A Prospective, Open-label, Multicenter Clinical Investigation to Assess the Safety and Performance of the ARGOS-IO System in Patients With Primary Open Angle Glaucoma (POAG)
Phase: NA
Conditions: Primary Open Angle Glaucoma (POAG)
Sponsor: Implandata Ophthalmic Products GmbH

 
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CONFIDENTIALITY NOTE 
The content of this document is confidential and proprietary to  
Implandata Ophthalmic Products GmbH 
Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
CLINICAL INVESTIGATION PLAN 
 
 
A prospective, open-label, multicenter clinical investigation to assess the 
safety and performance of ARGOS-IO system in patients with Primary Open 
Angle Glaucoma (POAG) 
 
 
 
Reference Number: ARGOS-02 
 
 
 
 
 
 
Revision: 
Rev. C 
Release Date: 
18-FEB-2014 
Sponsor: 
Implandata Ophthalmic Products GmbH 
Kokenstrasse 5 
30169 Hannover 
Germany 
 
Reviewed by
ingo.busch <ingo.busch@sacura-
cro.com>
(via e.tract - https://argos-02.e-tract.net)
Date: 2014.06.24 12:42:58 +0200

 
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Investigator Signature Page 
ARGOS-02 
A prospective, open-label, multicenter clinical investigation to assess the safety and performance of 
ARGOS-IO intraocular pressure sensor device in patients with Primary Open Angle Glaucoma (POAG) 
 
 
Investigator Statement 
I have read this protocol and agree to conduct this study in accordance with all stipulations of the 
Clinical Investigation Plan, any applicable standards for the conduct of clinical investigations with 
human patients, any requirements imposed by the responsible competent authority/ethics 
committee, any other applicable local, institutional or legal requirements and in accordance with the 
principles outlined in the Declaration of Helsinki. 
 
 
<Investigator Name> 
 
 
 
 
Signature  
 
Date 
 
 
Institution 
 
 
 
 
 
 
 
 
 
Institutional address / stamp 
 
 

 
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Responsibilities and Contact Information 
Sponsor 
Implandata Ophthalmic Products GmbH 
Kokenstrasse 5 
30159 Hannover, Germany 
Phone: +49 (0) 511 2204 2580 
Fax: +49 (0) 511 2204 2589 
 
Max Ostermeier, Managing Director 
mostermeier@implandata.com 
 
Stefan Meyer, Chief Technology Officer 
smeyer@implandata.com 
 
Jörg Breitkopf, Clinical Operations Manager 
jbreitkopf@implandata.com 
Coordinating Investigator 
Prof. Dr. med. Carl Erb 
Privatinstitut für angewandte Augenheilkunde 
Kleiststrasse 23-26 
10787 Berlin, Germany 
Phone: +49 30 2114862 
Email: glaukom.berlin@yahoo.de 
Country Lead Investigators 
Germany 
Prof. Dr. med. Hagen Thieme 
University Eye Clinic Magdeburg 
Leipziger Str. 44 
39120 Magdeburg, Germany 
Phone: +49 (0) 391 6713571 
Email: augenklinik@ovgu.de 
Investigational Sites 
A list of investigational sites is filed separately in 
the TMF. A final list will be shown in the clinical 
investigation report. 
 
Data Management and Statistics 
Prof. Dr. rer. nat. Ralf-Dieter Hilgers 
University Clinic Aachen 
Department of Medical Statistics 
Pauwelsstrasse 30 
52074 Aachen, Germany 
Phone: +49 (0) 241 8089359 
Email: rhilgers@ukaachen.de 

 
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Clinical Safety 
MDSS GmbH 
Schiffgraben 41 
30175 Hannover, Germany 
Phone: +49 (0) 511 6262 8630 
Fax: +49 (0) 511 6262 8633  
Email: info@mdss.com 
Data Safety Monitoring Board (DSMB) 
A list of members of the DSMB is filed 
separately in the TMF together with the DSMB 
charter. 
 
 

 
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SYNOPSIS 
Title 
A prospective, open-label, multicenter clinical investigation to assess the 
safety and performance of the ARGOS-IO system in patients with Primary 
Open Angle Glaucoma (POAG) 
Study Number 
ARGOS-02 
Sponsor 
Implandata Ophthalmic Products GmbH 
Name of IMD 
ARGOS-IO System 
The ARGOS-IO system is composed of the implant and its accessories: 
Implant: ARGOS-IO pressure sensor implant 
Accessories: 
MESOGRAPH reading device, 
Implant Injector and telemetric Multiline Connector 
Indication 
Patients with Primary Open Angle Glaucoma (POAG) and indicated cataract 
surgery 
Study Purpose 
The purpose of this study is to evaluate the safety and performance of the 
ARGOS-IO system in patients with POAG and indicated cataract surgery. 
Study Design 
This clinical investigation prospective, open-label, multicenter, single-arm 
clinical investigation will be conducted in two stages using a Simon two-stage 
design. Subjects will be enrolled as follows: 
First stage: 11 patients 
Second stage: 11 patients 
An interim analysis will be performed when the 11 patients of the first stage 
have completed their 3 month follow-up visits. The trial will be stopped if 2 
or more patients have experienced a serious adverse device events (SADE) 
at this time. Otherwise enrollment will be resumed and the trial continued 
until an additional 11 patients have been enrolled in stage 2 and received 
ARGOS-IO implants. A conclusion for safety will be made if in total no more 
than 2 of the total of 22 patients experience an SADE.  
Sample Size 
Considerations 
The primary aim of this study is to show “safety”, which will be evaluated 
based on the percentage of subjects who experience an SADE (= “non-
safety), as defined in the primary endpoints. 

 
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For the study as a whole, “safety” will be determined based on the following 
decision rule: if in stage 1 the non-safety event rate is greater than 25%, the 
trial will be stopped (type 1 error rate of 0.05). If the non-safety event rate is 
lower than 25%, the study will be continued into stage 2. It will be declared 
a success if the final non-safety event rate is less than 6% (type II error rate 
of 0.20) The calculation is based on a two-stage Simon design optimizing the 
minimum expected sample size with parameters α=0.05, β=0.20, p0 = 0.75, 
p1 = 0.94. 
Subject Population 
 
This study will enroll subjects with POAG and indicated cataract surgery until 
a maximum of 22 have undergone implantation with the ARGOS-IO pressure 
sensor. 
Study Objectives 
Primary Objectives 
Safety 
To evaluate the safety and tolerability of ARGOS-IO pressure sensor 
implantation by assessing the incidence of SADEs in the 3 months 
immediately following implantation. 
Performance 
To evaluate the limits of agreement between measurements with the 
Goldmann Applanation tonometry (GAT) and the ARGOS-IO system between 
day 30 through day 180. 
Secondary Objectives 
Safety 
 
To evaluate the safety and tolerability of ARGOS-IO pressure sensor 
implantation by assessing the incidence of adverse events and adverse 
device events between 3 months and 12 months following 
implantation. 
Performance 
 
To evaluate the performance of the ARGOS-IO system up to 12 months 
after implantation. 
Patient Selection 
Inclusion Criteria 
Eligible subjects must meet all the following inclusion criteria: 
1. Mentally competent and willing to provide written Informed consent 
2. Male or female aged ≥ 40 years ≤ 85 years on the day of screening 

 
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Female subjects of childbearing potential (not surgically sterilized or 
more than one year post-menopausal) must be willing to use adequate 
contraception throughout the trial and must have a negative pregnancy 
test (urine beta-hCG) within 24 hours prior to ARGOS-IO pressure sensor 
implantation. 
3. Diagnosis of primary open-angle glaucoma (POAG) including high 
pressure glaucoma (HPG), normal pressure glaucoma (NPG) and 
ocular hypertension (OH) as defined by the European Glaucoma 
Society guideline (Heijl, Traverso, & al, 2008) requiring regular IOP 
measurements 
4. Sufficiently controlled IOP 
5. Phakic eyes 
6. Only one eye per patient may be implanted with the ARGOS-IO 
implant 
7. Cataract surgery indicated. The medical indication for a cataract 
operation must be given irrespective of the study participation. 
Potential study patients will be solicited for participation in the 
clinical trial only after the patient has given consent to the cataract 
operation 
8. Pre-operative anterior chamber depth (ACD) ≥ 2.5 mm as measured 
from the corneal endothelium 
9. Axis length > 22 mm 
10. Endothelial cell density of the cornea ≥ 2000 cells/mm² 
11. Subjects able and willing to attend all scheduled visits and comply 
with all study procedures 
 
Exclusion Criteria 
Eligible subjects must not meet any of the following exclusion criteria: 
1. Any other type of glaucoma other than primary open-angle 
glaucoma as defined in inclusion criteria 3 
2. Severe POAG patients with a macular degeneration and visual field 
loss of -20dB or worse 
3. Exsudative age-related macular degeneration, instable macular 
degeneration 30 days prior to inclusion, or macular edema 
4. Retinal detachment 
5. Corneal diseases 
6. Diabetes mellitus 
7. Connective tissue diseases 
8. History or evidence of severe inflammatory eye diseases (i.e. uveitis, 
retinitis, scleritis) in one or both eyes within 6 months prior to 
ARGOS-IO implantation 

 
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9. Intraocular surgical procedure(s) within 6 months prior to ARGOS-IO 
implantation or any surgical procedure such as refractive eye surgery 
that can affect the assessment of IOP by Goldmann Applanation 
tonometry 
10. History of eye tumor 
11. Ocular disease other than glaucoma that may affect assessment of 
visual acuity and/or IOP by Goldmann Applanation tonometry 
(choroidal hemorrhage or detachment, lens subluxation, thyroid 
ophthalmopathy) 
12. Anterior chamber configuration that puts the subject at high risk to 
develop an angle closure glaucoma 
13. History of extensive keloid formation 
14. Severe dry eye syndrome 
15. Subjects who will need to undergo ancillary procedures in the study 
eye at the time of implantation or during the post-operative study 
period 
16. Any known intolerance or hypersensitivity to topical anesthetics, 
mydriatics, plaster or silicone (component of the device) 
17. Existence of other active medical eye implant and/or other active 
medical implants in the head/neck region 
18. Any contraindication for IOL implantation such as choroidal 
hemorrhage, concomitant severe eye disease, excessive vitreous 
loss, extremely shallow anterior chamber, microphthalmos, non-
age-related cataract, posterior capsular rupture, severe corneal 
dystrophy, untractable IOP, zonular separation, color vision 
deficiencies 
19. Severe generalized disease resulting in a life expectancy shorter than 
a year 
20. Any clinical evidence that the investigator feels would place the 
subject at increased risk with the placement of the device 
21. Currently pregnant or breastfeeding 
22. Participation in any study involving an investigational drug or device 
within the past 30 days or ongoing participation in a study with an 
investigational drug or device 
23. Patients who are not suitable for the study based on the surgeon’s 
evaluation 
24. Patients unable or unwilling to understand or comply with required 
study procedures 
25. Patients with psychiatric disorders influencing their judgement or 
autonomy 

 
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26. Subject and/or an immediate family member is an employee of the 
investigational site directly affiliated with this study, the sponsor or 
the contract research organization. 
27. Enrollment of the fellow eye in this clinical study 
Study Procedures 
Screening (SC) 
Consecutive potential subjects will undergo informed consent process up to 
28 days prior to surgery. Consenting subjects will be screened. Screening visit 
will include: 
 
Demographics 
 
Medical history 
 
Pregnancy tests for females of child-bearing potential 
General 
 
Optical biometry (IOL Master) 
 
Visual acuity (ETDRS) 
 
Perimetry 
 
Concomitant medication 
Anterior segment measurement 
 
Slit-lamp biomicroscopy 
 
Optical coherence tomography (OCT) 
 
Confocal Microscopy 
 
Gonioscopy 
Posterior segment measurement 
 
Biomicroscopy 
 
Optical coherence tomography (OCT) 
 
Fundus photography 
IOP measurement 
 
Goldmann Applanation tonometry (GAT) 
 
Surgery (V01) 
On day of surgery or one day prior to surgery, subjects will again be assessed 
for eligibility requirements including pregnancy testing for females of 
childbearing potential. Subjects who continue to meet eligibility 
requirements will undergo cataract surgery with ARGOS-IO pressure sensor 
implantation using the implant injector and standard clinical procedures. If it 

 
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becomes apparent during the surgery that the subject is not a suitable 
candidate for the ARGOS-IO pressure sensor implant, the cataract surgery 
will be carried out using standard of care and the subject removed from the 
study. 
At Visit 01, data will be collected regarding: 
General 
 
Implantation procedure questionnaire (surgeon) 
 
AE/ADE/SAE/SADE 
 
Concomitant medication 
 
Device deficiency 
 
Follow-up (V02 to V11) 
The follow-up period after surgery will consist of 10 visits (Day 1 until D360). 
The examinations performed at each visit are listed without mentioning the 
single visit in parentheses. Examinations that are carried out only at distinct 
visits are indicated in parentheses. The follow-up visits will include :  
General 
 
Optical Biometry (IOL Master) ( V09) 
 
Visual acuity (EDTRS) 
 
Perimetry (V07, V09, V11) 
 
External Eye Photography 
 
User acceptance questionnaire (patient) (V11) 
 
User acceptance questionnaire (investigator) (V11) 
 
AEs/ADEs, SAEs/SADEs 
 
Concomitant medication 
 
Device deficiency 
Anterior Segment 
 
Slit-lamp biomicroscopy 
 
Optical coherence tomography (OCT) (V07, V09, V11) 
 
Confocal Microscopy (V07, V09, V11) 
 
Gonioscopy (V07, V09, V11) 
Posterior segment measurement 
 
Biomicroscopy 
 
Optical coherence tomography (OCT) (V07, V09, V11) 

 
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 
Fundus photography (V07, V09, V11) 
IOP measurement 
 
Goldmann Applanation tonometry (GAT) 
 
ARGOS-IO system measurement 
Measurements will be performed in series of 1 GAT measurement 
followed by 3 consecutive measurements with the ARGOS-IO 
system, with not more than 10 minutes between the GAT and the 
ARGOS-IO system measurements of a single series and a minimum 
of 60 minutes between the end of the one series and the start of the 
next.  
At V02, V03 and V04 only GAT measurements will be made (at 
beginning and end of visit).  
At V06, V08 and V10 two series of measurements will be made (at 
beginning and end of visit).  
At visits V05, V07, V09 and V11 four series of measurements will be 
made. 
 
ARGOS-IO system self-measurement at home (Visit 05 to Visit 11) 
Data Analysis and 
Statistics 
Primary Endpoints 
Safety 
- 
Number of patients experiencing a device related SAE defined as any 
adverse event that both 
o Is considered by the Investigator to have a possible, probable or 
definite relationship to the device and  
o That meets any of the following criteria of a serious adverse 
event: 
 
Resulted in death, permanent damage or disability or a 
congenital anomaly 
 
Was life threatening 
 
Required hospitalization or intervention to prevent 
permanent impairment or damage 
Performance 
- 
Agreement between measurements made using GAT and the ARGOS-IO 
system from V05 (day 30) through V09 (day 180). If multiple ARGOS-IO 
system measurements have been made at time points for which paired 
GAT/ARGOS-IO system measurements are to be compared, the mean of 
the replicate ARGOS-IO system measurements will be used for 

 
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agreement evaluation. The agreement evaluation is based on the 
assumption, that the measurements are constant over the measurement 
period.  
Secondary Endpoints 
Safety 
- 
Incidence, nature, severity and seriousness of observed adverse events 
and adverse device events in the 3 months following implantation. 
- 
Incidence, nature, severity and seriousness of observed adverse events 
and adverse device events in the 6 months following implantation. 
- 
Incidence, nature, severity and seriousness of observed adverse events 
and adverse device events in the 12 months following implantation. 
Performance 
- 
Limits of agreement between measurements made using GAT and the 
ARGOS-IO system from V05 (day 30) through V11 (day 360). 
- 
Performance of the ARGOS-IO system after 6 months by means of 
incidence of observed device malfunctions. 
- 
Performance of the ARGOS-IO system after 12 months by means of 
incidence of observed device malfunctions. 
- 
User acceptance of the implantation procedure by means of evaluation 
of implantation procedure questionnaires (investigators). 
- 
User acceptance of the ARGOS-IO system at the investigational site by 
means of evaluation of investigator acceptance questionnaires 
(investigators). 
- 
User acceptance of the ARGOS-IO system at home by means of 
evaluation of patient acceptance questionnaires (patients). 
- 
Daily IOP self-measurement profiles (patients). 
 
Definition of the analysis populations 
The safety population comprises all subjects for whom ARGOS-IO pressure 
sensor implantation was attempted, whether or not the implantation was 
successful. In this clinical investigation the intention-to-treat (ITT) population 
comprises the same subjects as defined in the safety population. 
 

 
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Statistical analysis 
Safety analysis 
Incidence of SADE in the 3 month period immediately following implantation. 
The decision on safety follows the rule of the SIMON optimum two-stage 
design (parameters: α=0.05, β=0.20, p0 = 0.75, p1 = 0.94, minimize expected 
samples size). A corresponding 95% confidence interval will be given for the 
portion of SADE within the safety population. The confidence interval for the 
SADE rate will be calculated using the method proposed by Koyama (Koyama 
& Chen, 2008). These calculations will be based on the number of patients 
experiencing an SADE. 
 
Moreover, safety will be described in detail by frequency, seriousness, 
severity, nature and duration of events. Adverse events and the number of 
subjects reporting adverse events will be tabulated by system organ class 
and preferred terms. Adverse device events, device deficiencies and the 
number of subjects reporting adverse device events and device deficiencies 
will be tabulated by event/deficiency description. 
 
Performance analysis 
The Bland-Altman approach will be used to establish limits of agreement 
between the IOP measurements from GAT and the ARGOS-IO system within 
the ITT population. Two-sided 95% confidence intervals will be calculated 
accounting for repeated measurements based on the method proposed by 
Zou (2011). 
 
Other secondary performance endpoints will be analyzed by descriptive and 
explorative statistical methods. 
 
Interim Analysis 
An interim analysis to assess SADE will be performed, when the first 11 
patients have completed the 3 month follow-up visit.  
Safety Monitoring 
A data safety monitoring board (DSMB) will be established prior to 
enrollment of the first patient. The DSMB is to review the safety data, 
including SAEs/SADEs, on a regular basis and will advise on any changes 
required in the conduct this clinical investigation. The DSMB will also review 
the data of the interim analysis and give recommendations to the Sponsor to 
either continue the clinical investigation (with or without an amendment of 

 
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the clinical investigation plan) or to stop enrolment into the clinical 
investigation based on safety concerns. 
Data Collection 
Data will be collected using a paper-based Case Report Form (CRF). 
Study Duration 
The overall study duration for each individual patient is up to 13 months. 
Subjects will undergo screening for a maximum of 28 days prior to surgery 
and will be followed for 12 months afterwards.  
The overall recruitment period is expected to last 6 months. 
The estimated total duration of the study from first patient screened to last 
patient last visit is 21 months. 
 
 

 
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TABLE OF CONTENTS 
RESPONSIBILITIES AND CONTACT INFORMATION ...................................................................... 6 
SYNOPSIS ................................................................................................................................. 8 
TABLE OF CONTENTS .............................................................................................................. 18 
LISTINGS OF FIGURES AND TABLES .......................................................................................... 25 
2. 
ABBREVIATIONS AND DEFINITIONS .................................................................................. 26 
3. 
BACKGROUND INFORMATION ......................................................................................... 29 
3.1 
Glaucoma ............................................................................................................................... 29 
3.2 
Glaucoma Treatment ............................................................................................................ 29 
3.3 
Measurement of IOP ............................................................................................................. 29 
3.3.1 
Principle and Gold Standard .................................................................................................. 29 
3.3.2 
Available Devices ................................................................................................................... 30 
3.3.2.1 Direct Tonometers ................................................................................................................. 30 
3.3.2.2 Non-contact tonometers ....................................................................................................... 30 
3.3.3 
Limitations ............................................................................................................................. 31 
4. 
IDENTIFICATION AND DESCRIPTION OF THE INVESTIGATIONAL DEVICE ............................. 31 
4.1 
Summary description of the investigational device and its intended purpose..................... 31 
4.2 
Description of the investigational device including any materials that will be in contact with 
tissues or body fluids ............................................................................................................ 33 
4.3 
Details about the manufacturer of the investigational device ............................................. 34 
4.4 
Device and accessories identification ................................................................................... 34 
4.5 
Device accountability and storage ........................................................................................ 34 
4.6 
Necessary training and experience requirements ................................................................ 35 
4.7 
Description of any specific medical or surgical procedures involved in the use of the 
investigational device. .......................................................................................................... 36 

 
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5. 
JUSTIFICATION FOR THE DESIGN OF THE CLINICAL INVESTIGATION ................................... 37 
5.1 
Evaluation of pre-clinical testing/assessment ....................................................................... 37 
5.1.1 
In-vitro Testing ...................................................................................................................... 37 
5.1.1.1 Functional Testing ................................................................................................................. 37 
5.1.1.2 Biocompatibility and Cytotoxicity .......................................................................................... 37 
5.1.1.3 Sterilization Verification ........................................................................................................ 38 
5.1.1.4 Compatibility with other Medical devices and Examination methods .................................. 39 
5.1.1.5 Simulated Implantation in Enucleated Porcine Eyes ............................................................. 39 
5.1.2 
Animal Studies ....................................................................................................................... 39 
5.2 
Evaluation of clinical data ...................................................................................................... 40 
5.3 
Justification for Design and Evaluation Relevant to Use in Human Subjects ........................ 43 
6. 
RISK EVALUATION............................................................................................................ 45 
6.1 
Anticipated clinical benefits .................................................................................................. 45 
6.2 
Risk Management Process..................................................................................................... 46 
6.3 
Anticipated Adverse Device Effects associated with the ARGOS-IO sensor device and their 
control ................................................................................................................................... 49 
6.4 
Risks and Benefits associated with the participation in the clinical investigation ................ 52 
6.5 
Possible Interactions with Concomitant Medical Treatments .............................................. 53 
6.6 
Possible Alternative Treatments ........................................................................................... 56 
6.7 
Risk/Benefit Assessment ....................................................................................................... 56 
7. 
OBJECTIVES AND HYPOTHESES OF THE CLINICAL INVESTIGATION ...................................... 57 
7.1 
Objectives .............................................................................................................................. 57 
7.1.1 
Primary Objectives ......................................................................................................... 58 
7.1.1.1 
Safety ............................................................................................................................. 58 
7.1.1.2 
Performance .................................................................................................................. 58 
7.1.2 
Secondary Objectives ..................................................................................................... 58 
7.1.2.1 
Safety ............................................................................................................................. 58 
7.1.2.2 
Performance .................................................................................................................. 58 
7.2 
Primary and secondary hypothesis, to be accepted or rejected by statistical data from the 
investigation .......................................................................................................................... 58 

