject’s 
daily activities 
 
Moderate – marked symptoms, moderate interference with the 
subject’s daily activities 
 
Severe – considerable interference with the subject’s daily activities, 
unacceptable 
• 
Causality1: 
 
 
Not related 
Relationship to the device or procedures can be excluded when: 
- the adverse event is not a known side effect of the product category the 
device belongs to or of similar devices and procedures; 
- the event has no temporal relationship with the use of the investigational 
device or the procedures; 
- the serious event does not follow a known response pattern to the medical 
device (if the response pattern is previously known) and is biologically 
implausible; 
- the discontinuation of device application or the reduction of the level of 
activation/exposure – when clinically feasible – and reintroduction of its use 
(or increase of the level of activation/exposure), do not impact on the 
adverse event; 
- the event involves a body-site or an organ not expected to be affected by 
the device or procedure; 
- the adverse event can be attributed to another cause (e.g., an underlying or 
concurrent illness/clinical condition, an effect of another device, drug, 
treatment or other risk factors); 
- the adverse event does not depend on a false result given by the 
investigational device used for diagnosis, when applicable; 
- harms to the subject are not clearly due to use error; 
- in order to establish the non-relatedness, not all the criteria listed   above 
Unlikely 
The relationship with the use of the device seems not relevant and/or the 
adverse event can be reasonably explained by another cause, but additional 
information may be obtained. 
 
 
 
 
1 Guidelines on Medical Devices. Clinical Investigations: Serious Adverse Event Reporting Under Directives 
90/385/EEC/and 93/42/EEC; MEDDEV 2.7/3 revision 3; May 2015 

 
 
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Possible 
The relationship with the use of the investigational device is weak but cannot 
be ruled out completely. Alternative causes are also possible (e.g., an 
underlying or concurrent illness/clinical condition or/and an effect of another 
device, drug or treatment). Cases where relatedness cannot be assessed or 
no information has been obtained should also be classified as possible. 
Probable 
The relationship with the use of the investigational device seems relevant 
and/or the adverse event cannot be reasonably explained by another cause, 
but additional information may be obtained. 
Causal 
relationship 
The adverse event is associated with the investigational device or with 
procedures beyond reasonable doubt when: 
- the event is a known side effect of the product category the device belongs 
to or of similar devices and procedures; 
- the event has a temporal relationship with investigational device 
use/application or procedure; 
- the event involves a body-site or organ that 
- the investigational device or procedures are applied to; 
- the investigational device or procedures have an effect on; 
- the adverse event follows a known response pattern to the medical device 
(if the response pattern is previously known); 
- the discontinuation of medical device application (or reduction of the level 
of activation/exposure) and reintroduction of its use (or increase of the level 
of activation/exposure), impact on the event (when clinically feasible); 
- other possible causes (eg, an underlying or concurrent illness/clinical 
condition or/and an effect of another device, drug or treatment) have been 
adequately ruled out; 
- harm to the subject is due to error in use; 
- the event depends on a false result given by the investigational device used 
for diagnosis, when applicable; 
- in order to establish the relatedness, not all the criteria listed above might 
be met at the same time, depending on the type of device/procedures. 
 
 
18.3.2 
Timelines for reporting 
- 
After informed consent has been obtained but prior to first use of the IMD, only 
adverse events caused by a study specific procedure should be reported 
- 
After first use of the IMD, adverse events will be reported as follows: 
o 
All AEs, SAEs, AESIs and Device Deficiencies will be reported until 7 days 
after last use of IMD or until last follow-up visit (whichever occurs first) 
All SAEs and AESI as defined in the protocol must be reported to the principal investigator 
within 24 hours of the trial staff becoming aware of the event. The immediate report shall 
be followed by detailed, written reports. The immediate and follow-up reports shall identify 
subjects by code numbers. 
SAE details will be reported by the (sub-)investigator: 
• 
By completing the SAE form in the (e)CRF 
If an authorized Investigator from the reporting site is unavailable, initial reports without 
causality and expectedness assessment should be submitted to the Sponsor by a 
healthcare professional within 24 hours of becoming aware of the SAE, but must be 
followed-up by medical assessment as soon as possible thereafter. 