 
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7.3 
Claims and intended performance of the IMD to be verified ............................................... 58 
7.4 
Risks and anticipated adverse device effects to be assessed ............................................... 59 
8. 
DESIGN OF THE CLINICAL INVESTIGATION ........................................................................ 59 
8.1 
General Aspects ..................................................................................................................... 59 
8.1.1 
Description of the type of clinical investigation .................................................................... 59 
8.1.2 
Description of the measures to be taken to minimize or avoid bias .................................... 60 
8.1.3 
Primary and secondary endpoints......................................................................................... 60 
8.1.3.1 
Primary endpoints ......................................................................................................... 60 
8.1.3.2 
Secondary endpoints ..................................................................................................... 60 
8.1.4 
Equipment to be used to assess the clinical investigation variables and arrangements for 
monitoring maintenance and calibration ............................................................................. 61 
8.1.5 
Any procedures for the replacement of subjects .................................................................. 61 
8.2 
Investigational device(s) and comparator(s) ......................................................................... 61 
8.2.1 
Description of the exposure to the investigational device(s) or comparators, if used ......... 61 
8.2.2 
Justification of the choice of comparator ............................................................................. 62 
8.2.3 
Other medical devices or medication to be used ................................................................. 62 
8.2.4 
Number of investigational devices to be used ...................................................................... 62 
8.3 
Subjects ................................................................................................................................. 62 
8.3.1 
Inclusion Criteria .................................................................................................................... 62 
8.3.2 
Exclusion Criteria ................................................................................................................... 63 
8.3.3 
Discontinuation or Withdrawal Criteria ................................................................................ 65 
8.3.3.1 
Study stopping rules ...................................................................................................... 65 
8.3.3.2 
Screen Failures ............................................................................................................... 66 
8.3.3.3 
Premature subject withdrawal ...................................................................................... 66 
8.3.3.4 
Completed Subjects ....................................................................................................... 67 
8.3.3.5 
Subjects lost to follow-up .............................................................................................. 67 
8.3.3.6 
Pregnancy ...................................................................................................................... 67 
8.3.4 
Point of enrolment ................................................................................................................ 67 
8.3.5 
Total expected duration of the clinical investigation ............................................................ 68 
8.3.6 
Expected duration of each subject’s participation ................................................................ 68 
8.3.7 
Number of subjects required ................................................................................................ 68 

 
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8.3.8 
Estimated time needed to select the planned number of subjects ...................................... 68 
The estimated recruitment time is considered to be 3 months for the first stage of the study and 3 
months for the second. ......................................................................................................... 68 
8.4 
STUDY PROCEDURES ............................................................................................................. 68 
8.4.1 
Informed Consent .................................................................................................................. 68 
8.4.2 
Allocation of Patient Number ................................................................................................ 68 
8.4.3 
Methods and timing for assessing, recording, and analyzing parameters ........................... 69 
8.4.3.1 
Safety ............................................................................................................................. 69 
8.4.3.2 
Performance .................................................................................................................. 69 
8.4.4 
Assessments .......................................................................................................................... 70 
8.4.4.1 
Patient demographics/other baseline characteristics ................................................... 70 
8.4.4.2 
Medical history .............................................................................................................. 70 
8.4.4.3 
Pregnancy test ............................................................................................................... 70 
8.4.4.4 
Concomitant medication, treatments and devices ........................................................ 70 
8.4.4.5 
AEs/ADEs/SAEs/SADEs ................................................................................................... 70 
8.4.4.6 
Device Malfunctions ...................................................................................................... 71 
8.4.4.7 
Questionnaires ............................................................................................................... 71 
8.4.4.8 
Optical Biometry (IOL Master®) ..................................................................................... 71 
8.4.4.9 
Visual acuity (VA) ........................................................................................................... 71 
8.4.4.10 Visual field (Perimetry) .................................................................................................. 71 
8.4.4.11 External Eye Photography ............................................................................................. 72 
8.4.4.12 Anterior eye segment measurement ............................................................................. 72 
8.4.4.13 Gonioscopy .................................................................................................................... 72 
8.4.4.14 Posterior eye segment measurement ............................................................................ 73 
8.4.4.15 Intraocular pressure (IOP) measurement ...................................................................... 74 
8.5 
ARGOS-IO pressure sensor implantation .............................................................................. 75 
8.5.1 
IOL implantation ............................................................................................................ 75 
8.5.2 
ARGOS-IO pressure sensor implantation ....................................................................... 75 
8.5.3 
Concomitant medication and devices during surgical procedure ................................. 75 
8.5.4 
Concomitant medication after implantation ................................................................. 75 
8.5.5 
Concomitant therapy in case of inflammatory events after implantation .................... 75 

 
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8.6 
ARGOS-IO pressure sensor explantation, if medically necessitated ..................................... 75 
8.7 
Study Visits ............................................................................................................................ 76 
8.7.1 
Screening visit, SC (Day -28 to 0) ................................................................................... 76 
8.7.2 
Surgery, Visit 1 (Day 0) .................................................................................................. 77 
8.7.3 
Follow-up visits 02 to 04 (early post-surgical): days 1, 3 and 10 ................................... 78 
8.7.4 
Follow-up visits 05 to 11: days 30, 60, 90, 120, 180, 240 and 360 ................................ 78 
8.8 
Visit schedule and assessments ............................................................................................ 79 
9. 
STATISTICS ...................................................................................................................... 82 
9.1 
Statistical design, method and analytical procedures ........................................................... 82 
9.1.1 
Demographic and baseline characteristics .................................................................... 82 
9.1.2 
Patient Disposition......................................................................................................... 83 
9.1.3 
Safety Analysis ............................................................................................................... 83 
9.1.4 
Performance Analysis .................................................................................................... 83 
9.2 
Sample Size Calculation ......................................................................................................... 84 
9.3 
Level of significance and the power of the clinical investigation .......................................... 84 
9.4 
Expected drop-out rates ........................................................................................................ 84 
9.5 
Pass/fail criteria to be applied to the results of the clinical investigation ............................ 84 
9.6 
Interim analysis ..................................................................................................................... 84 
9.7 
Criteria for termination of the clinical investigation on statistical grounds ......................... 84 
9.8 
Procedures for reporting of deviations from the original statistical plan ............................. 85 
9.9 
Specification of Subgroups for Analysis ................................................................................ 85 
9.10 
Treatment of missing, unused and spurious data, including drop-outs and withdrawals .... 85 
9.11 
Datasets to be analyzed ........................................................................................................ 86 
9.11.1 Safety population .................................................................................................................. 86 
9.11.2 The Full-Analysis-Set (FAS) population .................................................................................. 86 
9.12 
Exclusion of particular information from the testing of the hypothesis ............................... 86 
9.13 
Number of subjects at each site ............................................................................................ 86 
10. DATA MANAGEMENT ...................................................................................................... 86 
10.1 
Site Monitoring ...................................................................................................................... 86 
10.2 
Data collection ....................................................................................................................... 87 

 
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10.3 
Database Management and Quality Control......................................................................... 87 
10.4 
Verification, validation and security of electronic data system ............................................ 87 
10.5 
Data retention and Retention period .................................................................................... 88 
10.5.1 Investigator Records Retention ............................................................................................. 88 
10.5.2 Sponsor Records Retention ................................................................................................... 88 
11. ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND DEVICE DEFICIENCIES ........................... 90 
11.1.1 
Definitions ...................................................................................................................... 90 
11.1.2 
Adverse Event (AE) ......................................................................................................... 90 
11.1.2.2 Serious Adverse Events .................................................................................................. 90 
11.1.2.3 Serious Adverse Device Effect (SADE) ............................................................................ 91 
11.1.2.4 Anticipated Serious Adverse Device Effect (ASADE) ...................................................... 91 
11.1.2.5 Unanticipated Serious Adverse Device Effect (USADE) .................................................. 91 
11.1.2.6 Device Deficiency ........................................................................................................... 91 
11.1.3 
Recording of Adverse Events (AEs) ................................................................................ 91 
11.1.4 
Reporting of Serious Adverse Events (SAEs) .................................................................. 94 
11.1.5 
Device Deficiencies ........................................................................................................ 95 
11.1.6 
Medical Care .................................................................................................................. 96 
11.1.7 
Safety monitoring .......................................................................................................... 96 
11.1.8 
Sponsor Responsibilities ................................................................................................ 96 
12. ADMINSTRATIVE PROCEDURES AND RESPONSIBILITIES .................................................... 97 
12.1 
Informed Consent .................................................................................................................. 97 
12.2 
Regulatory and Ethical Compliance ....................................................................................... 98 
12.3 
Approval from Ethics Committee or Regulatory Authority ................................................... 98 
12.4 
Investigator Responsibilities for Ethics Committees and Regulatory Authorities................. 99 
12.5 
Reporting responsibilities ...................................................................................................... 99 
12.5.1 
Investigator Reporting Responsibilities ......................................................................... 99 
12.5.2 
Sponsor Reporting Responsibilities .............................................................................. 100 
12.6 
Insurance ............................................................................................................................. 100 
12.7 
Amendments to the CIP ...................................................................................................... 100 
12.8 
Deviations from the CIP ....................................................................................................... 100 

 
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12.9 
Recording, Reporting, Analysis of CIP Deviations ............................................................... 101 
12.10 Corrective and preventive action and principal investigator disqualification criteria ........ 102 
12.11 Suspension or Premature Termination ............................................................................... 102 
12.12 Criteria for access to a breaking/masking code in the case of suspension or premature 
termination of the clinical investigation, if applicable ........................................................ 102 
12.13 Subject follow-up requirements .......................................................................................... 102 
12.14 Investigator and Site Selection ............................................................................................ 103 
13. PUBLICATION POLICY ..................................................................................................... 104 
13.1 
Study Report and Publication .............................................................................................. 104 
14. REFERENCES .................................................................................................................. 105 
 
 

 
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LISTINGS OF FIGURES AND TABLES 
Table 1. Combined Patient Months with the ARGOS-IO Implant ......................................................... 43 
Table 2. Levels of Severity used for Risk Assessment ........................................................................... 47 
Table 3. Levels of Probability used for Risk Assessment of ARGOS-IO system ..................................... 47 
Table 4. Risk Acceptability Matrix ......................................................................................................... 48 
Table 5. Recommended ARGOS-IO Implant Sizes ................................................................................. 73 
Table 6. Assessment Schedule .............................................................................................................. 80 
Table 7. Study design ............................................................................................................................. 82 
Table 8. Country-specific SAE reporting requirements ......................................................................... 94 
Table 9. Sponsor Reporting Responsibilities ......................................................................................... 96 
 
 
 

 
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2. 
ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definition 
α 
Type I error 
ACA 
Anterior Chamber Angle 
ACD 
Anterior Chamber Depth 
ADE 
Adverse Device Event 
AE 
Adverse Event 
AS 
Anterior Segment 
ASADE 
Anticipated serious adverse device effect 
ASIC 
Application specific integrated circuit  
β 
Type II error 
Beta-hCG 
Beta-subunit of human chorionic gonadotropin 
BfArM 
Bundesinstitut für Arzneimittel und Medizinprodukte 
C 
Celsius 
CA 
Competent Authority 
CIP 
Clinical Investigation Plan 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
D 
Day 
dB 
Decibel 
DCT 
Dynamic contour tonometry 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
EEPROM 
Electrically erasable programmable read-only memory 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EtO 
Ethylene oxide 
FAS 
Full-analysis-set 
GAT 
Goldmann Applanation Tonometry 
GCP 
Good Clinical Practice 
GDD 
Glaucoma Drainage Device 
HPG 
High pressure glaucoma 
IB 
Investigator’s Brochure 
ICD 
Implantable Cardioverter Defibrillator 
ICH 
International Conference on Harmonisation 
IFU 
Instruction for Use 

 
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IO 
Intraocular 
IOL 
Intraocular lens 
IOP 
Intraocular Pressure 
ISF 
Investigator Site File 
ISO 
International Organization for Standardization 
ITT 
Intention to treat 
KPro 
Keratoprosthesis 
LAL 
Limulus amebocyte lysate 
MD 
Macular degeneration 
MHz 
Megahertz 
Mm 
Millimeter 
mmHg 
millimeter(s) of mercury (a unit of pressure equal to the pressure that can 
support a column of mercury 1 millimeter high) 
MPG 
Medizinproduktegesetz 
MRI 
Magnetic resonance imaging 
N 
Sample number 
NCT 
Non-contact tonometry 
ND:YAG 
Neodymium doped yttrium aluminum garnet 
OCT 
Optical coherence tomography 
OH 
Ocular hypertension 
P 
Pressure 
p0 
Proportion of patients in stage 1 with positive outcome 
p1 
Proportion of patients overall with positive outcome 
PIC 
Patient informed consent 
POAG 
Primary open angle glaucoma 
PS 
Posterior Segment 
Rev. 
Revision 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SEM 
Scanning electron microscope 
SDV  
Source Data Verification 
T 
Tesla 
TMF 
Trial Master File 
V 
Visit 
VA 
Visual acuity 

 
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USADE 
Unanticipated serious adverse device effect 
WTW 
White-to-white 
 
 

 
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3. 
BACKGROUND INFORMATION 
3.1 
Glaucoma 
An estimated 1 in 40 adults over the age of 40 has glaucoma, a group of conditions that result in 
damage to the optic nerve head, is characterized by a progressive thinning of the retinal nerve fiber 
layer and the neuroretinal rim that appears as a central depression in the optic disc. It leads to loss of 
visual field and if not controlled eventually to blindness, of which it is the second most common cause 
worldwide (Quigley, 2011) (Mansouri & Shaarawy, 2011) (King, 2013). There are two types of primary 
glaucoma. In primary open angle glaucoma (POAG), which accounts for approximately 70% of the 
glaucoma cases seen, aqueous outflow from the eye is restricted, possibly due to increased resistance 
in the trabecular meshwork. In closed angle glaucoma, ocular tissue, usually the iris, obstructs the 
drainage pathway (King, 2013). 
3.2 
Glaucoma Treatment 
Glaucoma often remains asymptomatic until late in the disease, when irreversible vision problems 
become evident. Although it may be present with normal intraocular pressures (IOP), the higher the 
IOP, the more rapidly the damage progresses (Quigley, 2011). Reduction of IOP is the only known 
treatment, the main goal of which is the prevention of visual disability in the patient’s lifetime (King, 
2013). Lowering the IOP of patients with POAG by 20 to 40% can halve the rate of progressive damage 
(Quigley, 2011).  
IOP reducing treatments generally begin with eye drops containing prostaglandin analogues or ß-
adrenergic antagonists, although as in other chronic asymptomatic diseases, patient adherence to 
treatment is often poor. If eye drops do not satisfactorily reduce IOP, surgical methods such as laser 
trabeculoplasty or trabeculectomy to reduce production of intraocular fluid, or insertion of an artificial 
shunt into the anterior chamber to increase its drainage may be used (Quigley, 2011) 
3.3 
Measurement of IOP 
3.3.1 
Principle and Gold Standard 
Glaucoma generally develops slowly, with no obvious symptoms. For this reason the only way to 
determine if treatment is working is to monitor IOP regularly. The only method currently available to 
measure IOP directly requires the insertion of a large gauge needle into the eye and is rarely if ever 
used. Under normal clinical conditions, IOP is determined indirectly with one of numerous available 

 
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tonometer devices. Most of these are based on the Imbert-Fick principle that the force needed to 
flatten a defined area of a sphere is proportional to the pressure inside the sphere resisting the 
deformation (Frampton, 2012), (Kakaday, Hewitt, Voelcker, Li, & Craig, 2009). 
3.3.2 
Available Devices 
A number of different tonometric devices are available. These can be categorized based on whether 
or not they involve direct corneal contact. 
3.3.2.1 Direct Tonometers 
The Goldmann Applanation Tonometer (GAT) was first described in the 1950’s and is considered to 
this day to be the gold standard to which all other methods for measuring IOP are compared. It 
measures the force required to applanate the cornea by pressing a probe of defined area directly 
against it. The Perkins Tonometer is a hand-held tonometer that works on the same principles as the 
Goldmann Tonometer (Burr, et al., 2012).  
Dynamic contour tonometry (DCT) determines IOP by measuring the force required to mold the cornea 
to the shape of the concave probe (Frampton, 2012), while rebound tonometers calculate it from the 
induction current produced when a small plastic-tipped magnetized metal probe is bounced against 
the cornea (Burr, et al., 2012). 
The TonoPen is a hand-held portable tonometer that uses a transducer in its probe tip to measures 
the force required to applanate/indent the cornea, while the Ocuton S, another hand-held tonometer, 
requires direct contact of its prism with the cornea (Cihara, 2008). 
The Sensimed Triggerfish, a new system consisting of a micro-electromechanical strain gauge 
embedded in a disposable silicon contact lens, an adhesive antenna and a portable recorder, allows 24 
hour out-patient monitoring of changes in the diameter of the corneoscleral junction that results from 
changes in IOP (Mansouri & Shaarawy, 2011). 
3.3.2.2 Non-contact tonometers 
In non-contact (air-puff) tonometry (NCT) a rapid air pulse is used to applanate the cornea. Advantages 
to NCT include lack of direct contact with the eye and hence no need for anesthesia, and low/no risk 
of corneal abrasion or infection transmission. The probe of the Ocular Response Analyzer applies a 
slightly stronger force to actually indent the cornea and uses a pneumatic sensor to take two 
measurements, the force at which the cornea is applanated initially and the that at which it applanates 

 
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as it returns to normal. The difference between these two pressures is due to the viscous damping of 
the cornea (Frampton, 2012). 
In transpalpebral tonometry, IOP is calculated from the rebound of a free-falling rod as it hits the tarsal 
plate of the eyelid over the sclera (Burr, et al., 2012) 
3.3.3 
Limitations 
The accuracy of most of these devices is limited to the degree that the secondary biometric parameters 
they measure are affected by factors other than IOP, such as corneal thickness (Krug, Kompa, & 
Schrage, 2002). The majority of the direct tonometers require use of corneal anesthetics. The greatest 
limitation however is that almost all of the devices are cumbersome and require skill and training to 
use, which in effect limits their use to the clinic /office setting. 
The cost and inconvenience of the required office visits result in treatment decisions that are made 
based on only a few IOP measurements taken months apart. However fluctuations in IOP due to 
patient activity and circadian rhythm are normal. The level of imprecision in repeated IOP 
measurements has been estimated at +/- 5 mmHg, meaning that to be 95% certain there is any 
treatment effect, a difference greater than 7 mmHg must be seen between single pre- and post- 
treatment IOP levels (Rotchford & King, 2012). When 24 hour IOP profiles are taken, which require 
patients be admitted to the clinic, peak values – thought to be the most relevant for patient outcome 
in the long term – are seen outside of normal office hours in 80% of the cases, resulting in changes to 
treatment (Liang, Lee, & Shields, 2009) (Mansouri & Shaarawy, 2011). 
For these reasons, alternative methods are being sought that would allow more frequent IOP 
assessments in the home setting. 
According to company information, Sensimed Triggerfish measures a “profile of 24h ocular 
dimensional changes”, displayed in [arbitrary units], rather than changes in IOP in [mmHg]. To date, it 
is unknown how the measured changes in corneal curvature relate to IOP, especially in magnitude. 
4. 
IDENTIFICATION AND DESCRIPTION OF THE INVESTIGATIONAL DEVICE 
4.1 
Summary description of the investigational device and its intended purpose 
The ARGOS-IO system was developed for the wireless, contactless measurement of the hydrostatic 
pressure of the aqueous humor (IOP, intraocular pressure) in patients with diagnosed glaucoma, or 

 
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elevated or instable IOP that places them at a risk of ocular damage and loss of visual acuity. It is made 
up of four components: the ARGOS-IO implant, the external hand-held Mesograph reading device, the 
implant injector and the Multiline Connector. 
The ARGOS-IO implant is comprised of a micro-electromechanical system application specific 
integrated circuit (ASIC) bound to a micro-coil of gold and encapsulated in a silicone-rubber material 
that has been widely used for intraocular lenses. It is intended to be implanted during cataract surgery, 
and to remain in place indefinitely. The implant is introduced into the area between the intraocular 
lens and the iris (ciliary sulcus) using standard procedures that employ an implant injector similar to 
those commonly used to insert IOLs. 
Activation of the Mesograph reading device in the near vicinity of the eye establishes an inductive 
current between it and the micro-coil, thereby supplying the ASIC with power and permitting data 
transmission. Pressure-sensor cells and an A/D converter incorporated in the ASIC measure IOP directly 
and transmit the digitized data to the reader. When connected to the reader at the site or the patient’s 
home, the Multiline Connector uploads the data recorded by the reader to a secure dedicated data 
base that can be accessed remotely by the Investigator. Data is redundantly stored in non-volatile 
memory inside the reader device, preventing data loss in case of an error. 
Because the sensors are implanted in the eye, the ARGOS-IO pressure sensor measures IOP directly, 
without interference from corneal properties or due to operator skill. It enables numerous IOP 
measurements daily, providing a complete IOP profile for the entire interval between office visits, and 
allowing timely detection of both peaks due to patient activities and circadian rhythms and trends due 
to disease progression. It also permits easy patient self-monitoring, thereby providing patients 
immediate feedback on their IOP, which in turn should encourage adherence to the treatment 
regimen. 

 
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4.2 
Description of the investigational device including any materials that will be in 
contact with tissues or body fluids 
The ASIC and micro-coil components of the implant are hermetically encapsulated in a biocompatible 
silicone-rubber material (Nusil MED-6820) commonly used for ophthalmic implants. This layer of 
material: 
 
Forms a biocompatible, soft and atraumatic surface of the implant in order to avoid trauma to 
the tissues surrounding the implant 
 
Prevents and protects the patient from substances being washed out from the electronic 
module and leaking into the aqueous humor 
 
Provides a hermetic leak-proof seal around the electronic module, protecting it from the 
electrolytes and water contained in aqueous humor. 
In the event that the silicone coating were to become breached the patient may indirectly come into 
contact with the materials of the ASIC and the micro-coil as well. The sponsor commissioned a detailed 
risk assessment performed by NAMSA Advisory Services, Atlanta, USA to determine if these materials 
would pose any risk of an adverse biological effect to the patient. The materials under investigation 
comprised silicon, silicon dioxide, silicon nitride, gold, and traces of aluminum, titanium, phosphorus, 
arsenic, borium, polyimide and tungsten-titanium. The report states that all materials have been used 
previously within the eye and are considered to pose little if any risk (Cao, M, 2010). 
The implant is required to fit into the ciliary sulcus which is a relatively tight area in a phakic eye, but 
is deeper in the pseudophakic eye. The implant shape and profile is designed to: 
 
Be folded prior to implantation and to be manipulated through a relatively tight up to 5 mm 
corneo-scleral tunnel 
 
Not block the optical axis of the eye 
 
Avoid the IOL, although it may be in direct contact with parts of it 
 
Have a minimum profile and thickness 
 
Have rounded edges in order to avoid trauma when in long term contact with the surrounding 
tissue.  
The implant contains four haptics to maintain positional stability. In addition, the two haptics on either 
side of the ASIC act as a spacer to prevent the ASIC from being pressed into the surrounding tissue. 
Two flattened allantoid protrusions running from the bottom middle to the ASIC on the posterior 

 
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surface of the ring serve to facilitate unfolding of the implant after insertion into the eye, as well as to 
decrease force exerted on the ASIC by the ocular structures. 
The implant is packaged in multiple layers conforming to EN ISO 11607-1:2006 and then sterilized with 
ethylene oxide. 
4.3 
Details about the manufacturer of the investigational device 
The sponsor Implandata Ophthalmic Products GmbH is the manufacturer of the implant and the 
Mesograph reading device. The implant injector is manufactured by DEUTSCHMANN INSTRUMENTS, 
Germany. The Multiline Connector to transfer the data from the reading device to a secure customized 
database via GSM technology, is manufactured by Medscale systems GmbH. 
4.4 
Device and accessories identification 
Each ARGOS-IO pressure sensor implant will be identified by a unique 32-bit hexadecimal serial 
number stored in non-volatile memory on the ASIC. The reading device will be identified by a unique 
seven digit serial number. 
4.5 
Device accountability and storage 
The investigational team at each site is responsible for ensuring investigational device accountability 
throughout the course of the study in accordance with regulatory requirements. Upon receipt of the 
devices, the investigator or designee will check for accurate delivery and acknowledge receipt by 
signing and dating the documentation provided by the sponsor. A copy of the receipt will be retained 
in the Investigator Site File. 
Site staff will carefully record the serial number of each implant and reading device, as well as the ID 
number of the patient for which they were used, on the device accountability forms provided by the 
Sponsor. An accurate documentation of device accountability will be available for verification by the 
monitor at each monitoring visit. In addition, each patient will be given an implant pass identifying 
his/her device with type and serial number and listing further information including implantation date, 
sponsor contact information, implanting clinic and surgeon and warnings relevant to interactions with 
other medical procedures and devices as well as with metal detectors.  

 
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Investigational device accountability records will include: 
 Confirmation of Device delivery to the study site 
 Device inventory at the site 
 Device allocation to patients, including date of Device implantation, patient number and 
device identification number (serial number). 
The sponsor’s monitoring staff will verify that the study site’s device accountability records match the 
records of used devices recorded in the CRFs. 
The device must not be used for any purpose other than the present study. Unused devices will be 
returned to the sponsor at the end of the study period in accordance with the sponsor’s instructions. 
The investigator or authorized designee will alert the responsible monitor as soon as possible of any 
expected or potential shortage of devices during the study, so that the sponsor can organize the 
shipment of extra devices. Some extra devices will be provided in case any devices cannot be used. 
The investigational devices must be kept in a secure place with restricted access. The shelf life of the 
device is 6 months under temperature conditions ranging from 0° C to +60° C. 
4.6 
Necessary training and experience requirements 
It is assured that ophthalmic surgeons performing the surgery will be adequately trained on the 
ARGOS-IO pressure sensor implantation. Site personnel responsible for device handling including 
accountability, storage and shipment procedures will be trained during the initiation visit. If new site 
personnel are assigned during the study, they will be trained by the principal investigator or the 
monitor. 
Surgical implantation 
 
Only specially trained ophthalmic surgeons may perform the implantation. These surgeons 
must be made familiar with the handling and implantation of the ARGOS-IO pressure sensor 
either by special training through Sponsor representatives or by consultation of the User 
Manual, provided as a separate document. 

 
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Intraocular pressure measurement using the Mesograph Reading Device: 
 
Intraocular pressure (IOP) measurement may be carried out by any trained individual including 
patients and assistants. Health care professionals will be trained by sponsor representatives 
or their delegates. Trial staff will instruct patients on the use of the reading device for IOP self-
measurement at home at visit 05. Patients will also be given separate written handling 
instructions provided by the Sponsor.  
Setup of reading device, downloading of measurement data: 
 
Only specially trained site personnel may set up the reading device or download data from it. 
Special attention must be paid to maintaining data protection in this connection. Training will 
be provided by Sponsor representatives. 
Evaluation of data: 
 
The data obtained by the ARGOS-IO system measurement will only be used for the evaluation 
of the trial outcome. The ophthalmologist will use only the IOP measurements made with GAT 
for diagnosis, therapeutic assessments and decisions about additional medical treatments. 
4.7 
Description of any specific medical or surgical procedures involved in the use of 
the investigational device. 
Ophthalmic surgeons should perform the cataract surgery according to their local routine working 
procedures for cataract surgery. The implantation of the ARGOS-IO pressure sensor should occur 
according to the training received prior to any surgery given by the Sponsor.  
Detailed implantation instructions are presented in the Instructions for Use (IFU) (Implandata 
Ophthalmic Products GmbH, 2014) and the Investigator’s Brochure (IB) (Implandata, 2014). 

 
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5. 
JUSTIFICATION FOR THE DESIGN OF THE CLINICAL INVESTIGATION 
5.1 
Evaluation of pre-clinical testing/assessment 
5.1.1 
In-vitro Testing 
5.1.1.1 Functional Testing 
The ARGOS-IO pressure sensor is intended to remain permanently implanted and as such must retain 
accuracy and precision indefinitely. Six devices were subjected to simulated physiological conditions 
and assessed using calibrated lab reference sensors over the entire absolute pressure and temperature 
range. The sensor was found to have an initial drift of less than 3 mmHg per year that stabilized over 
time, a pressure accuracy of +/- 1.32 mmHg, and a temperature accuracy of +/- 0.14°C. Aging had no 
significant impact on the device (Görtz, M, 2010). 
The system has been tested (01-RE-18-A) for safety in accordance with the relevant standards (ASTM F 
2052 (Displacement), F 2182 (Heating), F2119-07 (Artifacts) by means of magnetic resonance 
tomography (MRT) devices and found to be safe in MRT with a magnetic field strength up to 3 T. It is 
unlikely that there is a danger in MRT devices with higher field strengths; the manufacturer is to be 
contacted if an examination in such a device should be necessary.  
For similar applications it was shown that an embedding of electronic components for implantation in 
the human body in the manner of the ARGOS-IO implant allows a stability of > 20 years (Donaldson, 
1991). 
Since the implant’s mechanical and thermal stress after the implantation is regarded as minimal, it is 
assumed that a lifespan of > 10 years is achievable. 
5.1.1.2 Biocompatibility and Cytotoxicity 
The ARGOS-IO implant is intended to be permanently implanted and as such will have constant contact 
with tissue and tissue fluid. The three individual components of the implant (encapsulation, ASIC and 
micro-coil) as well as the complete implant were tested for biocompatibility and cytotoxicity.  
The encapsulation material, MED-6820 silicone, which forms a hermetic seal around the ASIC and 
micro-coil, is the only component with which tissues are intended to have contact. This material has 

 
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been used for years in the manufacture of intraocular implants. The manufacturer, Nusil Silicone 
Technologies has tested the material for cytotoxicity, sensitization, acute intracutaneous reactivity, 
acute systemic toxicity, material mediated pyrogenicity, genotoxicity and implantation. The material 
was found to be non-toxic, non-sensitizing, non-irritating, non-pyrogenic and non-mutagenic. 
Carcinogenicity tests were deemed to be unnecessary because the Ames test for genotoxicity was 
negative and the material has been in use for so long. More detail can be found in the IB and the 
Master Access File provided by Nusil. 
In the event that the MED-6820 coating becomes breeched, the patient will be exposed indirectly to 
the materials making up the ASIC and the micro-coil. The consultancy NAMSA Advisory Services 
performed an analysis of the risks posed by exposure to the materials contained in these components 
(silicon, silicon dioxide and traces of silicon nitride, gold, aluminum, titanium, phosphorus, arsenic, 
borium, polyimide and tungsten-titanium) and found that all been used previously in the eye and 
would pose little risk of adverse biological effects. Additional detail can be found in the IB and the 
NAMSA report (Cao, M, 2010). 
The Sponsor conducted cytotoxicity testing according to ISO 10993-5 on the device as a whole 
(ISO10993). No relevant cytotoxicity was found with the device in direct or indirect cell contact 
(Niedhart, C; Müller, U, 2011).  
5.1.1.3 Sterilization Verification 
Encapsulation and packaging of the implants are carried out under monitored clean room conditions 
by Mecora GmbH, an ISO 13485 certified contract manufacturer.  
Once packaged, the devices are transferred to a second ISO certified manufacturer, Sterigenics 
Germany GmbH, where they undergo ethylene oxide sterilization according to EN ISO 11135-1:2007 
and AAMI TIR16:2009 requirements. Various tests have been performed on the EtO sterilized product: 
 
Residual EtO analysis (ISO 10993-7:2008/DIN EN ISO 10993-7:2009) 
 
Product sterility testing (ISO 11737:2006) 
 
Bioburden testing (ISO 11737:2006) 
 
Endotoxin (LAL) testing: additional test that has been implemented for the last small batch 
release process (ISO 11979-8:2006). 

 
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To date, small batch release process was conducted according to ISO 11737-1:2006 on 4 consecutive 
batches and no contamination was found (Sterigenics). 
5.1.1.4 Compatibility with other Medical devices and Examination methods 
The influence of silicone oil, which can be utilized in surgical interventions on the retina as a temporary 
tamponade, on the ARGOS-IO implant was examined (Investigator’s brochure, 01-RE-17A). Small 
quantities of silicone oil can find their way into superficial layers of the sensor encapsulation under 
certain circumstances. The influence of silicone oil on the sensor is slight, but it is recommended to 
review the sensor measurement in comparison with an alternative IOP measurement method. This 
fundamentally applies to any ocular intervention.  
An implantation of a glaucoma drainage device (GDD) may not be possible in the standard method 
(see document 01-RE-09A in the IB). In such cases the investigator must be contacted before the 
intervention. 
The investigator must be contacted before any surgical ocular intervention.  
5.1.1.5 Simulated Implantation in Enucleated Porcine Eyes 
The effects of implantation were tested on 5 devices, which underwent functionality testing before 
being implanted in freshly enucleated porcine eyes using the same techniques, including folding, 
intended for the implantation of the device in humans, again after implantation using standard 
implantation procedures, and after removal through dissection and storage under physiological 
conditions for at least 14 days, at which time they were also examined microscopically and via SEM. 
There were no measureable deterioration in the device performance and no signs of any damage to 
either the sensors or the surface of the devices (Dreher, WF; Kern, N; Warres, C, 2010). 
5.1.2 
Animal Studies 
In conjunction with removal of the natural crystalline lens, Todani et al (Todani, et al., 2011) implanted 
transducers in either the ciliary sulcus (5 eyes) or the vitreous cavity (1 eye) of 6 rabbits eyes and 
subjected a 7th rabbit to sham. All 7 rabbits showed transient, mild anterior chamber inflammation 
consistent with the procedure in the initial post-surgical period. No signs of toxicity or intolerability 
were seen over a follow-up of up to 25 months, including in histological examination of 2 eyes 
enucleated at 5.5 and 20 months. Two devices showed a downward drift. In one of these, a sudden 

 
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downward drift of 2 mm Hg per month that resolved when manometry was performed on the eye was 
seen approximately 1 year after implantation. A second device showed a sudden drop in readings at 
approx. 1.5 years, but remained stable in comparison to pneumotonometry. IOP measurements with 
the transducers otherwise showed good repeatability as well as good agreement with measurements 
made by direct manometry (Todani, et al., 2011).  
In an additional study involving one rabbit from the above mentioned study, an antenna combined 
with a motion detector was employed to permit reliable IOP readings to be made without human 
involvement (Paschalis, et al., 2014). 
5.2 
Evaluation of clinical data 
To date, nine patients have been implanted with the ARGOS-IO pressure sensor. 
In a case study performed at the Beirut Eye Specialist Hospital, Lebanon, in cooperation with the 
Boston Eye Group, USA, lasting from June 2011 to June 2012, the ARGOS-IO pressure sensor was 
implanted in the ciliary sulcus of a 66 year old woman following phacoemulsification of the cataract 
and “in-the-bag” implantation of a Rayner 620 plate haptic IOL. Following an unsuccessful attempt to 
place the implant in the anterior chamber, the first implant was removed and replaced with a second, 
which was placed directly in the sulcus space with the sensor side towards the cornea. Post-operative 
recovery was normal, with no persistent intraocular inflammation, pigment dispersion or angle 
narrowing. YAG capsulotomy was required at weeks 6 and 31. Good concordance with GAT was 
observed, with a p-value of 0.527 found using the Brown-Forsythe test. A wide range of IOP values 
were obtained during office hours (16.7 to 31.5 mmHg), at home (12.2 to 43.5 mm Hg), as well as 
during a 4-day period of nocturnal measurements (1.5 to 33.1mmHg). At the patient’s last site visit in 
December 2012, 18 months following implantation, the sensor continued to function properly. No 
deficiencies or adverse effects were noted at this time. At the end of 2013, approximately 30 months 
post-implantation, the patient’s attending ophthalmologist reported that the sensor remained in situ 
and continued to function (Melki, Todani, & Cherfan, 2014).  
In a case study conducted from May 2009 to May 2011 at the Santo Domingo Centro Láser, Dominican 
Republic, in cooperation with the Boston Massachusetts Eye and Ear Infirmary (Harvard Medical 
School), USA, the ARGOS-IO pressure sensor was implanted in conjunction with a Boston 
Keratoprosthesis Type I (which prevents IOP measurement using available instruments) and corneal 
grafts in two male patients, aged 18 (patient I) and 23 (patient II), who had severe corneal scarring 

 
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with fluctuating vision and poorly controlled secondary glaucoma (frequently reported in patients 
qualifying for KPro implantation) resulting from severe ammonia burns. Following extracapsular 
cataract extraction, the ARGOS-IO pressure sensor was implanted into the ciliary sulcus, after which a 
Boston KPro Type I keratoprothesis device was implanted in a carrier corneal graft to replace the 
central opaque cornea. Topical antibiotic treatment was instilled and a soft lens applied, after which 
the eye was patched and shielded. Postoperative medication for both patients included topical 
antibiotics, steroids and anti-glaucoma medication. Both patients showed only the post-operative 
reactions known for Boston KPro implantation. These post-operative reactions gradually subsided over 
1-2 months on standard doses of topical antibiotics and steroids. Subsequently, no cells in the anterior 
chamber, retroprosthesis, epi-retinal membrane or retinal detachment were identified. 
At day 1 Patient I had a visual acuity of 20/200. At one week after surgery, the visual acuity improved 
to 20/30 and after one month all postoperative signs of inflammation had resolved. After four months 
post-surgery, this patient’s IOP increased over 40 mmHg despite aggressive anti-glaucoma medication 
treatment. An Ahmed drainage device was then implanted, which significantly lowered the IOP. After 
5 months, the visual acuity was 20/70 and no signs of inflammation were detected. IOP remained 
between 20-25 mmHg despite topical medication. Gradual opacification of the posterior capsule 
developed and necessitated YAG laser capsulotomy after 22 months. After 24 months, visual acuity 
was 20/60 and there was no evidence of inflammation in the anterior chamber. 
In patient II, vision remained at only light perception despite clear media after surgery. One month 
after surgery, all signs of inflammation had resolved. IOP remained consistently high, which resulted 
in an Ahmed drainage device implantation after 8 months. IOP could be reduced for some time, but 
the glaucoma damage was considered end-stage. The ARGOS-IO system IOP readings appeared very 
reasonable and promising when compared to finger palpation. Peaks in IOP were detected in a timely 
manner, facilitating the adjustment or initiation of medical treatments or medical procedures. To date, 
both patients are still implanted with the ARGOS-IO pressure sensor and functionality is checked at 
regular hospital visits. (Lopez, Melki, & Dohlmann, 2013).  
In a pilot study (ARGOS-01) performed at the University Eye Clinic Aachen, Germany, lasting from 2011 
to 2013 (last patient out 28 November 2013), six glaucoma patients (2 normal pressure glaucoma, 4 
POAG; 2 male; mean age 73 years) received an ARGOS-IO implant in their ciliary sulcus in conjunction 
with phacoemulsification and IOL implantation for cataract. 

 
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In the first week following surgery, all patients showed signs of trauma to the anterior chamber in the 
form of 
 
Mild to moderate conjunctival irritation and corneal edema (all patients) 
 
Mild (1 patient), moderate ( 1 patient) or major (4 patients) anterior chamber cells 
 
Minor (3 patients) moderate (1 patient) or major (3 patients) Tyndall flares 
During this week, five patients also had fibrin reactions (two major, three minor), two of which were 
associated with hypopyons < 1mm. Samples were taken from two patients were both found to be 
sterile. All five patients were treated with topical steroids and antibiotics. The patients experiencing 
sterile hypopyons were also treated with systemic steroids and antibiotics following standard 
procedures. All patients recovered without sequelae by day 21. Because the inflammation in all cases 
cleared quickly and did not return, as would have been expected if it was a reaction to the implant 
itself, it was concluded by the DSMB that the reaction was most likely caused by the operational 
procedure. On the basis of this information, the DSMB concluded that the implantation and use of the 
ARGOS IO pressure sensor in further study patients is justifiable (Implandata, 2013).  
In addition, one participant had minor Descemet folds at day 3 to 7, and another both mild pigment 
dispersion and endothelial sediment at days 1-3 and 4-7. With the exception of two patients who 
continued to have mild to moderate corneal edema and conjunctival irritation throughout the study, 
these symptoms abated in all other patients before day 28. Two isolated incidents of conjunctival 
irritation and corneal edema and one of anterior chamber cells were seen at individual visits later in 
the study. Other adverse effects observed included transillumination (two patients), pigment 
dispersion (five patients), pupil distortion (five patients, flattening of the anterior chamber (three 
patients) and posterior lens opacification (three patients). 
There were no apparent changes in corneal thickness or endothelial cell density as measured with 
Pentacam and Confoscan, respectively. The anterior angle was found to be open to the ciliary body in 
all patients at all gonioscopy examinations. Anterior synechiae were noted in one patient at 12 months 
(Implandata, 2014). 
To date, nine patients have been successfully implanted with the earlier ARGOS-IO implant design, 
with which there is to date a combined 279 patient-months experience. 
 