 
 
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18.3.3 
Follow-up 
The Investigator must record follow-up information by updating the patient’s medical 
records and the appropriate forms in the (e)CRF. The worst case severity and seriousness 
of an event must be kept throughout the trial. 
SAE follow-up information should only include new (e.g. corrections or additional) 
information and must be reported within 24 hours of the Investigator’s first knowledge of 
the information. This is also the case for previously non-serious AEs which subsequently 
become SAEs. 
• 
All SAEs must be followed up until the outcome of the event is ‘recovered’, 
‘recovered with sequelae’, ‘not recovered’ (in case of death due to another cause) 
or ‘death’ (due to the SAE) and until all related queries have been resolved, or until 
end of trial (whichever occurs first). 
• 
Non-serious AEs must be followed up until the patient’s last study visit, and until 
all related queries have been resolved. 
 
SAEs after the end of the trial: If the Investigator becomes aware of an SAE with 
suspected causal relationship to the IMD or experiment after the subject has ended the 
trial, the Investigator should report this SAE within the same timelines as for SAEs during 
the trial. 
 
 
18.3.4 
Death 
All deaths (unless defined under section ‘Adverse events that do not require reporting’ that 
deaths should not be reported for the trial as SAE) will be reported without delay to the 
principal investigator (irrespective of whether the death is related to disease progression, 
the IMD, study procedure or is an unrelated event). The principal investigator will notify 
all deaths as soon as possible after becoming aware to the Central EC and the EC of the 
concerned site and provide additional information if requested. 
 
18.4  Recording and reporting of Device Deficiencies 
Each Device Deficiency must be documented by the Investigator in the source 
documents and reported to the Sponsor on a Device Deficiency form (Appendix 
B). 
If the Device Deficiency leads to the occurrence of a (S)ADE, the (S)ADE must also be 
reported by the Investigator to the Sponsor on the appropriate forms and within the 
specified timelines. 

 
 
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18.5 Reporting requirements to Ethics Committee’s (EC’s) and Competent 
Authorities (CA’s) 
The Investigator is responsible for ensuring that all safety events are recorded in the 
(e)CRF and reported to the principal investigator in accordance with instructions provided 
below. 
The principal investigator will promptly evaluate all SAEs, AESIs and Device Deficiencies 
against medical experience to identify and expeditiously communicate possible new safety 
findings to Investigators, ECs and applicable CA’s based on applicable legislation. 
18.5.1 
Sponsor’s reporting of Serious Adverse Events and Device 
Deficiencies 
The sponsor (PI) is responsible to report to the EC’s and CA’s where the clinical 
investigation has commenced: 
- 
Any SAE, 
- 
Any Device Deficiency that might have led to a SAE if: 
a) Suitable action had not been taken or, 
b) Intervention had not been made or, 
c) If circumstances had been less fortunate 
- 
New findings/update in relation to already reportable events. 
These ‘reportable events’ must be reported within the following timelines: 
• 
an SAE which results in imminent risk of death, serious injury, or serious illness that 
requires prompt remedial action for other patients, users or other persons or a new 
finding to it must be reported immediately, but not later than 2 calendar days after 
awareness of a new reportable event or of new information in relation with an already 
reported event. 
• 
another SAE or a new finding/update to it must be reported immediately, but not later 
than 7 calendar days following the date of awareness of the new reportable event or 
of new information in relation with an already reported event. 
 
18.6 Annual reporting 
The sponsor (PI) has the obligation to, once a year throughout the clinical trial (or on 
request), submit a progress report to the EC’s and CA’s containing an overview of all SAEs 
occurred during the reporting period and taking into account all new available safety 
information received during the reporting period. 
 
 
 

 
 
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Appendix A: List of adverse events in eCRF (source document in Formasa)   
 
• 
Anterior segment surgery 
 
 
 
 
 
• 
Posterior segment surgery 
 
 
 
 
 

 
 
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Appendix B: List of device issues not leading to (S)AE recorded in the Formasa 
surgical report (and in the eCRF) 
 
 
 
 

 
 
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Appendix C: (S)AE Report form in eCRF (source document in Formasa)  
 
 

 
 
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Appendix D: Device deficiency report form in eCRF (source document in Formasa) 
 
 
 
 

 
 
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