 

 
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Table 1. Combined Patient Months with the ARGOS-IO Implant 
Study 
Combined patient months 
Case study (Lebanon): ARGOS-IO (n=1) 
57 
Case study (Dominican Republic): Boston KPro + ARGOS-IO (n=2) 
89 
Pilot study (Germany): ARGOS-IO (n=6) 
133 
Total combined patient months 
279 
 
5.3 
Justification for Design and Evaluation Relevant to Use in Human Subjects 
If it is demonstrated to be safe and reliable in humans, the ARGOS-IO system would offer several 
valuable advantages to current devices for the measurement of IOP: 
 
Frequent measurements in the patient’s daily environment 
 
Complete IOP profile upon which to base treatment decisions, as opposed to single IOP 
measurement every 3 months 
 
Detection of peaks and trends 
 
Ability of patient to self-monitor, with accompanying increase in motivation to adhere to 
treatment 
The device has been shown to be well tolerated and to have good agreement with manometry in 
rabbits, with use durations ranging up to four years (Todani, et al., 2011). Once implanted, it was easily 
used, and has even been employed together with a motion detector to permit reliable IOP readings to 
be made without human involvement in laboratory animals (Paschalis, et al., 2014).  
In an initial case study, a single POAG patient received an earlier ARGOS-IO implant, which then was 
followed for 18 months. The IOP measurements obtained in this patient with the ARGOS-IO system 
showed a good agreement with those obtained using GAT at the same time points. With the exception 
of posterior opacification that required two YAG capsulotomy procedures to correct, no significant AEs 
were reported. This incident could also have been a result of the normal cataract surgery with IOL 
implant (Melki, Todani, & Cherfan, 2014) 
Two patients who received an earlier ARGOS-IO implant in conjunction with a Boston Keratoprosthesis 
Type 1 in a carrier corneal graft, showed no significant AEs. IOP measurements obtained with the 

 
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ARGOS-IO system demonstrated reasonable IOP comparability when compared to finger palpation in 
these patients in whom use of alternative tonometry methods were not possible. Peaks in IOP could 
be detected timely, permitting medical treatments and procedures to be adjusted or initiated. 
In a recently completed early feasibility study (ARGOS-01), six glaucoma patients (4 POAG and 2 NPG) 
at a single university eye clinic in Germany had an earlier version of the ARGOS-IO pressure sensors 
implanted in the ciliary sulcus concomitantly to cataract surgery. Promising concurrence was seen 
between IOP profiles obtained with ARGOS-IO, GAT and DCT over the 12 months follow-up period and 
the ARGOS-IO system was easily used by the patients in the home setting. However, after two fibrin 
reactions classified as procedure-related SAEs were observed, as were multiple adverse events 
possibly caused by the size and/or form of the implant, the sponsor stopped the study to investigate 
the cause.  
Analysis of an extensive databank of eye MRIs, obtained from MRI Research Inc., a company supported 
by the American National Institute of Health National Eye Institute, demonstrated that the ciliary 
sulcus undergoes a distortion in the first months following cataract extraction. This distortion, which 
is extenuated by the use of single piece IOLs such as those received by all patients in the ARGOS-01 
study, caused a radial force to be exerted on the ARGOS-IO pressure sensor. In vitro testing was then 
conducted using a tool specially designed to mimic such pressure in a controlled manner. It was 
determined that when exposed to such force, the original ARGOS-IO pressure sensor prototype 
produces aberrant pressure readings and develops a curvature in its horizontal plane.  
As a result of these tests and the ARGOS-01 study, modifications were made to the form of the device 
and the implantation procedure to improve the device’s safety profile. The implant thickness was 
reduced from 0.9 mm to 0.5 mm overall, tapering to a rounded outer edge of only 0.1 mm, and haptics 
were added to the device to better maintain its positional stability and to reduce mechanical stresses 
of the sensor on the eye. In addition, four haptic arms and two allantoid protrusions on the posterior 
surface of the ring were added to the ring to improve its positional stability, facilitate unfolding and 
better distribute pressure on the ring. When subjected to radial force, the redesigned sensor ring did 
not show the abnormalities in pressure readings or the plane distortions seen in the earlier version.. 
The implant is also now available in three different diameters to allow selection of the implant size 
that best fits the individual participant. Related procedural changes, including the use of a cartridge 
injector similar to those used to insert foldable IOLs to insert the implant and first use of the sensor at 
30 days post-surgery instead of at day 1 to 3 as in the previous study, are expected to reduce potential 

 
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stress to the patients’ anterior chambers during surgery and the initial post-surgical period. Together, 
these changes are expected to reduce irritation of the iris and pressure drifting observed in the 
ARGOS-01 study.  
Due to the unique form of the human eye, and the exacting nature of the fit, it is not possible to assess 
the effects of the design modification in animals.  
At this point further clinical investigations are required to assess the safety and performance of the 
modified ARGOS-IO system. It should become apparent in the first stage of this study if these changes 
were sufficient to reduce the rate of inflammatory reaction. If as anticipated the investigation is 
successful, an innovative device will be made available that will permit easy measurement of IOP on a 
daily basis in the hospital, at the ophthalmologist and/or at home. This in turn will permit more 
frequent and exacting adjustments to treatment, thereby slowing disease progression and the 
blindness that accompanies it. 
6. 
RISK EVALUATION 
6.1 
Anticipated clinical benefits 
Reduction of IOP is to date the only proven therapy for glaucoma (Quigley, 2011). Improved control of 
IOP is linked to better long-term outcomes for glaucoma patients (King, 2013). Most of the currently 
available methods to measure IOP require office or clinic visits and are not feasible for frequent, round-
the-clock or continuous use or for use in the patient’s daily environment. At the same time, IOP 
fluctuates as a result of the patient’s daily activities and circadian rhythm. Peak values – which are 
thought to be the most significant for long-term outcomes – are often not detected. Under normal 
clinical conditions for example in Germany, IOP of patients with diagnosed glaucoma is measured only 
once every 3 months, which does not provide enough information to adequately adjust patient 
treatment. The ARGOS-IO system will make numerous IOP measurements every day on a permanent 
basis, requiring only that the patient hold the external reader near the eye to activate the implant and 
download the readings several times daily. The physician is able to access the readings so recorded, 
thereby obtaining a complete profile of IOP changes, including peak values and values as influenced 
by all patient activities, for the entire time interval since the last treatment visit.  

 
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One objective of this study is to verify the device’s accuracy in the patient population. Until this is done, 
only the control readings made via GAT will be used as the basis for treatment decisions. Study patients 
will however benefit from a more intensive than normal monitoring of their IOP during the study and 
are enabled to measure IOP daily themselves between D30 and D360. If and when the device’s 
usefulness has been verified, the patients and the general patient population will benefit from the 
increased insight gained from a continuous long-term monitoring of IOP independent from visits to the 
ophthalmologist. If the device proves successful, the Sponsor plans to develop an internet platform 
that will permit the physician to remotely access information from individual readings, allowing 
patients’ IOP to be monitored between visits. This should permit a more rapid response to changes in 
IOP and a better fine-tuning of treatment protocols. 
Because glaucoma progresses slowly and does not generally cause any immediate symptoms, patients 
have no way of registering the success or failure of their treatment between clinic visits. As a result, as 
with other chronic diseases, adherence to prescribed treatment regimens may be poor (Hermann, 
Bron, & Creuzot-Garcher, 2010). The consequences of poor IOP control are however serious and 
irreversible loss of vision and accompanying handicap. The frequent feedback the patient will receive 
from the device is expected to motivate better compliance with the treatment regimen, thereby 
facilitating improved IOP control and optimizing long-term patient outcome. 
6.2 
Risk Management Process 
Potential risks related to the intended use and foreseeable misuse of the ARGOS-IO system are 
identified and mitigated on an ongoing basis according to the risk management analysis prescribed by 
ISO 14971:2012 in combination with ISO/TR 24971: 2013 and detailed in the document ARGOS-IO 
Implant: Risk Management Report (01-RE-00D). The analysis is updated at least once annually, 
including the specific time points: before the start of the clinical investigation of the device, at the 
completion of the first phase of the study, at each interim analysis and whenever significant new 
information regarding the risk profile or AEs becomes available. Risks were identified based on a list of 
questions contained in Annex C of ISO 14971:2012, information and data obtained from published 
standards, scientific technical data, field data from similar devices already in use, clinical and preclinical 
evidence, results of appropriate investigations and expert opinion.  

 
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The sources listed above were also used to assign rankings for severity of possible harms and 
probability of occurrence for each identified risk. The rankings used are defined in Table 2 and Table 
3, respectively. 
 
Table 2.  Levels of Severity used for Risk Assessment 
Level of 
Severity 
Possible Harm 
 
1 
No harm 
 
2 
Very brief, harmless discomfort 
 
3 
Short term discomfort 
 
4 
Minor damage or disablement, no expert medical intervention required 
 
5 
Minor damage or disablement, that may require expert medical intervention 
 
6 
Slight damage or disablement that requires expert medical intervention 
 
7 
Temporary damage or marked disablement that requires expert medical intervention 
 
8 
Permanent damage or disablement without further disease 
 
9 
In combination with the diseases potentially lethal damage or disablement 
 
10 
Patient death 
Source: (Meyer, S, 2014) 
 
Table 3. Levels of Probability used for Risk Assessment of ARGOS-IO system 
Level of Probability 
Frequency of Occurrence  
 
1 
Improbable 
 
2 
1 in 105 uses 
 
3 
1 in 5x104 uses 
 
4 
1 in 104 uses 
 
5 
1 in 5x103 uses 
 
6 
1 in 103 uses 
 
7 
1 in 5x102 uses 
 
8 
1 in 102 uses 
 
9 
1 in 10 uses 
 
10 
Every use 
Source: (Meyer, S, 2014) 
 
A dichotomy was seen in severity of risks, with all risks having a severity higher than 7 related to the 
implant itself or the surgical procedure and those having a severity of 7 or less related to IOP 
measurements. On the basis of both severity and probability, the identified risks were categorized as 
either acceptable, as low as reasonably possible given the available risk mitigation measures or 
unacceptable. The rankings used are shown in Table 4. 

 
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Table 4. Risk Acceptability Matrix 
 
 
Severity 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Probability 
1 y 
 y 
 y 
 y 
 y 
 y 
 y 
 y 
 n 
 n 
2 y 
 y 
 y 
 y 
 y 
 y 
 y 
 y 
 n 
 n 
3  y 
 y 
 y 
 y 
 y 
 y 
 y 
 y 
 n 
 n 
4  y 
 y 
 y 
 y 
 y 
 y 
 y 
 a 
 n 
 n 
5  y 
 y 
 y 
 y 
 y 
 y 
 a 
 n 
 n 
 n 
6  y 
 y 
 y 
 y 
 y 
 y 
 n 
 n 
 n 
 n 
7  y 
 y 
 y 
 y 
 y 
 y 
 n 
 n 
 n 
 n 
8  y 
 y 
 y 
 y 
 y 
 a 
 n 
 n 
 n 
 n 
9  y 
 y 
 y 
 y 
 y 
 n 
 n 
 n 
 n 
 n 
10  y 
 y 
Y 
 y 
 a 
 n 
 n 
 n 
 n 
n  
 
  
 
 
 
 
 
 
 
 
 
Source: (Meyer, S, 2014) 
 
 
Risk control measures were undertaken to reduce the probability of unacceptable and borderline 
acceptable risks. Where ever possible, priority was given to mitigating the risk first through design 
changes to eliminate it and if this was not feasible, by integrating protective measures in the medical 
device itself or in the manufacturing process to minimize the risk. Risks due to human factors that 
could not be eliminated or checked in advance, such as mistakes in the implant or explant procedures 
will be mitigated by including clear warnings and cautions in the literature and packaging 
accompanying the device and by limiting implantation use to experience ophthalmic surgeons. Finally, 
the resulting measures were reassessed to ensure that no new risks had been introduced during the 
mitigation process. 
 
 

 
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6.3 
Anticipated Adverse Device Effects associated with the ARGOS-IO sensor device 
and their control 
Anticipated potential risks of a long-term implantation of the ARGOS-IO pressure sensor are associated 
with: 
 
Surgical implantation of the ARGOS-IO pressure sensor 
 
Possible side effects and/or tolerance in the early or deferred post-operative period 
 
Possible crowding of ocular structures due to presence of the implant 
 
Side effects of the wireless IOP measurement 
 
Incompatibility with other surgical procedures or medical devices, such as silicone oil 
tamponade, glaucoma drainage device (GDD) and cochlear implants 
 
Incompatibility of interactions of the ARGOS-IO implant with topically applied ophthalmic 
medications and vice versa 
 
Potential unplanned explantation of the ARGOS-IO implant from the eye  
 
In addition, the following risks, although not expected with the ARGOS-IO implant, have been 
associated with similar devices: 
 
 
Uncontrolled increase in IOP 
 
Changes in anterior chamber structures including ACD and ACA 
 
Fibrin reactions 
 
Anterior chamber hemorrhage 
 
Endophthalmitis 
 
Amotio Retinae 
At the end of the risk mitigation process, possible risks were identified that could not be assessed in 
pre-clinical trials. These risks, which are the subject of the clinical investigation, include (Meyer, S, 
2014): 
 
Risks caused by ARGOS-IO implant size and/or form: If the implant is too large for an 
individual, it could cause mechanical stresses on the sensor and the surrounding eye structure, 
leading to effects on the eye structure and/or affecting the function of the sensor. If the 
implant is too small, it could allow the implant to become visible in low light conditions or 

 
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cause positional instability. Both localized pressure and positional instability could also result 
from the form of the implant. Possible adverse device effects that could result include: 
o Angle Block:  The implant could theoretically push the iris forward, creating an angle 
block that leads to subsequent IOP elevation.  
o Aqueous flow inhibition: Because the aqueous flows from the ciliary body through the 
pupil into the anterior chamber, it is remotely possible that the implant could interfere 
with the aqueous flow. According to animal studies and consultation with the advising 
physicians, it is unlikely that the implant will inhibit the flow of aqueous through the 
pupil. 
o Blockage of the optical axis: There is a remote chance that the patient may experience 
shadowing or aperture effects as a consequence of the limited inner diameter of the 
device. This issue would be compounded if the implant becomes dislocated.  
o Irritation / Inflammation of the Eye, Iris Pigment Abrasion: Tests in animals indicated 
a low level of irritation in the long term and inflammation levels as expected in the 
short term following eye surgery. However, due to the position of the implant within 
the human eye, there is a chance of higher levels of irritation and inflammation. Mild 
to moderate pigment dispersion was observed late in the ARGOS-01 study. 
o Incompatibility with the IOL: Because both are being implanted in a confined area, 
there is a possibility that they will interfere with each other. 
 
Mitigation: The following measures were undertaken to mitigate the above mentioned 
effects: 
o It was concluded that due to the large volume of the natural lens that is removed 
during cataract surgery, there should be enough space in normal eyes for both the IOL 
and the ARGOS-IO implant without mutual interference. The ARGOS-IO pressure 
sensor implantation is contraindicated in eyes with an axial length less than 22 mm 
and an anterior chamber depth less than 2.5 mm. Eyes with an axial length less than 
22 mm are excluded from the study. Physicians using state-of-the-art imaging 
technology are likely to identify, and exclude patients with a very shallow anterior 
segment. 

 
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o To ensure aqueous flow remains uninhibited, a surgical iridectomy is mandatory in the 
clinical trial. 
o The inner and outer diameters of the implant were chosen to limit the chance of 
shadowing and aperture effects. In the ARGOS-02 study, the ASIC will be placed at the 
12 o’clock position where any such effects will be limited by the morphology of the 
eye. 
o A silicone material often used for IOLs was chosen for the surface of the implant. It has 
well known biocompatibility properties, a soft surface and rounded, smooth edges. 
Possible small material flashes are soft and non-traumatic. 
o As a consequence of the ARGOS-01 study results, several changes were made to the 
form of the ARGOS-IO implant. The changes include the following: 
 
Thickness of the implant has been reduced from 0.9 mm to 0.5 mm overall, 
tapering to a rounded outer edge of only 0.1 mm. The previous prototype had 
a uniform thickness including the outer edges. 
 
Three different ARGOS-IO implant sizes (11.3 mm, 11.7 mm, 12.1 mm) are 
available to allow the selection of an optimal size for each patient by using 
WTW measurements. 
 
Four haptic arms were added to the plane of the ring and two flat, rounded, 
allantoid protrusions were added to its posterior surface to both improve 
positional stability, facilitate unfolding after implantation and to better 
distribute pressure resulting. 
 
Inaccuracy, imprecision and sensor drift: measurements taken with the ARGOS-IO are 
ultimately to be used to guide treatment decisions. If the measurements are incorrect, 
inappropriate treatment and inadequate control of IOP could result. 
o Mitigation: accuracy, precision and sensor drift were tested and validated in bench 
tests and animal trials. A main objective of this clinical investigation is to evaluate 
these properties in humans. The ARGOS-01 study showed that although IOP values 
obtained with the ARGOS-IO system were constantly higher than those measured with 
GAT or DCT, there was good correlation between the IOP patterns over time. In this 

 
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study, only IOP values determined by GAT will be used to guide treatment decisions. 
Because the risk of undetected device failure will always remain, cautions are included 
in the IFU (ARGOS-IO Implant) and IB requiring that IOP values obtained with the 
ARGOS-IO system be confirmed with an alternative method of IOP measurement such 
as GAT on a regular basis. 
 
Usability issues: issues involving the handling and usability of the device, especially by the 
patient during self-tonometry have been considered. 
o Mitigation: Appropriate data will be collected during the clinical investigation to 
evaluate the practicality of the device. 
6.4 
Risks and Benefits associated with the participation in the clinical investigation 
 
ARGOS-IO system associated risks – As described in section 6.2, a full risk analysis was performed 
during the development of the ARGOS-IO system to anticipate and eliminate or at least minimize 
all foreseeable ARGOS-IO system-related risks. However – as with any new device – it is possible 
that unknown risks remain that will only become apparent as more experience is gained with the 
device. The safety of the study patients is of paramount importance and will be monitored 
throughout the study at all times. If at any time a safety issue arises that is thought to be related 
to the ARGOS-IO implant, to the specific procedures necessary to implant it, or to its use to 
measure IOP, appropriate measures will be initiated immediately to minimize risk to current and 
future study patients. All investigators will be kept informed of such issues. The ARGOS-IO was 
designed to be able to remain in the eye even in the event of failure. If it must be removed, for 
example due to adverse effects, the risks of removal correspond to those associated with 
implantation. 
 
Data Privacy Risks – Health data about study patients will be collected and transferred to an 
electronic database. Although, all currently required methods will be used to protect patients’ 
privacy, the security of such databases can never be completely ensured. For this reason, no 
information that can identify study patients other than the pseudonymising participate number 
will be used on the database or on any study documentation other than the patient log, which will 
remain at the site. Potential patients will be informed of the data privacy policy during the 
informed consent process. 

 
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 
Because of patients’ vulnerable nature, there is a risk that they may either feel obligated to 
participate in the study or that their knowledge of the study may influence their decision whether 
or not to undergo cataract surgery at this time. To mitigate these risks, only patients who have 
already consented to cataract surgery will be informed of the study and all potential study patients 
will be told explicitly that they are free to choose not to participate, and that refusing will not affect 
their treatment except in regards to the ARGOS-IO system. 
 
It is possible that the study will show the ARGOS-IO system is not suitable for its intended use. In 
this event, future patients will be spared exposure to the ARGOS-IO system and information may 
have been gained to develop alternatives. Patients in this study may still have benefitted from 
their participation in the form of a closer follow-up and a positive altruistic feeling.  
 
Patients will be requested to attend visits on a regular basis. It is possible that this will be 
uncomfortable or inconvenient for them. Patients will be reminded that the information they 
provide is confidential, that it will be used to better the care they and fellow patients receive, and 
that their continued participation is voluntary. 
6.5 
Possible Interactions with Concomitant Medical Treatments 
Interaction of the ARGOS-IO implant with other medical treatments and devices is possible both during 
the implantation, which is intended to occur concomitantly with cataract removal and implantation of 
an IOL, and indefinitely following implantation due to the intended permanence of the implantation 
and the continuing use of the external reader. 
Possible interactions of the ARGOS-IO implant with other devices and/or substances used in 
treatments of the eye:  
 
Instrumentation and substances used during the implantation procedure:  
o Forceps for folding and extra- and intraocular manipulation of the implant 
o Folding fixture or injector 
o Other instruments commonly used for manipulation during intraocular implantation 
procedures: to prevent damage to the surface of the implant, it is important to avoid 
contact of the implant with sharp or pointed instruments such as toothed forceps 
o Viscoelastic surgical devices 

 
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 
Intraocular lenses (no silicone lenses should be used in conjunction with the ARGOS-IO 
implant) 
 
Keratoprothesis devices 
 
Glaucoma Drainage Devices: GDD implantation is considered to be a final escalation stage for 
use in severe cases of refractory IOP elevation. The ARGOS-IO may be incompatible with 
insertion of the GDD tubing into the anterior chamber of the eye in certain anatomies. 
However, there are alternative methods of GDD tube implantation that will be compatible with 
ARGOS-IO implant. 
 
Surgical Trabeculectomy: this procedure is not likely to be affected by the implantation of the 
device.  
 
High power ND:YAG Laser: It is highly probable that After Cataract removal will be required in 
this patient population. If the laser is pointed directly at the implant it is likely to cause damage 
to the implant’s electronic components. However, because laser beams can be precisely 
guided and controlled, pointing the laser beam at the contact would be likely only result from 
a grave treatment error. 
 
Laser Trabeculoplasty: it is unlikely that the ARGOS-IO will be a hindrance for laser 
trabeculoplasty. 
 
Trabeculectomy: it is unlikely that the ARGOS-IO will be a hindrance for trabeculectomy. 
 
Interaction of the device with topically applied ophthalmic medications: Although the device 
could theoretically affect effectiveness of the medication, thereby compromising therapeutic 
success for medication could interfere with functionality of the device, these risks are 
considered very unlikely. Chapman et al (1992) studied the absorption of common topical 
ophthalmic medications by silicone IOLs in vitro and found pharmaceutically negligible 
absorption. As the ARGOS-IO implant, which is encapsulated by a similar silicone material, has 
a surface area that is slightly larger than an IOL, the amount of absorption is expected to be 
slightly greater. However, given the low concentrations of pharmaceuticals found in the 
aqueous humor, and the low rates of absorption, effects are expected to be insignificant. In 
addition, although the encapsulation material is known to allow diffusion of several substances 
in the gas phase, the bubble free encapsulation method as well as the hermetic sealing of all 
chip openings with a hermetic gold cap make corrosion unlikely. No drug-device interaction 
was observed either during pre-clinical studies in rabbits (Paschalis, et al., 2014), during the 

 
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case studies or the ARGOS-01 study. Data will be collected in this investigation to allow further 
assessment of this risk. 
 
Interaction of the device with topically applied ophthalmic ointments: Isolated cases of 
silicone IOL contaminations caused by the seeping of antibiotic and steroid ointments applied 
to the eye following surgery through the incision have been reported. These cases, considered 
to be caused by incorrect bandaging procedures following surgery, required subsequent in 
explantation of the IOL (Werner, Apple, & Mamalis, 2010). 
 
Silicone Oil used in Vitroretinal Surgery: Silicone oil used in vitroretinal surgery has been 
reported to deteriorate the optical properties of silicone IOLs. This has however only been a 
problem in patients having severe vitroretinal disease requiring radical treatment with silicone 
oil (Werner, Apple, & Mamalis, 2010). The influence of silicone oil on the (non-optical) ARGOS-
IO implant has been tested by the sponsor (01-RE-17A). No direct influence has been detected. 
However, if silicone oil has to be used in conjunction with the ARGOS-IO implant, performance 
has to be closely monitored. 
 
Ocular dyes: Although some dyes have been reported to permanently discolor some types of 
IOLs, silicone lenses are not known to be affected by commonly used ophthalmic dyes 0 
(Werner, Apple, & Mamalis, 2010). 
Interactions with other general medical procedures: 
 
Magnetic Resonance Imaging (MRI): testing has demonstrated safety of use of MRI (up to a 
magnetic field strength of 3T) with the ARGOS-IO pressure sensor, however imaging artifacts 
are likely to be seen in the proximity of the implant. The manufacturer should be consulted 
before the subject undergoes an MRI examination. 
 
X-ray: medical X-rays are unlikely to cause deletion of the EEPROM from the ASIC. Gamma 
radiation must not be used on the ARGOS-IO because it will very likely erase the EEPROM. 
Interactions with other active implanted medical devices: 
 
Cochlear Implants: the ARGOS-IO is contraindicated in patients with cochlear implants 
 
Brain nerve stimulators: the ARGOS-IO is contraindicated in patients with nerve stimulators 
 
Pacemakers: the ARGOS-IO reader must not be activated in direct proximity to a pacemaker 
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 
Implantable cardioverter defibrillator (ICD): the ARGOS-IO reader device must not be 
activated in direct proximity to an ICD generator. 
 
Other devices generating high-frequency electromagnetic fields: although it is conceivable 
that the device could be influenced by exposure to high-frequency electromagnetic energy, 
because it operates only on a narrow band length (13.56 MHz) the likelihood of this occurring 
is small. However interaction with oncological therapy or other hypothermia devices having 
high performance levels cannot be ruled out. 
6.6 
Possible Alternative Treatments 
To be enrolled in this study, all patients must have glaucoma and cataracts requiring surgery.  
Potential study patients must have consented to undergo cataract surgery with concurrent 
implantation of an IOL prior to enrollment in the study. If they decide not to participate in the study, 
they will undergo the same cataract surgery regardless of whether they participate in the study or not. 
The only differences will be any adaptations to the surgery required by the ARGOS-IO implant related 
procedures, such as a slightly larger incision size (4.5 mm), the iridectomy and the slightly longer 
surgery time. 
Alternative methods for monitoring IOP are described in section 3.3.2 of this CIP as well as in the IB. 
The objective of this study is to evaluate the accuracy and reliability of IOP measurements with the 
ARGOS-IO system. Until these have been demonstrated, IOP will continue to be monitored using the 
standard GAT method. If potential subjects choose not to participate in the study, their IOP levels will 
continue to be monitored using GAT or other approved IOP measuring devices. 
6.7 
Risk/Benefit Assessment 
Identified risks associated with the implantation and use of the ARGOS-IO system have been identified 
and minimized through the risk management process. This process, which is described in sections 6.1 
to 6.5 of this CIP, and in more detail in the IB and the Risk Management Report, followed all relevant 
guidelines and industry standards. Unidentified residual risks of the ARGOS-IO system may remain. 
Although the risk profile for the patient is not expected to differ significantly from those seen with 
predicate devices such as IOLs and surgical procedures, that have been used in the clinical setting for 
decades, higher than expected safety events were seen in the ARGOS-01 study, in which an earlier 
ARGOS-IO implant prototype was used:   

 
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 
fibrin reactions (4 from 6 patients) 
 
pigment dispersion (6 from 6 patients)  
 
pupillary distortion (5 from 6 patients)  
As a consequence, modifications were made to the form of the device, the implantation procedure 
and the eligibility criteria to mitigate risk. Ongoing collection and analysis of information about any 
adverse events related to the device that do occur will allow rapid identification of previously unknown 
risks. The implementation of a two-stage design will also prevent the exposure of further patients to 
the device if risks are higher than currently anticipated. 
These risks are to be balanced against the medical benefit of the quasi-continuous IOP measurement 
permitted by the device. Ophthalmologists will obtain valuable information about individual patients 
to better guide their treatment, and better insight into the progression of glaucoma in general. The 
ability of patients to actively monitor their condition on a daily basis will motivate them to better 
adhere to their prescribed treatment regimen for a condition that progresses gradually with few if any 
short term symptoms but devastating irreversible consequences.  
Given the serious and permanent long-term consequences of poor IOP control in glaucoma patients 
and the difficulties associated with current methods of IOP monitoring, the residual risks of the ARGOS-
IO system and their probability of occurrence are clearly within the range found acceptable for other 
similar ophthalmic devices currently on the market. 
7. 
OBJECTIVES AND HYPOTHESES OF THE CLINICAL INVESTIGATION 
7.1 
Objectives 
The aim of this trial is to verify the safety and performance of the ARGOS-IO system in patients with 
Primary Open Angle Glaucoma (POAG) and indicated cataract surgery. The measurements of 
intraocular pressure through the pressure sensor shall be compared with Goldmann Applanation 
Tonometry (GAT), which is generally accepted as the clinical gold standard. The ARGOS-IO pressure 
sensor will be implanted during cataract surgery and is to remain permanently in the eye. 

 
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7.1.1 
Primary Objectives 
7.1.1.1 Safety 
 
The primary objective of this clinical investigation is to evaluate the safety and tolerability of 
the ARGOS-IO pressure sensor in the first 3 months following implantation. 
7.1.1.2 Performance 
 
To evaluate the performance of the ARGOS-IO system compared to GAT from day 30 through 
day 180. 
7.1.2 
Secondary Objectives 
7.1.2.1 
Safety 
 
To evaluate the safety and tolerability of ARGOS-IO pressure sensor implantation between 3 
and 12 months 
7.1.2.2 
Performance 
 
To evaluate the performance of the ARGOS-IO system compared to GAT up to 12 months 
after implantation. 
7.2 
Primary and secondary hypothesis, to be accepted or rejected by statistical data 
from the investigation 
 
The specific hypothesis to be tested in this single arm two-stage design study is, that the 
SADE rate is at most 6%. 
 
If this hypothesis is proven, agreement of the measurements made with the ARGOS-IO 
system to those with GAT will be described by evaluation of the bias and limits of agreement. 
7.3 
Claims and intended performance of the IMD to be verified 
This study aims to estimate the agreement of measurements taken with the ARGOS IO system to those 
obtained using GAT and to collect further information on the occurrence of AEs and ADEs and about 
the reliability of the device in humans. 

 
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7.4 
Risks and anticipated adverse device effects to be assessed 
Information will be collected on all AEs and ADEs. Particular attention will be paid to the following 
AEs, for which increased risks are considered possible:  
 
Uncontrolled increase in IOP 
 
Changes in anterior chamber structures including ACD and ACA 
 
Fibrin reactions 
 
Anterior chamber hemorrhage 
 
Endophthalmitis 
 
Amotio Retinae 
 
Pigment dispersion during surgery 
 
Postsurgical pigment dispersion  
 
Hypopyons 
 
Pupillary distortion 
 
Peripheral flattening or raising of the AC, including position and extent. 
8. 
DESIGN OF THE CLINICAL INVESTIGATION 
8.1 
General Aspects 
8.1.1 
Description of the type of clinical investigation 
The trial will be conducted as an open, prospective, multicenter single-arm clinical trial using the two- 
stage design described by Simon (Simon, 1989). In the first stage, 11 patients will have an ARGOS-IO 
pressure sensor implanted, after which enrollment will be halted until the patients have completed 
their 3 months follow-up visits and an interim analysis has been performed. The interim analysis will 
be reviewed by the DSMB. If two or more of these 11 patients in the first stage are found to have had 
an SADE, further enrollment into the study will be stopped. If not, enrollment will resume until another 
11 patients have had an ARGOS-IO pressure sensor implanted. If two or fewer of the total 22 patients 
experience an SADE, a conclusion for safety will made at the 5% significance level. A corresponding 
95% confidence interval for the SADE rate will be calculated according to the procedure of Koyoma 
(2008). 

 
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All patients who receive an ARGOS-IO implant will return for 10 follow-up visits to the clinic (day 1, 3, 
10, 30, 60, 90, 120, 180, 240, 360) during the 12-month post-surgical period (see Table 6: Assessment 
Schedule). To allow comparison of the IOP measurement methods, IOP measurements will be made 
at every visit with GAT and with the ARGOS-IO systems beginning at V5 (day 30). 
8.1.2 
Description of the measures to be taken to minimize or avoid bias 
No randomization and blinding/masking procedures will be used in this study. To avoid bias resulting 
from prior knowledge of the IOP value from the ARGOS-IO system on the measurement obtained with 
GAT, GAT will be used first. 
8.1.3 
Primary and secondary endpoints 
8.1.3.1 
Primary endpoints 
Safety 
 
Number of patients experiencing a device related SAE defined as any adverse event that both 
o Is considered by the Investigator to have a possible, probable or definite relationship 
to the device and  
o That meets any of the following criteria of a serious adverse event: 
 
Resulted in death, permanent damage or disability or a congenital anomaly 
 
Was life threatening 
 
Required hospitalization or intervention to prevent permanent impairment or 
damage 
Performance 
 
Limits of agreement between IOP measurements made using GAT and the ARGOS-IO system 
from V05 (day 30) through V09 (day 180). 
8.1.3.2 
Secondary endpoints 
Safety 
 
Incidence, nature, seriousness, severity and duration of adverse events and adverse device 
events in the 3 months immediately following implantation of the ARGOS-IO pressure sensor. 
 
Incidence, nature, seriousness, severity and duration of adverse events and adverse device 
events in the first 6 months following implantation of the ARGOS-IO pressure sensor 

 
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 
Incidence, nature, seriousness, severity and duration of adverse events and adverse device 
events in the 12 months following implantation of the ARGOS-IO pressure sensor. 
Performance 
 
Limits of agreement between IOP measurements made using GAT and the ARGOS-IO system 
from V05 (day 30) through V11 (day 360). 
 
Incidence of device deficiencies in the 6 months following implantation 
 
Incidence of device deficiencies in the 12 months following implantation 
 
User acceptance of the implantation procedure by means of evaluation of the Implantation 
Procedure Questionnaire (Investigators) 
 
User acceptance of the ARGOS-IO system at the investigational site by means of evaluation 
of the Investigator Acceptance Questionnaire (Investigators) 
 
User acceptance of the ARGOS-IO system at home by means of evaluation of the Patient 
Acceptance Questionnaire (patients) 
 
Daily IOP self-measurement profiles (patients). 
8.1.4 
Equipment to be used to assess the clinical investigation variables and 
arrangements for monitoring maintenance and calibration 
Sites will use their own ophthalmology diagnostic devices. The CRA will verify that the sites maintain 
and calibrate these devices on a regular basis. 
8.1.5 
Any procedures for the replacement of subjects 
Screen failures (withdrawn for any reason up to implant) will be replaced. Subjects who withdraw their 
consent after implantation will not be replaced. 
8.2 
Investigational device(s) and comparator(s) 
8.2.1 
Description of the exposure to the investigational device(s) or comparators, if 
used 
The ARGOS-IO pressure sensor is intended to be permanently implanted. Subjects will be exposed to 
the tip of the ARGOS-IO pressure sensor implant injector transiently during the implantation procedure 
and transiently to low-levels of electromagnetic energy induced by the MESOGRAPH reading device 

 
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during the reading sessions, at which time their skin may also be exposed to the MESOGRAPH outer 
surface. 
The ARGOS-IO system will be directly compared to the non-invasive Goldmann Applanation tonometry 
(GAT). Therefore, subjects will not be exposed to any other active implantable comparators. 
8.2.2 
Justification of the choice of comparator 
GAT is the standard tonometry method to which all other tonometers have traditionally been 
compared. 
8.2.3 
Other medical devices or medication to be used 
No other investigational medical devices or medications will be used specifically for this clinical 
investigation, except for standard of care during surgery, standard devices for ophthalmic diagnostics, 
surgery follow up or Glaucoma treatment. 
8.2.4 
Number of investigational devices to be used 
The ARGOS-IO pressure sensor will be implanted in up to 22 patients diagnosed with Primary Open 
Angle Glaucoma (POAG) and indicated cataract surgery. Sites will initially be provided with implants in 
all available sizes. Upon usage, individual implants will be resupplied. Approximately 90 devices (30 
devices per implant size including replacement devices, if needed) will be required for this study. 
8.3 
Subjects 
8.3.1 
Inclusion Criteria 
In order to ensure that the study population is representative of the eligible patient population, the 
Investigator must ensure that all patients who meet the following inclusion criteria are offered 
enrolment in the study. The investigator may not apply any additional eligibility criteria. Eligible 
subjects must meet all the following inclusion criteria: 
1. Mentally competent and willing to provide written Informed consent. 
2. Male or female aged ≥ 40 ≤ 85 years on the day of screening. 
Female subjects of childbearing potential (not surgically sterilized or more than one year post-
menopausal) must be willing to use adequate contraception throughout the trial and must 

 
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have a negative pregnancy test (urine beta-hCG) within 24 hours prior to ARGOS-IO pressure 
sensor implantation. 
3. Diagnosis of primary open-angle glaucoma (POAG) including high pressure glaucoma (HPG), 
normal pressure glaucoma (NPG) and ocular hypertension (OH) as defined by the European 
Glaucoma Society guideline (Heijl, Traverso, & al, 2008) requiring regular IOP measurements. 
4. Sufficiently controlled IOP. 
5. Phakic eyes. 
6. Only one eye per patient may be implanted with the ARGOS-IO implant. 
7. Cataract surgery indicated. The medical indication for a cataract operation must be given 
irrespective of the study participation. Potential study patients will be solicited for 
participation in the clinical trial only after the patient has given consent to the cataract 
operation. 
8. Pre-operative anterior chamber depth (ACD) ≥ 2.5 mm as measured from the corneal 
endothelium. 
9. Axis length > 22 mm. 
10. Endothelial cell density of the cornea ≥ 2000 cells/mm². 
11. Subjects able and willing to attend all scheduled visits and comply with all study procedures. 
8.3.2 
Exclusion Criteria 
Eligible subjects must not meet any of the following exclusion criteria: 
 
1. Any other type of glaucoma other than primary open-angle glaucoma as defined in inclusion 
criteria 3 
2. Severe POAG patients with a macular degeneration and visual field loss of -20dB or worse 
3. Exsudative age-related macular degeneration, instable macular degeneration 30 days prior to 
inclusion or macular edema 
4. Retinal detachment 
5. Corneal diseases 
6. Diabetes mellitus 
7. Connective tissue diseases 

 
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8. History or evidence of severe inflammatory eye diseases (i.e. uveitis, retinitis, scleritis) in one 
or both eyes within 6 months prior to ARGOS-IO pressure sensor implantation. 
9. Intraocular surgical procedure(s) within 6 months prior to ARGOS-IO pressure sensor 
implantation or any surgical procedure such as refractive eye surgery that can affect the 
assessment of IOP by Goldmann Applanation tonometry. 
10. History of eye tumor. 
11. Ocular disease other than glaucoma that may affect assessment of visual acuity and/or IOP by 
Goldmann Applanation tonometry (choroidal hemorrhage or detachment, lens subluxation, 
thyroid ophthalmopathy). 
12. Anterior chamber configuration that puts the subject at high risk to develop an angle closure 
glaucoma. 
13. History of extensive keloid formation. 
14. Severe dry eye syndrome. 
15. Subjects who will need to undergo ancillary procedures in the study eye at the time of 
implantation or during the post-operative study period. 
16. Any known intolerance or hypersensitivity to topical anesthetics, mydriatics, plaster or silicone 
(component of the device). 
17. Existence of other active medical eye implant and/or other active medical implants in the 
head/neck region. 
18. Any contraindications for IOL implantation such as choroidal hemorrhage, concomitant severe 
eye diseases, excessive vitreous loss, extremely shallow anterior chamber, microphthalmos, 
non-age-related cataract, posterior capsular rupture, severe corneal dystrophy, untractable 
IOP, zonular separation, color vision deficiencies 
19. Severe generalized disease resulting in a life expectancy shorter than a year. 
20. Any clinical evidence that the investigator feels would place the subject at increased risk with 
the placement of the device. 
21. Currently pregnant or breastfeeding. 

 
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22. Participation in any study involving an investigational drug or device within the past 30 days 
or ongoing participation in a study with an investigational drug or device. 
23. Patients who are not suitable for the study based on the surgeon’s evaluation. 
24. Patients unable or unwilling to understand or comply with required study procedures. 
25. Patients with psychiatric disorders influencing their judgment or autonomy 
26. Subject and/or an immediate family member is an employee of the investigational site directly 
affiliated with this study, the sponsor or the contract research organization. 
27. Enrollment of the fellow eye in this clinical study. 
8.3.3 
Discontinuation or Withdrawal Criteria 
8.3.3.1 
Study stopping rules 
As described in section 9, the study will be conducted in two stages. In the first stage, 11 subjects will 
receive ARGOS-IO implants, after which implantation will be halted. Once these subjects have 
completed their 3 months follow-up visits, the interim results will be evaluated by the DSMB. The study 
will be stopped for safety reasons if at the time of the interim analysis two or more of these 11 subjects  
have had SADEs or if the DSMB otherwise determines that severe safety risks to the subjects exist. 
If more than two patients in the first stage of the study experience SADEs, the study will be stopped 
for safety reasons. 
The study may be discontinued at any time for administrative reasons; if new negative data about the 
investigational device resulting from this or any other studies becomes available; and/or on advice of 
the DSMB, the sponsor, the investigators, and/or the EC or regulatory authorities.  
If the study is prematurely terminated or suspended, the sponsor will promptly inform the 
investigators, the Regulatory Authorities and the ECs of the reason for termination or suspension. If 
the study is prematurely terminated for any reason, the investigator should promptly inform the study 
subjects and assure they receive appropriate therapy and/or follow-up. 
The study can be terminated at any time for any reason by the sponsor. 

 
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8.3.3.2 
Screen Failures 
Screen failures are subjects who have signed the informed consent form but fail to meet eligibility 
criteria for enrolment e.g. they do not meet one or more of the inclusion criteria or do meet one or 
more of the exclusion criteria. Such subjects will return to standard treatment and will not be enrolled 
in the study. The only data collected on them will be the date of their screening visit, the date they 
gave informed consent and reason they are a screen failure. This data will be entered on the 
demography and study discharge pages in the CRF. 
8.3.3.3 
Premature subject withdrawal 
Subjects will be informed that they have the right to withdraw from the study at any time. The 
investigator must determine whether voluntary withdrawal is due to safety concerns. 
All subjects who withdraw from the study after implantation and before completing the follow-up visits 
per protocol will be considered to be drop-outs. Subjects who drop-out or are withdrawn after 
implantation will not be replaced. Unless the patient revokes his/her permission to use it, any data 
collected up to the point of the patient’s withdrawal will be included in the safety analysis. The data of 
all subjects who undergo implantation of the ARGOS-IO pressure sensor will be included in the efficacy 
analysis under the Full Analysis Set. 
A patient will be withdrawn for any of the following reasons: 
• 
The patient withdraws informed consent. 
• 
It is determined during surgery that the patient is not feasible for ARGOS-IO pressure sensor 
implantation. 
• 
The ARGOS-IO pressure sensor must be removed or replaced for any reason. 
If the patient permits, all end-of-study assessments indicated in the visit schedule should be performed 
for implanted early discontinuing subjects. 
Any subject who has been discontinued from the study because of an AE related to a study device or 
procedure will be followed as deemed appropriate by the investigator until resolution or stabilization 
of the event. This will be documented in the medical chart and in the CRF. Any patient who has been 
discontinued from the study because of an AE not related to a study device or procedure will be 
followed as deemed appropriate by the investigator. 

 
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The investigator will classify the termination reason of each subject at the end of the study in the 
termination page of the CRF according to the following: 
• 
AE 
• 
Non-compliance with clinical investigation plan (CIP) 
• 
Lost to follow up 
• 
Voluntary withdrawal not for AE  
• 
Other reason. 
8.3.3.4 
Completed Subjects 
A completed subject is considered to be a subject that completed all procedures as defined by the 
clinical investigation plan. 
8.3.3.5 
Subjects lost to follow-up 
If a subject fails to appear for a follow-up examination, reasonable effort should be made to locate or 
contact them to at least to determine their health status while fully respecting the subject’s rights. 
Reasonable effort consists of at least three documented attempts to contact the patient by phone or 
post. These efforts should be documented in both the source documents and the subject’s CRF. 
8.3.3.6 
Pregnancy 
If a patient becomes pregnant between screening and surgery, she will be withdrawn from the study. 
If a subject becomes pregnant between surgery and the end of the study, she may remain in the study 
if she wishes. Her follow-up will be limited at the discretion of the Investigator until the end of the 
pregnancy as necessary to protect her health and that of the fetus/embryo. The pregnancy will be 
documented as an AE and as a protocol deviation. The pregnancy will be followed until the end to 
determine its outcome. 
8.3.4 
Point of enrolment 
A subject is considered as being enrolled into the clinical investigation when he/she gives consent in 
writing to participate in this investigation. 

 
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8.3.5 
Total expected duration of the clinical investigation 
The estimated total duration of the study from first patient screened to last patient last visit is 21 
months. 
8.3.6 
Expected duration of each subject’s participation 
The maximum duration of each patient’s participation in this clinical intervention is 13 months. The 
point of enrolment is considered to be the time point at which potentially eligible subjects sign the 
informed consent form. Surgery will be performed within 28 days of this time point. The patient will 
be followed-up for 12 months post-surgery to obtain data on safety and performance. 
8.3.7 
Number of subjects required 
According to the sample size calculation described in section 9.2, 22 patients are considered to be 
adequate in order to gain sufficient data to support the analysis of the study endpoints.  
8.3.8 
Estimated time needed to select the planned number of subjects 
The estimated recruitment time is considered to be 3 months for the first stage of the study and 3 
months for the second. 
8.4 
STUDY PROCEDURES 
8.4.1 
Informed Consent 
Eligible patients may only be included in the study after providing written informed consent as 
described in Section 12.1. Failure to obtain signed informed consent renders the patient ineligible for 
the study. 
8.4.2 
Allocation of Patient Number 
Each subject is uniquely identified in the study by a combination of his/her country identifier, number 
and patient number. The number is assigned by the sponsor to the investigational site. Upon signing 
the Informed Consent Form, the subject is assigned a patient number by the investigator. The patient 
number will be composed of the country letter code (DE) and a 5-digit string with a 2-digit center 
identifier and a 3 digit patient identifier. This 3 digit patient identifier corresponds to the chronological 
order of enrollment in the center (e.g. the 21st subject included in the study in Germany at site 01 will 

 
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be patient DE-01-021). Once the patient number has been assigned to a subject, a number will not be 
reused even if the subject is a screen failure. 
8.4.3 
Methods and timing for assessing, recording, and analyzing parameters 
During the study, subjects will attend 12 clinic visits, including 1 screening visit (up to 28 days prior to 
surgery), 1 surgery visit (day 0 = V01 surgery), and 10 follow-up visits (days 1, 3, 10, 30, 60, 90 120, 
180, 240 and 360). The assessment schedule in Table 6 summarizes all visits and the assessments to 
be performed at each. The visit window given in the table should be adhered to as closely as possible. 
8.4.3.1 
Safety 
At each follow-up visit, the Investigator will examine the patient and record information about any 
new or ongoing adverse events, adverse device events or clinically significant anomalies. In addition, 
the Investigator or designated site staff will ask the patient non-leading questions to ascertain if the 
patient experienced any adverse events or adverse device events between visits. 
8.4.3.2 
Performance 
Starting at V05, IOP level will be assessed at every follow-up visit with both GAT and the ARGOS-IO 
system. Measurements will be performed in series of 1 GAT measurement followed by 3 consecutive 
measurements with the ARGOS-IO system, with no more than 10 minutes between the GAT and the 
first of the ARGOS-IO system measurements in the series. Two series of measurements, one each at 
the beginning and end of the visit, will be made at visits 06, 08 and 10. Four series of measurements, 
at the beginning (1), in the middle (2) and at the end (1) will be made at each of visits 05, 07, 09 and 
11. There will be a minimum of 60 minutes between the last ARGOS-IO system measurement of one 
series and the GAT measurement of the next. 
To assess device deficiencies, at each follow-up visit site staff will record any deficiencies observed 
during the visit and will examine the patient’s hand-held reader device and ask patients non-leading 
questions starting at V06 (D60) to determine if any device deficiencies occurred during the home use. 
To ensure accuracy and comparability of the recorded parameters, all responsible site personnel will 
be thoroughly instructed on the agreed measurement methods. In particular, to ensure that IOP 
measurements will be comparable between each patient’s individual assessments as well as between 
the different subjects and sites.  

 
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To access the user acceptance of the implantation procedure and the general usability of the ARGOS-
IO system, surgeons, personnel performing the ARGOS-IO system measurements and patients (self-
measurement) will be asked to complete user acceptance questionnaires. 
8.4.4 
Assessments 
8.4.4.1 
Patient demographics/other baseline characteristics 
Patient demographic and baseline characteristic data to be collected on all subjects include: year of 
birth, sex, race, weight, height, educational level, pre-treatments and source of patient referral. 
8.4.4.2 
Medical history 
Relevant medical history/current medical condition data includes data until start of ARGOS-IO 
pressure sensor implantation. Relevant medical history should be supplemented by review of the 
subject’s medical chart and/or by documented dialog with the subject’s referring physician. If 
possible, diagnoses and not symptoms are to be recorded. 
8.4.4.3 
Pregnancy test 
Urine dip stick test at screening (SC) and before surgery (V01) will be performed in female patients of 
childbearing potential. The test type and results will be recorded in the subject’s source documents. A 
positive result necessitates the exclusion of the subject from the study. For further details please refer 
to section 7.3.6. 
8.4.4.4 
Concomitant medication, treatments and devices 
There are no restrictions for the use of concomitant medications and treatments required for 
ophthalmological or systemic diseases during this clinical investigation. The use of concomitant 
medication and treatments will be documented in the patient’s file and in the CRF. 
8.4.4.5 
AEs/ADEs/SAEs/SADEs 
Starting with the implantation of the ARGOS-IO pressure sensor, all AEs/ADEs/SAEs/SADEs will be 
recorded. 

 
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8.4.4.6 
Device Malfunctions 
Starting with the implantation of the ARGOS-IO system IOP measurements at V05 (D30), all observed 
device malfunctions will be recorded. 
8.4.4.7 
Questionnaires 
In the study, three types of questionnaires will be used to assess potential strength and weaknesses of 
the ARGOS-IO system. Surgeons are asked to complete an implantation procedure questionnaire after 
each implantation at V01 (D0). At V11 (D360), the site staff responsible for IOP measurement as well 
as the patients will be asked to complete a user acceptance questionnaire for the MESOGRAPH reading 
device and the general measurement procedure.  
The aim of these questionnaires is to gain more information about the level of user-acceptance of the 
ARGOS-IO system during implantation and during IOP measurement. The data collected with these 
questionnaires is only of exploratory nature and will not be included in the analysis. Results will provide 
the sponsor with data that could influence future device system improvements. 
8.4.4.8 
Optical Biometry (IOL Master®) 
The IOL Master (Carl Zeiss Meditec, Germany) uses the principle of optical biometry partial coherence 
interferometry (PCI) to measure the axial length of the globe. The IOL Master is a non-contact optical 
biometry assessment method to determine which power of the intraocular lens (IOL) should be 
implanted during cataract surgery. Standard site procedure will be followed. 
8.4.4.9 
Visual acuity (VA) 
The best corrected visual acuity will be determined after objective and subjective determination of 
refraction with the ETDRS chart in accordance with the ETDRS protocol. The number of characters read 
and the reading distance will be recorded. The standard testing distance is 4 meters. 
8.4.4.10 Visual field (Perimetry) 
The purpose of visual field testing is to determine both the outer limits of visual perception by the 
peripheral retina and the varying qualities of vision within that area. Perimetry is performed to obtain 
an accurate examination of the peripheral extent of the visual field. Automated perimeters will be used 
either with standard glaucoma field, field 30-2 or equivalent. 

 
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8.4.4.11 External Eye Photography 
Standard external eye photography will be performed in order to document potential changes to the 
outer eye involving the iris or pupil structure. 
8.4.4.12 Anterior eye segment measurement 
Slit-lamp biomicroscopy (undilated, anterior segment) 
Slit-lamp biomicroscopy involves the examination of the external ocular structures and the front of the 
eye. The following anatomic parameters will be assessed by using the slit-lamp biomicroscopy through 
an undilated pupil: 
a) Lids 
b) Conjunctiva 
c) Cornea 
d) Anterior chamber 
e) Iris 
f) Pupil 
g) Lens 
h) Anterior vitreous. 
Optical coherence tomography (OCT) 
Standard anterior segment OCT will be used to evaluate effects on change in chamber angle after 
surgery and to assess the central corneal thickness. 
Confocal microscopy 
Standard confocal microscopy will be performed to determine corneal endothelial cell density. 
8.4.4.13 Gonioscopy 
Gonioscopy 
Standard gonioscopy will be used to confirm the glaucoma classification and to assess other problems 
within the anterior chamber, such as the presence of foreign bodies hidden in the recess of the angle. 
The method clearly confirms the POAG diagnosis by distinguishing primary open-angle glaucoma from 
secondary open-angle glaucoma. The gonioscopic grading system according to Spaeth (Spaeth, 1971) 
is used in this clinical investigation. 

 
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ARGOS-IO implant size assessment 
The ARGOS-IO implant size will be determined based on the horizontal White-to-White (WTW) 
measurement obtained with the IOL Master. At least three WTW measurements will be taken and the 
average calculated. The average in mm will then determine the right ARGOS-IO implant size (Table 5).  
 
Table 5. Recommended ARGOS-IO Implant Sizes 
WTW Measurement 
(mm) 
Recommended ARGOS-IO ring size 
(mm) 
11.2 to 11.59 
11.3 
11.6 to 11.99 
11.7 
12.0 to 12.4 
12.1 
8.4.4.14 Posterior eye segment measurement 
Biomicroscopy (dilated, fundus) 
The posterior eye segment will be examined using a slit lamp in combination with a 90D or “Superfield” 
or comparable lenses. The following parameters will be assessed through a pupil dilated using 
mydriatic agents: 
a) Optic nerve lesions 
b) Other posterior pole lesions 
c) Vitreous opacities 
d) Optic nerve head 
e) Fundus lesions 
f) Retinal arteries and veins (AV) 
g) Macular area 
h) Fundus periphery 
i) Normal and abnormal variations of the fundus. 
Optical coherence tomography (OCT) 
Posterior segment OCT will be used to assess macular structures and the peripapillary nerve fiber 
layer. 

 
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Fundus photography 
Standard fundus photography will be performed at screening and at V07, V09 and V11 to document 
potential changes to the interior surface of the eye, including the retina. 
8.4.4.15 Intraocular pressure (IOP) measurement 
Intraocular pressure (IOP) will be measured using two techniques. Goldmann Applanation Tonometry 
(GAT) will be performed in the clinic at every visit. Beginning at V05, IOP measurement will also be 
performed with the ARGOS-IO system, both by site personnel at clinic visits and by the patient at home 
between visits. Only GAT will be used to guide any treatment decisions. The GAT must be performed 
by preferably one or at maximum two dedicated investigators at each site to reduce potential bias. 
IOP measurement in the clinic 
Each IOP measurement will be conducted as a series of 1x GAT followed by 3x ARGOS-IO system, except 
for Visits SC through V04 when only GAT will be used. When series of measurements are made, the 
GAT must always be used first to avoid operator bias. There should be no more than 10 minutes 
between the GAT measurement and the first of the ARGOS-IO system measurements in a series, and 
at least 60 minutes will lie between the last measurement with the ARGOS-IO system in one series and 
the GAT of the next.  
IOP will be measured at least two times at every visit, preferably at the beginning and end of the visit. 
At Visits 05, 07, 09 and 11, IOP will be measured 4 times. Again, effort should be made to ensure there 
are at least 60 minutes between measurement series. 
ARGOS-IO system measurement by the patient at home 
At V05 (D30), after detailed instruction in their use, the patients will receive an individual Mesograph 
reading device and the Multiline Connector to perform self-tonometry at home. The patients will be 
requested to perform at least 4 IOP measurements with the Mesograph daily, evenly spread 
throughout the day. They will also be requested to connect the reader to the Multiline Connector on 
a regular basis to transfer the recorded IOP data directly into the secure database. No manual 
recording of data by the patient will be required. 
Patients shall be instructed to bring the Mesograph reading device to every visit to permit site staff to 
check its functionality and to delete the measured IOP data from the device. The device routinely 
stores up to 3.000 measurements. 

 
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8.5 
ARGOS-IO pressure sensor implantation 
8.5.1 
IOL implantation 
Ophthalmic surgeons should perform the surgery according to their local routine working procedure 
for IOL implantation. 
8.5.2 
ARGOS-IO pressure sensor implantation 
After implantation of the IOL, the ARGOS-IO pressure sensor ring will be inserted into the ciliary sulcus 
using the IOL implant injector provided by the sponsor. Please refer to the IFU for the ARGOS-IO 
implant and the IB for a detailed description of the process.  
If during surgery, the ophthalmic surgeon decides for any reason that ARGOS-IO pressure sensor 
implantation is not in the subject’s best interest, the surgeon will stop the ARGOS-IO pressure sensor 
implantation and will proceed as dictated by the subject’s condition and standard of care. 
8.5.3 
Concomitant medication and devices during surgical procedure  
Medication and devices routinely used during surgery (such as anesthesia, etc.) will not normally be 
recorded in the CRF. However, if there is a SAE during surgery, all medication administered during 
surgery will also be recorded. 
8.5.4 
Concomitant medication after implantation 
The use of concomitant medication is at the discretion of the Investigator. Prophylactic use of steroid 
therapy and antibiotics according to standard local procedure is recommended following surgery. 
8.5.5 
Concomitant therapy in case of inflammatory events after implantation 
If the patient shows signs of an inflammatory reaction following implantation, treatment such as 
administration of local and/or systemic steroid and antibiotic therapy is recommended, according to 
the local procedure regimens. In the event a hypopyon develops, an anterior chamber biopsy is 
recommended to determine whether it is sterile or due to an infectious agent. 
8.6 
ARGOS-IO pressure sensor explantation, if medically necessitated 
The ARGOS-IO implant can be explanted at any time, when medically indicated. In case the ARGOS-IO 
implant has to be removed, follow the following steps: 

 
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 
Corneal incision (approximately 3 mm) with appropriate instrument 
 
Viscoelastic injection to stabilize the anterior chamber 
 
Transect the ARGOS-IO implant at the microcoil area with appropriate scissors (e.g. Vannas 
scissors) 
 
Extrude one end of the transected implant through the wound with forceps and gently pull 
the rest of the implant out of the eye. 
 
Close the corneal incision with a suture following standard procedure. 
8.7 
Study Visits 
8.7.1 
Screening visit, SC (Day -28 to 0) 
Only patients who have already independently agreed to undergo cataract surgery will be approached 
by the trial team about participation in the study.  
At the SC, the investigator will conduct the informed consent process (section 12.1), ensuring that the 
subject’s signature has been obtained on the patient informed consent (PIC) form and that the subject 
has received a copy before any study specific procedures are conducted. Once the PIC is signed, the 
subject will be assigned a patient number (section 8.2) and the Investigator will determine if the 
subject meets the eligibility criteria, the surgery visit will be scheduled and the screening fax form 
completed and faxed to the sponsor.  
In addition, the following procedures will be performed at this visit: 
 
Collection of background information about the subject including: demographics, medical 
history with prior treatments and current medications. 
 
Pregnancy test, when applicable 
 
Visual acuity (ETDRS) 
 
Visual field (perimetry) 
 
Optical Biometry (IOL Master) including ARGOS-IO implant size assessment 
 
External eye photography 
 
Anterior Segment measurements (Slit-lamp biomicroscopy, AS-OCT, gonioscopy and confocal 
microscopy) 
 
Posterior Segment measurement (Biomicroscopy , PS-OCT, fundus photography) 
 
IOP measurement with GAT 

 
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 
Instruct subjects on the need to report as soon as possible any SAEs occurring at any time 
during the study (starting from surgery, Visit 1) 
 
Complete the screening fax form and send to sponsor 
 
Complete the CRF. 
8.7.2 
Surgery, Visit 1 (Day 0) 
The following procedures may be carried out one day before surgery (in subjects already hospitalized 
for the surgery) or on the day of surgery: 
 Verify that the subject continues to meet eligibility criteria 
 For female subjects of childbearing potential: collect urine for pregnancy test. A test done 
within 24 hours prior to surgery must be negative 
 Perform external eye photography prior to surgery. 
The following procedures are to be performed on the day of the surgery: 
 Cataract surgery and ARGOS-IO pressure sensor implantation as described in section 8.5, 
including the recording of any AEs, SAEs starting from implantation of the ARGOS-IO pressure 
sensor; any concomitant medication related to SAE/SADEs during surgery; and any device 
malfunctions. 
 Completion of the implantation procedure questionnaire (surgeon) and the CRF  
 Complete the patient inclusion form and fax it to the sponsor 
 Instruct subjects on the need to report promptly any SAE that may occur at any time during 
the study. 
 Arrange a date for Visit 2 (V02). 
 The duration of the patient’s hospitalization is at the discretion of the Investigator. 
Recommended duration is 1 to 3 days, but durations of up to 7 days will not be considered in 
themselves to be SAEs. 
 
 

 
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8.7.3 
Follow-up visits 02 to 04 (early post-surgical): days 1, 3 and 10 
Procedures to be conducted at the early post-surgical visits include: 
 Visual acuity  
 External eye photography 
 Recording of AEs/SAEs/ADEs/SADEs, concomitant medications (all)  
 Anterior Segment Measurements: Slit-lamp microscopy only 
 Posterior Segment Measurements: Biomicroscopy only 
 IOP Measurement (GAT only) 
 Complete the CRF and arrange the next visit. 
8.7.4 
Follow-up visits 05 to 11: days 30, 60, 90, 120, 180, 240 and 360 
Procedures to be conducted at the early post-surgical visits include: 
 Visual acuity  
 Perimetry (Visits 07, 09 and 11 only) 
 External eye photography 
 Recording of AEs/SAEs/ADEs/SADEs, concomitant medications (all)  
 Anterior Segment Measurements:  
 Slit-lamp microscopy at all visits  
 AS-OCT, gonioscopy and confocal microscopy at V07, V09 and V11  
 Posterior Segment Measurements: 
 Biomicroscopy at all visits  
 PS-OCT, gonioscopy and fundus photography at V07, V09 and V11  
 IOP Measurement: GAT and ARGOS-IO system 
 4 series at visits 05, 07, 09 and 11  
 2 series at Visits 06, 08 and 10 
 ARGOS-IO system  self-measurement (by patients at home between visits) 
 Complete the CRF and arrange the next visit 

 
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Visit 11 is in addition the study discharge visit. At this visit, patients will complete a User Acceptance 
Questionnaire for patients and the Investigator will complete a User Acceptance Questionnaire for 
Investigators. Site personnel will collect the Mesograph reader from the patient. After this visit, 
patients will return to standard care. They will be informed about the planned surveillance registry and 
asked if they wish to participate.  
8.8 
Visit schedule and assessments 
Table 6. lists all assessments and indicates with an “X” the visits at which they and related assessments 
are to be performed. The visit window given in the table should be adhered to as closely as possible. 
 
 

 
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Table 6. Assessment Schedule 
 
Visit 
SC 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
V11 
Indicative Days (D) 
Up to 
28 days 
before 
surgery 
D0 
D1 
D3 
D10 
+/- 1 
Day 
D30 
+/- 5 
Days 
D60 
+/- 5 
Days 
D90  
+/- 10 
Days 
D120 
+/- 10 
Days 
D180  
+/- 10 
Days 
D240  
+/- 10 
Days 
D360  
+/- 10 
Days 
GENERAL 
Informed consent signed 
X 
 
 
 
 
 
 
 
 
 
 
 
Allocation of  subject 
number 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion & exclusion 
criteria 
X 
X1 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
Past and current 
significant medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (urine beta-
hCG) 
X 
X2 
 
 
 
 
 
 
 
 
 
 
Optical Biometry  
(IOL Master) 
X3 
 
 
 
 
 
 
 
 
 
 
 
Cataract surgery and 
ARGOS-IO pressure sensor 
implantation 
 
X 
 
 
 
 
 
 
 
 
 
 
Visual acuity (ETDRS)4 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Perimetry5 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
External eye photography6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
User acceptance 
questionnaire (patient) 
 
 
 
 
 
 
 
 
 
 
 
X 
Implantation procedure 
questionnaire (surgeon) 
 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE/ADE/SAE/SADE 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Device malfunction 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ANTERIOR SEGMENT 
Slit-lamp biomicroscopy7 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Optical coherence 
tomography (OCT)8 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
Gonioscopy9 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
Confocal Microscopy10 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
POSTERIOR SEGMENT 
Biomicroscopy11 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Optical coherence 
tomography (OCT)12 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
Fundus photography 
X 
 
 
 
 
 
 
X 
 
X 
 
X 

 
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1 Eligibility must be reassessed at V01 prior to surgery. 
2 For females of childbearing potential, a pregnancy test performed within 24 hours preceding surgery must be negative to confirm eligibility. 
3 The Optical Biometry measurement using the IOL Master made at SC will be used to determine the implant sizes (IOL and ARGOS-IO  implant). 
4 The best corrected visual acuity will be determined after objective and subjective determination of refraction with the ETDRS chart in accordance 
with the EDTRS protocol. 
5 Perimetry is performed to obtain an accurate examination of the peripheral extent of the visual field. Automated perimeters will be used either 
with standard glaucoma field, field 30-2 or equivalent. 
6 External eye photography is performed through a slit lamp camera or equivalent. The outer eye shall be photographed in order to document 
potential changes to the iris or pupil structure. 
7 Slit-lamp biomicroscopy is performed though an undilated pupil to assess the following anatomic parameters of the anterior segment: lids, 
conjunctiva, cornea, anterior chamber, iris, pupil, lens and anterior vitreous. 
8 Anterior segment OCT is performed to evaluate effects on change in chamber angle after surgery and to assess the central corneal thickness. 
9 Standard gonioscopy is used to confirm glaucoma classification and to determine predilation angle evaluation, the presence of iris tumors, 
foreign bodies, anterior synechiae and to predict the anterior chamber angle. The gonioscopic grading system according to Spaeth is used in 
this clinical investigation. 
10 Standard confocal microscopy is used to determine the corneal endothelial cell density. 
11 Posterior segment biomicroscopy is performed though a dilated pupil using mydriatic agents by means of indirect ophthalmoscopy on a slit 
lamp with the aid of a 90D or “Superfield” or comparable lenses. This method is used to evaluate the following parameters: optic nerve lesions, 
other posterior pole lesions, vitreous opacities, optic nerve head, fundus lesions, retinal arteries and veins (AV), macular area, fundus 
periphery, normal and abnormal variations of the fundus. 
12 Posterior segment OCT is used to assess macular structures and the peripapillary nerve fiber layer. 
13 IOP measurements will be made in series of 1 Goldmann Applanation tonometry (GAT) standard measurements followed by 3 ARGOS-IO 
system measurements, the first of which must occur within 10 minutes of the GAT. A series of measurements will be made at both the 
beginning and end of each visit. An interval of at least 60 minutes should lie between the last measurement of one series and the first 
measurement in the next. 
14 At visits 5, 7, 9 and 11 at least 4 series of IOP measurements will be performed, with at least 60 minutes between the last measurement in 
one series and the first measurement in the next. 
15 All patients will receive a MESOGRAPH reading device at Visit 05 in order to measure the IOP daily at home. Measurements shall be taken at 
least 4 times per day (morning, noon, afternoon, evening). The MESOGRAPH reading device will be connected to an external GSM module, 
which will transfer the measured value directly to a secure database. Investigators can log into the database in order to track the pressure 
levels of their patients as required. 
 
Visit 
SC 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
V11 
Indicative Days (D) 
Up to 28 
days 
before 
surgery 
D0 
D1 
D3 
D10 
+/- 1 
Day 
D30 
+/- 5 
Days 
D60 
+/- 5 
Days 
D90  
+/- 10 
Days 
D120 
+/- 10 
Days 
D180  
+/- 10 
Days 
D240  
+/- 10 
Days 
D360  
+/- 10 
Days 
IOP Measurement 
Goldmann Applanation 
tonometry13 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ARGOS-IO pressure sensor 
measurement13 
 
 
 
 
 
X14 
X 
X14 
X 
X14 
X 
X14 
ARGOS-IO pressure sensor 
self-measurement15 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 

 
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9. 
STATISTICS 
9.1 
Statistical design, method and analytical procedures 
The primary purpose of this investigation is to assess safety of the investigational device. This will be 
judged statistically based on the number of individual patients experiencing serious device-related 
adverse events (SADEs). The study will be implemented in a two-stage design equivalent to the Simon 
optimum design to minimize the expected sample size (Simon, 1989). In the first stage, enrollment will 
be halted after 11 patients have received ARGOS-IO implants. An interim analysis will be conducted 
when these 11 patients have been followed-up for 3 months. If two or more patients experience SADEs 
in this time, the study will be stopped for safety reasons (Type I error rate = 0.05). If fewer than two 
have experienced SADEs, enrollment will be resumed and will be continued until a total of 22 patients 
have received ARGOS-IO implants. A final decision for safety will be drawn, if overall two or fewer of 
the total 22 patients have an SADE [SIMON optimum two stage design to minimize expected sample 
sizes, parameters: α=0.05, β=0.20, p0 = 0.75 (proportion in stage 1 without SADE), p1 = 0.94 (proportion 
overall without SADE)]. A corresponding 95% confidence interval for the proportion of the safety 
population with SADEs will be calculated using the method proposed by Koyoma and Chen (2008). 
 
Table 7. Study design 
 
First Stage 
Overall 
SADE-free Subjects 
Proportion 
Minimum number required 
 
p0 = 0.75 
10 
 
p1 = 0.94 
20 
Subjects with SADE 
Proportion 
Maximum number allowed 
 
1 - p0 = 0.25 
1 
 
1 - p1 = 0.06 
2 
Total Number of Subjects 
11 
22 
 
 
9.1.1 
Demographic and baseline characteristics 
Demographic characteristics (year of birth, sex, race, weight, height, educational level, pre-treatments 
and source of patient referral), length of time since diagnosis of glaucoma, anti-glaucoma medication, 
and other previous and concurrent treatments will be tabulated for the FAS. 

 
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9.1.2 
Patient Disposition 
The number and percentage of screened, enrolled and implanted patients, as well as those who 
complete the follow-up will be tabulated for the FAS and ITT population. The number and percentage 
of screen failures and early withdrawals will also be tabulated, along with the reason for the screen 
failure or drop-out. 
9.1.3 
Safety Analysis 
The safety rate within the safety population will be estimated with a 95% confidence interval taking 
into account the two-stage Simon design.  
9.1.4 
Performance Analysis 
The Bland-Altman method, which compares the mean of paired measurements to their difference will 
be used to determine the upper and lower limits of agreement expected to contain 95% of the IOP 
value pairs obtained with the ARGOS-IO system and GAT. The two-sided 95% confidence intervals for 
each of these limits will be calculated using the Mover method (Zou, 2011) to account for repeated 
observations. IOP values will be displayed as Bland-Altman plots of individual measurement pairs by 
measurement technique for each individual participant as well as mean plots over time.  
Because the ARGOS-IO implant is in direct contact with the aqueous humor and gives a digital readout 
of IOP, it is anticipated to objectively measure the true IOP. In comparison, although GAT is considered 
the gold standard, it measures IOP indirectly through applanation of the cornea and is known to be 
influenced by corneal thickness and biomechanical properties (Burr, et al., 2012). In addition, 
measurements with GAT are known to be subject to operator bias. 
Consequently, the absolute IOP values obtained with the ARGOS-IO system are expected to show a 
systematic shift in measurements compared to those obtained from indirect methods. However, 
deviation between the IOP measurements obtained with ARGOS-IO system and GAT over time should 
agree well with the shape of those obtained with the other methods. The limits of agreement will be 
calculated to provide an estimate of the agreement to allow direct comparison of values obtained with 
different methods. 
 
 

 
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9.2 
Sample Size Calculation 
The sample size calculation was based on the study’s purpose of establishing safety. 
To minimize the required sample size and consequently the number of patients exposed to risk while 
at the same time maximizing the chances of detecting safety events, a two-stage design based on the 
rate of non-events was chosen (Simon, 1989). The event of interest was defined as a serious device-
related adverse events (SADEs). Based on a probability of non-events of p0=0.75 for the first stage and 
an overall acceptable probability of p1=0.94, a sample size of at least 11 evaluable patients in the first 
stage and additional 11 patients in the second stage are required. This maintains a type 1 error 
probability of 5% and the power of 80% based on minimizing the maximal sample size and results in 
an expected sample size of 13.2 patients. 
9.3 
Level of significance and the power of the clinical investigation 
Significance level is set to 0.05, Power to 80%. 
9.4 
Expected drop-out rates 
This section is not applicable. 
9.5 
Pass/fail criteria to be applied to the results of the clinical investigation 
This investigation will be considered a success if fewer than two of the total 22 patients (stage 1 and 
2) experience SADEs during the follow-up period. 
9.6 
Interim analysis 
One interim analysis is planned for this study. It will take place when all patients in the first stage have 
completed the first 3 months of the follow-up period and will determine whether or not to continue 
the study to the second stage based on the number of patients experiencing an SADE.. 
9.7 
Criteria for termination of the clinical investigation on statistical grounds 
The participation of an individual site in the study will be discontinued if the sponsor, the investigator 
or the responsible ethics committee deems it necessary for any reason. 
The complete study will be discontinued: 

 
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 
If the sponsor and/or any responsible regulatory authority or ethic committee judge/s it 
necessary for any reason. See also section 8.9 Early Patient Withdrawal and section 12.10 
Criteria for Suspension and Premature Termination of Study 
 
If, during the course of the study, the DSMB comes to the conclusion that further implantation 
of the ARGOS-IO pressure sensor would subject study patients to undue risk 
 
If more than 1 patient in the first stage of the study experiences SADEs during the first 3 
months of the post-surgical follow-up period. 
Patients who until that time had had an ARGOS-IO pressure sensor implanted will continue to be 
followed up. 
9.8 
Procedures for reporting of deviations from the original statistical plan 
Significant deviations from the original statistical analysis plan will be listed and clarified in the final 
clinical investigation report. 
9.9 
Specification of Subgroups for Analysis 
In order to investigate the impact of certain characteristics on performance, the co-primary endpoints 
will also be examined by the following variables: 
 
Gender 
 
Post-surgery complications 
 
Successful implantation 
 
Age groups  
 
Concomitant medication 
 
Pre-treatment 
 
Size of ARGOS-IO implant 
 
Country of investigational site 
 
Educational level. 
9.10 
Treatment of missing, unused and spurious data, including drop-outs and 
withdrawals 
The handling of missing data will be detailed in the statistical analysis plan. 

 
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9.11 
Datasets to be analyzed 
9.11.1 
Safety population 
The data of all patients, with successful implantation of the ARGOS-IO implant, will be used for the 
safety evaluation. 
9.11.2 
The Full-Analysis-Set (FAS) population 
The FAS population comprises all subjects in whom an ARGOS-IO pressure sensor was successfully 
implanted. Measurements recorded by the patient will not be included into the evaluation of the FAS 
population. Additional information about the drop-outs: all patients who revoke their consent and 
agreement preoperatively will be regarded as screen failures and will not be included in the statistical 
evaluation. All patients who revoke their consent and agreement postoperatively will be considered 
withdrawals and their data will be evaluated in the safety analysis. 
9.12 
Exclusion of particular information from the testing of the hypothesis 
No particular information is planned for exclusion from the analysis. 
9.13 
Number of subjects at each site 
It is planned to enroll an approximately equal number of subjects at each site. 
10. 
DATA MANAGEMENT 
10.1 
Site Monitoring 
The study will be monitored in compliance with the Declaration of Helsinki, ISO 14155:2011, the 
Clinical Investigation Plan (CIP) and all applicable national and local regulations. All monitoring 
activities will be conducted by trained and qualified monitors, who will document each individual 
monitoring visit. In general, during monitoring visits the monitor will ensure that the study is being 
conducted according to the CIP, ISO 14155:2011, ICH GCP (International Conference on Harmonisation 
Good Clinical Practice) and other applicable regulations, and will compare the CRF entries to original 

 
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source data. He/she will also make sure the informed consent procedure has been appropriately 
carried out and will ensure that all SAEs have been reported within applicable timeframes. He/she will 
also ensure that investigational device accountability has been maintained and will, after completion 
of the study, perform final accountability and arrange return or destruction of investigational products. 
Detailed monitoring procedures will be described in a separate monitoring plan. 
10.2 
Data collection 
Data will be collected through a paper-based Case Report Form (CRF) provided by the sponsor or its 
designee to the centers prior to study start. The site will enter study data directly into the CRF during 
or as soon after the visit as possible. 
10.3 
Database Management and Quality Control 
The investigator is responsible for maintaining accurate, complete, and up-to-date records for each 
subject. This includes maintaining any source documentation related to the study. The anonymity of 
participating subjects must be maintained. The sites will maintain a list of the subjects´ names and the 
Patient ID assigned to each individual patient. Documents that identify the subject beyond the Patient 
ID will not be submitted to the sponsor (e.g. the signed informed consent document) and must be 
maintained in strict confidence by the investigator, except to the extent necessary to allow inspections 
by the regulatory authorities and audits by the study monitor or sponsor representatives. 
The investigator must promptly review the completed CRFs for each subject. As the person ultimately 
responsible for the accuracy of all CRF data, the investigator must confirm the entries with his/her 
signature at the end of each documented subject’s visit in the CRF. 
After data review, a paper-based query will be generated by data management for any missing, out of 
range or questionable data and sent to the physician for completion. The physician will answer the 
query and this answer will be documented. All queries must be answered and the database locked 
before any (interim) analysis of the data may begin.  
10.4 
Verification, validation and security of electronic data system 
It has been verified by the sponsor that only validated and secure electronic data systems will be used 
in this clinical investigation. Electronic data systems include the clinical data management database 

 
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and the ARGOS-IO system measurement database. Database validation and security follow the 
respective national and international requirements. 
10.5 
Data retention and Retention period 
10.5.1 
Investigator Records Retention 
All study documents must be retained by the investigator for a period of at least 15 years after 
completion of the study. The investigator at each investigational site must maintain adequate records 
of the clinical study, including: 
 Completed case report forms 
 Medical records 
 Signed informed consent forms 
 Product accountability 
 Shipment and receipt records  
 Adverse Events reports  
 All correspondence between the Investigator and the Ethics Committee, Regulatory 
Authorities, the sponsor and the CRO  
 Any other pertinent data relevant to the study 
The investigator must not destroy any study specific documentation before receiving written 
permission for this from the sponsor. Hospital records will be archived according to local regulations. 
10.5.2 
Sponsor Records Retention 
The sponsor will maintain the following records for at least 15 years after the last device has been 
manufactured or until the company ceases to exist: 
 All correspondence pertaining to the investigation 
 Signed and dated Investigator Agreements and signed and dated investigator curriculum vitae 
that were current at the time of the study 
 Copies of all EC approval letters, the EC review and approval procedures, and relevant EC 
correspondence  
 Names and addresses of the institutions where the clinical investigation was conducted, as 
well as records of approval from site administration 

 
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 Correspondence with authorities as required by national legislation 
 Insurance certificates 
 Adverse Events report forms 
 Names/contact addresses of monitors 
 Statistical analyses and underlying supporting data 
 Final and all interim reports of the clinical investigation 
 Study training records for site personnel and sponsor/CRO personnel. 
 Quality assurance 
To assure accurate, complete and reliable data, the sponsor or its representatives will do the following: 
 Provide instructional material to the investigational sites as appropriate 
 Perform a detailed initiation visit to instruct and train the investigational site personnel 
concerning the investigational device and all relevant study procedures 
 Perform regular monitoring visits at the investigational sites 
 Be available for consultation and stay in contact with study site personnel by mail telephone 
and fax 
 Review and evaluate CRF data on a regular basis 
 Conduct assessment of the site’s electronic patient database. 
In addition, the sponsor or its representatives may periodically check a sample of subject data recorded 
against source documents at the study site. 
To ensure the safety of study patients, and to ensure accurate, complete, and reliable data, the 
investigator will keep records of clinical notes and subject medical records in the patient files as original 
source documents for the study. If requested, the investigator will provide the sponsor, applicable 
regulatory agencies, and applicable ethical committees with direct access to original source 
documents. 
The study may be audited by the sponsor or its representatives at any time. Such an audit will be 
conducted according to a specific audit plan. Investigators will be given notice before an audit occurs. 
The regulatory authorities, both national and foreign, may inspect the study site at any time. The  
Investigator is responsible for notifying the sponsor of such an inspection immediately upon gaining 
knowledge of it. During the audit or inspection, the investigator/institution will permit the auditor, and 

 
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regulatory inspector(s) direct access to all relevant medical records and other source data, study 
related files and CRFs. 
11. 
ADVERSE 
EVENTS, 
ADVERSE 
DEVICE 
EFFECTS 
AND 
DEVICE 
DEFICIENCIES  
11.1.1 
Definitions 
The following definitions are based on ISO 14155:2011 and MEDDEV 2.7/3 (2010). 
11.1.2 
Adverse Event (AE) 
An Adverse Event (AE) is defined as any untoward medical occurrence, unintended disease or injury, 
or untoward clinical signs (including abnormal laboratory findings) in a subject, whether or not related 
to the investigational medical device 
NOTE 1: This definition includes events related to the investigational medical device or the control. 
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. 
11.1.2.1 Adverse Device Effect (ADE) 
Any Adverse Event (AE) that is related to the use of the investigational medical device is defined as 
Adverse Device Effect (ADE). 
NOTE 1: This definition includes adverse events resulting from insufficient or inadequate instructions 
for use, deployment, implantation, installation, or operation, or any malfunction of the investigational 
medical device. 
NOTE 2: This definition includes any event resulting from use error or from intentional misuse of the 
investigational medical device. 
11.1.2.2 Serious Adverse Events 
A Serious Adverse Event is defined as any Adverse Event that: 
 Led to death 
 Led to a serious deterioration in the health of a subject that: 
1. Resulted in a life-threatening illness or injury 

 
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2. Resulted in a permanent impairment of a body structure or body function 
3. Required in-patient hospitalization or prolongation of existing hospitalization 
4. Resulted in medical or surgical intervention to prevent permanent impairment to body 
structure or a body function 
 Led to fetal distress, fetal death or a congenital abnormality or birth defect  
NOTE: An Adverse Event is considered ‘Serious’ if any one of the conditions 1, 2, 3, or 4 applies in 
combination with serious deterioration in health (e.g. a pre-planned hospitalization for a pre-existing 
condition, without a serious deterioration in health, is not considered to be a SAE). 
NOTE for Germany: In Germany the term SAE is defined according to §2 Section 5 MPSV [Medical 
Devices Safety Plan Ordinance]. 
11.1.2.3 Serious Adverse Device Effect (SADE) 
An Adverse Device Effect that has resulted in any of the consequences characteristic of a SAE. 
11.1.2.4 Anticipated Serious Adverse Device Effect (ASADE) 
A Serious Adverse Device Effect (SADE) which by its nature, incidence, severity or outcome has been 
identified in the risk analysis report is defined as an Anticipated Serious Adverse Device Effect (ASADE).  
11.1.2.5 Unanticipated Serious Adverse Device Effect (USADE) 
A Serious Adverse Device Effect (SADE) which by its nature, incidence, severity or outcome has not 
been identified in the current version of the risk analysis report is defined as an Unanticipated Serious 
Adverse Device Effect (USADE). 
11.1.2.6 Device Deficiency 
An inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety or 
performance is defined as a Device Deficiency. 
NOTE: Device Deficiencies include malfunctions, use errors, and inadequate labeling. 
11.1.3 
Recording of Adverse Events (AEs) 
All Adverse Events (AEs) will be documented from the point of surgery until the subject is discharged 
from the study. 

 
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AEs will be collected with a non-leading question at each visit: “Have you had any new or worsening 
health problems since the last visit?” as well as by reporting those events directly observed and 
spontaneously reported by the subject. Clearly related signs, symptoms and abnormal diagnostic 
procedures should preferably be grouped together and recorded as a single diagnosis or syndrome 
whenever possible. Seriousness, severity (mild, moderate or severe), outcome and relationship to 
investigational device as well as expectedness and action taken will be recorded in the AE page of the 
CRF. Start and end date and time of the event will also be recorded. 
Seriousness 
Seriousness will be recorded as described in section 11.1.2.2. 
Intensity/Severity 
Severity of AEs will be assessed according to the following definitions: 
 Mild: sign or symptom of the AE is apparent but is easily tolerated by the subject 
 Moderate: the AE interferes somewhat with the subject’s usual activities (disturbing)  
 Severe: the AE prevents the subject from working or performing his/her usual activities 
(unacceptable).  
Relationship to study device 
Assessment of causality is based on the following considerations: associative connections (time and/or 
place), pharmacological explanations, previous knowledge of the device, presence of characteristic 
clinical or pathological phenomena, exclusion of other causes, and/or absence of alternative 
explanations. 
The investigator will assess causal relationship to the investigational device according to following 
classifications: 
 None: The time course between use of the device and occurrence or worsening of the AE rules 
out causal relationship; and/or another cause is confirmed and no indication for involvement 
of the study device in the occurrence/worsening of the AE exists 
 Unlikely: The time course between use of the device and occurrence/worsening of the AE 
makes causal relationship unlikely; and/or the known effects of the device provides no 
indication for involvement of the study device in the occurrence/worsening of the AE; and/or 

 
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although it is conceivable based on previous knowledge that study device may have causal 
relationship to occurrence/worsening of the AE, another cause is much more probable; and/or 
another cause is confirmed and involvement of the study device in the occurrence/worsening 
of the AE is unlikely 
 Possible: It is conceivable based on previous knowledge that study device may have causal 
relationship to the occurrence/worsening of the AE but other factors exist that are equally 
likely to be causative factors; or although the previous knowledge on study device does not 
provide any support for causal relationship, no other possible causative factors exist. 
 Probable: Time relationship exists; and previous knowledge on study device supports causal 
relationship although another cause cannot be ruled out. 
 Definite: The criteria for probable relationship are fulfilled and no other possible causative 
factors exist. 
Action taken 
The investigator will document the action taken in relation to the investigational device and to other 
treatments. The categories in relation to the investigational device are: 
 No action taken 
 Device removed 
 Subject withdrawn from the study 
 Other, specify 
The categories in relation to other treatments are: 
 No action 
 Medication given (must be specified in the concomitant medication page) 
 Non-medication treatment given (must be specified) 
 Hospitalization 
 Other, specify 
Outcome The investigator will document the outcome by choosing one of the following alternatives: 
 Recovered 
 Recovered with sequelae 
 Recovering 

 
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 Not recovered 
 Death 
 Unknown. 
All AEs will be reported on an Adverse Event Form, one for each Adverse Event, which is part of the 
Case Report Form. AEs will be followed for 2 years after surgery.  
11.1.4 
Reporting of Serious Adverse Events (SAEs) 
The reporting modalities for SAEs are defined in ISO 14155, MEDDEV 2.7/3 (Dec 2010) and local laws 
and regulations, in compliance with the requirements of Annex X of Directive 93/42/EEC, its 
amendment Directive 2007/47/EC, Annex 7 of Directive 90/385/EEC and local laws and regulations. 
SAEs need to be reported starting from ARGOS-IO pressure sensor implantation onwards. 
Information reported on the SAE form shall include (see MEDDEV 2.7/3 Appendix, SAE Report Table 8 
and/or national laws and regulations): 
 A description of the event 
 The date of event onset  
 The relatedness of the event to the procedure  
 The relatedness of the event to the device  
 The expectedness of a SADE  
 Actions taken as a result of the event  
 The outcome of the event 
 The date the event was first noticed by or reported to the investigator 
 The date the event was reported to the sponsor. 
Initial SAE reporting may be done by telephone or email, followed by the completed SAE form. Contact 
information is given on each SAE form and is available in the Investigator Site File. 
All other Adverse Events will be documented in the source documents and reported on the Adverse 
Event form in the CRF in a timely manner after the investigator first learns of the event. 
Table 8. Country-specific SAE reporting requirements 
Country 
SAE Form to be 
used 
Reporting 
Responsibilities 
Governing Law 
Reporting Timeline 

 
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Germany 
SAE Form 
(current version) 
provided by the 
Federal Institute 
for Drugs and 
Medical Devices 
(BfArM) 
Sponsor and 
investigator has to 
report the SAE to the 
Federal Institute for 
Drugs and Medical 
Devices (BfArM) 
German Medical Device 
Law (MPG) and 
Ordinance for Safety 
Reporting (MPSV) 
paragraph 3 section 5 
and paragraph 5 section 
2; EU directives 
90/385/EEC Annex 7 
number 2.3.5 and 
93/42/EEG (modified by 
directive 2007/47/EC) 
Annex X number 2.3.5 
Immediate 
reporting after 
occurrence 
Regulatory authorities and ECs will be informed about SAEs according to local regulations as described 
in Table 8. 
In case of an immediately reportable Adverse Event the investigators can contact MDSS GmbH and the 
Medical Device Safety Officer Tom Barkow via Phone, Fax or Email. 
Please send the completed form to: 
MDSS GmbH 
Schiffgraben 41 
30175 Hannover, Germany 
Phone: +49 (0) 511 6262 8630 
Fax: +49 (0) 511 6262 8633 
Email: info@mdss.com 
The sponsor should be informed in a parallel process. 
11.1.5 
Device Deficiencies 
The investigator will record all observed device deficiencies by completing a Device Deficiency Form. 
The reporting modalities are defined in ISO 14155:2011 and MEDDEV 2.7/3 in line with the 
requirements of Annex X of Directive 93/42/EEC and its amendment Directive 2007/47/EC, Annex 7 of 
90/385/EEC and local laws and regulations. 
All device deficiencies must be reported to the sponsor immediately. Any Investigational Medical 
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 must be reported as 
described in Table 8.6.3 following the SAE reporting modalities. 

 
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11.1.6 
Medical Care 
At all times during the study, the medical care of the subject is at the discretion of the investigator. 
Following the study, the subjects will return for standard control visits as needed. 
11.1.7 
Safety monitoring 
A Data Safety Monitoring Board (DSMB) was established prior to enrolment of the first subject. The 
composition, frequency of the meetings, and roles is detailed in the DSMB charter which was approved 
by the DSMB at its first meeting. 
In brief, the DSMB is composed of at least 3 members including two clinicians with expertise in 
Glaucoma and cataract surgeries and a biostatistician. Neither sponsor employees nor investigators 
participating in the study may be members of the DSMB. The DSMB is to review the safety data, 
including reported SAEs/SADEs, on a regular basis and advise the sponsor on any changes required to 
the conduct of the study.  
The first meeting is planned when the 11 patients in the first stage have completed their 3 month 
follow-up visits. Enrollment will be halted to allow the DSMB to review their data and for changes to 
be made to the clinical investigation plan, if recommended. The DSMB may hold additional meetings 
whenever deemed appropriate.  
It is foreseen that the DSMB may come to one of three types of recommendations, namely: 
1. 
Continue the study as planned --No safety issues exist and it is ethical and feasible to continue 
the study as planned. 
2. 
Continue the study with protocol amendments – Ethical to continue the study but recommend 
an amendment to the protocol (e.g. incorporate additional or more frequent safety 
examinations). 
3. 
Stop enrollment and treatment -- Sufficient evidence for a serious safety concern exists, 
making further implantation of ARGOS-IO pressure sensors in subjects unethical. 
11.1.8 
Sponsor Responsibilities 
The Sponsor is responsible for reporting Serious Adverse Events, interim or annual safety reports, 
premature termination or suspension of the clinical investigation, and the final Study Report to 
Regulatory Authorities, the ECs and investigators. Refer to Table 8. and  Table 9 for details.  
 
Table 9. Sponsor Reporting Responsibilities 

 
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Reporting Responsibility 
Reports to 
Description 
Serious Adverse Events 
(SAEs) 
Regulatory Authorities, 
ECs 
See Sections 11.1.2.2 for details 
Interim or annual safety 
reporting 
ECs and/or CA per local 
regulations 
An interim or annual safety report may be required 
by country regulations, or may be specifically 
requested by the EC/CA 
Premature termination or 
suspension of the clinical 
investigation 
Investigators, ECs, 
relevant Regulatory 
Authorities 
Provide prompt notification of termination or 
suspension and reasons 
Final Study Report 
Investigators, ECs, 
relevant Regulatory 
Authorities 
The sponsor will notify the investigators of the 
completion or termination of the study. A Final Study 
Report will be submitted to the investigators and the 
ECs following local regulations. 
 
12. 
ADMINSTRATIVE PROCEDURES AND RESPONSIBILITIES 
12.1 
Informed Consent 
Eligible patients may only be included in the study after providing written informed consent as 
approved by the responsible ethic committee. The Patient Informed Consent (PIC) form must be fully 
signed and dated prior to any study related activities required by the protocol (including any diagnostic 
testing, questionnaires, or other study-related procedures). Failure to obtain signed informed consent 
renders the patient ineligible for the study. 
A proposed PIC that complies with the ISO 14155:2011 standard and is considered appropriate for this 
study will be submitted to the Ethics Committees. The PIC will be translated into the local language of 
each country in which the study will be conducted and will contain language that is non-technical and 
understandable to the patient. Any changes to the PIC suggested by the investigator must be agreed 
to by Implandata Ophthalmic Products GmbH before submission to the EC and a copy of the EC 
approved version must be provided to the monitor after EC approval. 

 
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The Investigator or designated sub-investigator must explain the study to the patient in detail, talking 
through all points described in the PIC. The patient must be given the opportunity to ask questions and 
ample time to consider his/her participation. The patient will also be informed of his/her right to 
withdraw from the study at any time without giving a reason. If the patient is willing to participate in 
the study, he/she must sign and date two copies of the PIC, which must also be signed and dated at 
the same time by the investigator or designated sub-investigator who explained the study.  
One copy of the PIC will be given to the patient and the other will be retained in the Investigator Site 
File (ISF). 
Subject information and the PIC will be revised if new information becomes available or a CIP 
amendment is issued regarding patient’s safety, study procedures or any aspects of the study that 
could potentially influence the patient’s willingness to continue in the study. After the new patient 
information documents have been approval by EC and regulatory authorities, the patient will be 
informed of the changes and will be asked to sign the new consent form to confirm his/her 
continuation in the study. The investigator is to ensure that the patient is informed in a timely manner 
about any new safety-relevant information that could affect the patient’s willingness to continue in 
the study and agrees to request the patient’s consent again, if necessary. 
12.2 
Regulatory and Ethical Compliance 
This clinical study was designed and shall be implemented and reported in accordance with ISO 
14155:2011, with applicable local laws and regulations, and with the ethical principles laid down in the 
Declaration of Helsinki and described in the ICH-GCP guidelines. 
12.3 
Approval from Ethics Committee or Regulatory Authority 
The Clinical Investigation Plan (CIP) and the proposed PIC must be reviewed and approved by a properly 
constituted Ethics Committee (EC) before study start. A signed and dated statement from the EC that 
the CIP and PIC have been approved by the EC must be given to Implandata Ophthalmic Products 
GmbH before study initiation. 
The study must be reviewed and approved by the responsible Regulatory Authorities before study 
initiation, according to local and national regulations, if required. When an approval process is not 
required by the Regulatory Authority at least a notification shall be performed. Any additional 
requirements imposed by the EC or Regulatory Authority will be followed. 

 
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If any alterations, other than changes of an administrative nature only, are made to the study CIP, a 
formal CIP amendment will be issued and submitted to the relevant EC for approval. The amendment 
will not be implemented until EC approval, except in cases where immediate implementation is 
necessary to eliminate or prevent imminent hazard to the subjects. 
12.4 
Investigator Responsibilities for Ethics Committees and Regulatory Authorities 
Prior to study start, the investigator is required to sign a protocol signature page confirming his or her 
agreement to conduct the study in accordance with all of the instructions and procedures found in this 
protocol and associated documents and to give access to all relevant data and records to Implandata 
Ophthalmic Products GmbH, monitors, auditors, Quality Assurance representatives, designees, Ethics 
Committees, and regulatory authorities as required. If an inspection of the investigational site is 
requested by a regulatory authority, the investigator must immediately inform Implandata Ophthalmic 
Products GmbH that this request has been made. 
12.5 
Reporting responsibilities 
12.5.1 
Investigator Reporting Responsibilities 
The investigator or designee is responsible for completing (including review and signature) and 
submitting to the sponsor all case report forms, as well as reports of any Adverse Events (according to 
country-specific collection requirements), deaths or deviations from the clinical investigation plan. If 
any action is taken by the EC with respect to the investigation, the investigator will forward the 
information to the sponsor as soon as possible. Reports are subject to inspection and to the retention 
requirements as described in section 10.5. Refer to Table 6 for SAE reporting responsibilities. 
 
 

 
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12.5.2 
Sponsor Reporting Responsibilities 
The sponsor is responsible for reporting Serious Adverse Events, interim or annual safety reports, 
premature termination or suspension of the clinical investigation, and the Final Study Report. Refer to 
Table 7 for details. 
12.6 
Insurance  
The sponsor maintains appropriate clinical trial liability insurance coverage as required under 
applicable laws and regulations and will comply with applicable local law and custom concerning 
specific insurance coverage. If required, proof of the clinical trial insurance policy will be provided to 
the Ethics Committee. If required by national regulations, indemnification will be provided. 
12.7 
Amendments to the CIP 
The sponsor will inform the investigator about any relevant changes to the CIP. Changes will be 
documented as an amendment to the CIP that will be signed by each investigator. Unless required to 
prevent harm to a subject, no changes to the CIP may be implemented by the investigator before a 
fully approved amendment is available. If applicable, due to the nature of the amendment and in 
accordance with local regulations, EC and CA notification and/or approval is also required before the 
amendment is implemented.  
The investigator is expected to take any immediate action required to ensure the safety of any patient 
included in this study, regardless of any need for approval of formal protocol amendments, even if this 
action represents a deviation from the protocol. In such cases, the sponsor should be notified of this 
action promptly and the Ethics Committee responsible for the study site should be informed. 
12.8 
Deviations from the CIP 
The investigator is not allowed to deviate from the CIP, except when necessary to protect the life or 
physical well-being of a subject in an emergency situation or when caused by unforeseen 
circumstances that are beyond the investigator’s control (e.g. subject did not attend scheduled visit). 
Such approval will be documented in writing and maintained in the Investigator Site File (ISF) and Trial 
Master File (TMF). 

 
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The site will report all deviations, regardless of whether medically justifiable or taken to protect the 
subject in an emergency, to the sponsor in a timely manner on a protocol deviation form. In addition, 
the investigator is required to adhere to the Ethics Committee procedures for reporting deviations.  
Deviations include, but are not limited to the following list: 
 
Failure to obtain informed consent prior to conducting study specific activities  
 
Incorrect version of the PIC used 
 
Subject did not attend treatment visit, or visit was outside the required timeframe 
 
CIP-required testing and/or measurements were not done or were done incorrectly  
 
Adverse Events not reported by investigators within the required timeframe as specified in the 
CIP 
 
Source data permanently lost 
 
Pregnancy. 
A sponsor representative or monitor will review site compliance with regard to deviations at each 
monitoring visit. The monitor will discuss any deviations that occurred at the investigational site 
directly with the investigator and will summarize the findings in a follow-up letter to the site. In 
addition, all deviations from the CIP will be documented in the final study report. 
12.9 
Recording, Reporting, Analysis of CIP Deviations 
The site will report all deviations, regardless of whether medically justifiable, or taken to protect the 
subject in an emergency, to the sponsor in a timely manner on a protocol deviation form. In addition, 
the investigator is required to adhere to the Ethics Committee procedures for reporting deviations.  
Deviations include, but are not limited to the following list: 
 
Failure to obtain informed consent prior to conducting study specific activities  
 
Incorrect version of the PIC used 
 
Subject did not attend treatment visit, or visit was outside the required timeframe 
 
CIP-required testing and/or measurements were not done or were done incorrectly  
 
Adverse Events not reported by investigators within the required timeframe as specified in 
the CIP 
 
Source data permanently lost 

 
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 
Pregnancy. 
A sponsor representative or monitor will review site compliance with regard to deviations at each 
monitoring visit. The monitor will discuss any deviations that occurred at the investigational site 
directly with the investigator and will summarize the findings in a follow-up letter to the site. In 
addition, all deviations from the CIP will be documented in the final study report. 
12.10 
Corrective and preventive action and principal investigator disqualification criteria 
See section 12.8 Deviations from CIP. After analyzing and taking corrective actions, site personnel will 
be retrained by the sponsor or its representatives on the relevant study procedures. All necessary 
measurements will be taken to prevent re-occurrence of the protocol deviation. If despite this 
retraining an investigational site continues to deviate from the CIP, the site will be discontinued from 
the study. 
12.11 
Suspension or Premature Termination 
The sponsor may temporarily or permanently discontinue the study at a single site or at all sites for 
safety, ethical, compliance or other reasons. If this is necessary, the sponsor will endeavor to provide 
advance notification to the site. If the study is suspended or discontinued, the investigator or the 
sponsor will be responsible for promptly informing the ethics committee. The monitor will visit the site 
to conduct a study site closure visit. 
12.12 
Criteria for access to a breaking/masking code in the case of suspension or 
premature termination of the clinical investigation, if applicable 
This section is not applicable. 
12.13 
Subject follow-up requirements 
All pregnancies will be followed to birth. All on-going AEs will be followed-up until resolution or until 
7 days after the last subject has been discharged from the study. All SAEs will be followed-up until 
resolution or stabilization. 

 
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12.14 
Investigator and Site Selection 
Site selection will be based on the site’s experience with and access to patients requiring mitral valve 
repair/annuloplasty. Sites need to meet the following criteria: 
 Compliance: 
 Willing to comply with the Clinical Investigation Plan (CIP), all required procedures, the 
Declaration of Helsinki, ISO 14155 and national and local regulations 
 Expertise  
 Investigator experienced in the procedure of annuloplasty 
 Access to the patient population  
 Patient recruitment potential 
 Potential of 2-8 patients in the given timeline 
 Patient enrolment and site commitment not expected to be impacted by any competing 
studies 
 Clinical support staff  
 Study nurse/assistant/coordinator or equivalent who are adequately trained and willing 
to invest time in study administration and electronic data input 
 Time investment 
 Investigator has sufficient time to fulfill the study requirements, including reporting, and 
to attend the study meetings. 
 Equipment / Procedures 
 Separate rooms to perform study procedures 
 Sufficient, lockable storage capacities for study materials. 
 
 

 
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13. 
PUBLICATION POLICY 
13.1 
Study Report and Publication 
The sponsor is responsible for generating a Clinical Study Report of the study after the study is 
completed. This report, or parts of it, must be submitted to the relevant authorities if applicable. 
The publication of study results will be agreed between the sponsor and the investigator(s). The 
sponsor is interested in publishing the results of the study, but to prevent publication of any 
confidential information, the sponsor retains the right to review all publications and presentations 
before they are made public. 
 
 

 
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14. 
REFERENCES 
 
Bland, J., & Altman, D. (1986). Statistical methods for assessing agreement between two methods of 
clinical measurement. Lancet, S. i: 307-310. 
Burr, J., Botello-Pinzo, P., Takwoing, Y., Hernández, R., Vazques-Montes, M., Elders, A., & al, e. 
(2012). Surveillance for ocular hypertension: an evidence synthesis and economic evaluation. 
Health Technology Assessment, S. 16 (29). 
Cao, M. (2010). Silicone-Coated Microchip for Ocular Implantation. Atlanta, USA: NAMSA Advisory 
Services. 
Chapman, J. M., Cheeks, L., & Green, K. (Vol. 18, September 1992). Drug interaction with intraocular 
lenses of different materials. J Cataract Refract Surg, S. 456-459. 
Cihara, E. (2008). Assessment of true intraocular pressure: the gap between theory and practical 
data. Surv Ophthalmol, S. 203-218. 
Donaldson, P. (1991). Aspects of silicone rubber as an encapsulant for nerological prostheses Part 1. 
Osmosis. Medical and Biological Engineering and Computing, S. 29(1):34-49. 
Dreher, WF; Kern, N; Warres, C. (2010). 56586 Characterisation of Sensor Surface. Tübingen: NMI 
Natural and Medical Sciences Institute. 
Frampton, P. (2012). Tonometry: Does Historical Precedent and Familiarity Constrain Development. 
Ophthalmology Times. 
Görtz, M. (2010). Exemplarische Driftmessungen und Dichtigkeitstest für den 8D12-Prozess. 
Fraunhofer IMS,. 
Heijl, A., Traverso, C., & al, e. (2008). Terminology and Guidelines for Glaucoma. European Glaucoma 
Society. 
Hermann, M., Bron, A., & Creuzot-Garcher, C. D. (2010). Measurement of Adherence to Brimonidine 
Therapy for Glaucoma Using Electronic Monitoring. J Glaucoma, S. 8:502-508. 
Implandata. (2013). Klinischer Sicherheitsreport: Klinische Prüfung Intraokulärer Drucksensor 
"ARGOS", ref nr. Implandata GmbH. 
Implandata. (2014). Clinical Investigation Report: ARGOS 01. Hannover, Germany. 
Implandata. (2014). Investigator's Brochure: ARGOS-02 (01-RE-17A).  
Implandata Ophthalmic Products GmbH. (2014). Instructions for Use: ARGOS-IO Implant.  
ISO 14155. (2011). Clinical investigation of medical devices for human subjects - Good clinical 
practice. International Organization for Standardization. 
Kakaday, T., Hewitt, A., Voelcker, N., Li, J., & Craig, J. (2009). Advances in telemetric continuous 
intraocular pressure assessment. Br J Ophthalmology, S. 93: 992-996. 
King, A. (2013). Glaucoma. BMJ, S. 346: 3518. 
Koyama, T., & Chen, H. (2008). Proper inference from Simon's two-stage designs. Stat Med, S. 27 
(16):3145-54. 

 
Clinical Investigation Plan 
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ARGOS 02 
CIP Rev. C_20140218 
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Krug, A., Kompa, S., & Schrage, N. F. (25. 3 2002). The Aachen-keratoprothesis--a felxible KPro That 
Permits Intraocular Pressure Measurement. The International Journal of Artifical Organs, S. 
238-242. 
Liang, S., Lee, G., & Shields, D. (2009). Self-tonometry in Glaucoma Management -- Past, Present and 
Future. Survey of Ophthalmology, S. 54: 450-462. 
Lopez, M., Melki, S., & Dohlmann, C. H. (2013). Two keratoprosthesis patients with intraocular 
pressure sensor - followed for two years. Unpublished Data. 
Mansouri, K., & Shaarawy, T. (2011). Continuous intraocular pressure monitoring with a wireless 
ocular telemetry sensor: initial clinical experience in patients with open angle glaucoma . Br J 
Ophthalmol, S. 95: 627-629. 
MEDDEV 2.7/3. (2010). Clinical Investigations: Serious Adverse Event Reporting under Directives 
90/385/EEC and 93/42/EEC. European Commission Directorate General for Health and 
Consumers. 
Melki, S., Todani, A., & Cherfan, G. (2013). Telemetric Intraocular Pressure Measurement: Report of 
First Human Implantation. Unpublished data. 
Melki, S., Todani, A., & Cherfan, G. (2014). An Implantable Intraocular Pressure Transducer: Initial 
Safety Outcomes. in press. 
Meyer, S. (2014). ARGOS-IO Implant: Risk Management Report. Hannover, Germany: Implandata 
Ophthalmic Products GmbH. 
Niedhart, C; Müller, U. (2011). Investigation Report B0062/11 Cytotoxicity Investigations. Aachen: 
BMP Labor für medizinische Materialprüfung GmbH. 
Paschalis, E., Cade, F., Melki, S., Pasquale, L., Dohlman, C., & Ciolino, J. (2014). Reliable intraocular 
pressure measurement using automated radio-wave telemetry. Clinical Ophthalmology, S. 8: 
177-185. 
Quigley, H. (2011). Glaucoma. S. 377: 1367-77. 
Rotchford, A., & King, A. (2012). Repeatability of measurements of effectiveness of glaucoma 
medication. Br J Ophthalmol, S. 96: 1494-1497. 
Simon, R. (10 1989). Optimal Two-Stage Designs for Phase II Clinical Trials. Controlled Clinical Trials, S. 
1-10. 
Spaeth, G. L. (Vol. 91 1971). The normal developmentof the human anterior chamber angle: a new 
system of descriptive grading. Trans Opthalmol Soc UK, S. pp. 709-739. 
Todani, A., Behlau, I., Fava, M., Cade, F., Cherfan, D., Zakka, F., . . . Melki, S. (2011). Intraocular 
Pressure Measurement by Radio Wave Telemetry. Invest Ophthalmol Vis Sci, S. 52: 9573-
9580. 
Werner, L., Apple, D., & Mamalis, N. (2010). Opacification and coloration of Intraocular Lenses. In R. 
Steinert, Cataract Surgery, 3rd Edition. 
Zou, G. (2011). Confidence interval estimation for the Bland-Altman limits of agreement with 
multiple observations per individual. Stat Methods Med Res, S. 0 (0): 1-13. 
 

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Addendum to Clinical Investigation Plan: A prospective, 
open'label,
multicenter 
clinical investigation 
to assess 
the safety and performance 
of
ARGOS-IO 
system in patients with Primary Open Angle Glaucoma 
(POAG)
To Current Revision: ARGOS-O2 CIP RevC 2OL4O2L8
Part 1: Enrollment
Page 8, Table: Synopsis, Row: Study Design:
RevC
This clinical investigation 
prospective, 
open-label, 
multicenter, 
single-arm 
clinical investigation 
will be
conducted in two stages using a Simon two-stage design. Subjects will be enrolled as follows:
First stage: 11 patients
Second stage: 11 patients
An interim analysis will be performed when the 11 patients of the first stage have completed their 3
month follow-up visits. The trial will be stopped if 2 or more patients have experienced a serious
adverse device events (SADE) 
at this time. Otherwise enrollment will be resumed and the trial
continued untilan additional 11 patients have been enrolled in stage 2 and received ARGOS-IO
implants. A conclusion 
for safety will be made if in total no more than 2 of the total of 22 patients
experience 
an SADE.
Ammended
This prospective, open-label, multicenter, single-arm clinical investigation will enroll 22 consecutive
Patients.
Enrollment will be temporarily halted in case a serious adverse device effect (SADE) 
occurs, and a
Data and safety Mohitoring Board (DSMB; see section "safety Monitoring" on page 16) meeting will
be conducted as soon as possible. 
The DSMB will then recommend whether to further continue the
study as planned, or whether enrollment shall be stopped. A conclusion 
for safety will be made if in
total no more than 2 of the total of 22 patients experience an SADE.
Page & Table: Synopsis, 
Row: Sample Size Considerations:
RevC
The primary aim of this study is to show "safety'', which will be evaluated based on the percentage of
. " subjects who experience 
an SADE (= "non-safety), 
as defined in the primary endpoints.
. 
For the study as a whole, "safety" will be determined based on the following decision rule: if in stage
1 the non-safety event rate is greater than 25oÄ,the trial will be stopped (type 1 error rate of 0.05). lf

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the non-safety event rate is lower than 25To, the study will be continued into stage 2. lt will be
declared a success if the final non-safety event rate is less than 5% (type ll error rate of 0.20) The
calculation 
is based on a two-stage Simon design optimizing the minimum expected sample size with
parameters c=0.05, F=0.2O ps= 0.75, Fr = 0.94.
Ammended
The primary aim of this study is to show "safety", which will be evaluated based on the percentage 
of
subjects who experience 
an SADE (= "non-safety), 
as defined in the primary endpoints.
The study will be declared a success if the final non-safety event rate is less than 5% (type ll error
rate of 0.20) The calculation 
is based on a design optimizing the minimum expected sample size with
parameters c=0.05, F=0.20, po = 0.75, Fr = 0.94.
Page 16, Table: Synopsis, Row: Safety Monitoring:
RevC
A data safety monitoring board (DSMB) will be established 
prior to enrollment of the first patient.
The DSMB is to review the safety data, including SAEs/SADEs, 
on a regular basis and will advise on
any changes required in the conduct this clinical investigation. 
The DSMB will also review the data of
the interim analysis and give recommendations 
to the Sponsor to either continue the clinical
investigation 
(with or without an amendment of the clinical investigation 
plan) or to stop enrolment
into the clinical investigation 
based on safety concerns.
Ammended
A data safety monitoring board (DSMB) 
will be established 
prior to enrollment of the first patient.
The DSMB is to review the safety data, including SAEs/SADES, 
on a regular basis, or if a SADE occurs,
and will advise on any changes required in the conduct of this clinical investigation.
Page 60, 8.1.1 Description of the type of clinical investigation:
RevC
The trial will be coiducted as an open, prospective, 
multicenter single-arm 
clinical trial using the
two- stage design described by Simon (Simon, 1989). In the first stage, 11 patients will have an
ARGOS-IO 
pressure sensor implanted, after which enrollment will be halted untilthe patients have
completed their 3 months follow-up visits and an interim analysis 
has been performed. The interim
analysis 
will be reviewed by the DSMB. lf two or more of these 11 patients in the first stage are found
to have had an SADE, 
further enrollment into the study will be stopped. lf not, enrollment will
resume until.another 11 patients have had an ARGOS-IO 
pressure 
sensor implanted. lf two or fewer
of the total 22 patients experience 
an SADE, 
a conclusion 
for safety will made at the 5% significance
fevel. A coriespondingg5oÄ 
confidence interval for the SADE rate will be calculated 
according to the
procedure of Koyoma (2008).

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All patients who receive an ARGOS-IO 
implant will return for 10 follow-up visits to the clinic (day 1, 3,
10, 30, 60, 90, 120, 180, 240,360l,during the 12-month post-surgical 
period (see Table 5: Assessment
Schedule). 
To allow comparison 
of the IOP measurement 
methods, IOP measurements 
will be made
at every visit with GAT and with the ARGOS-IO 
systems beginning 
at V5 (day 30).
Ammended
The trial will be conducted as an open, prospective, 
multicenter single-arm 
clinical trial. All 22
patients will be enrolled consecutively, 
until a SADE occurs. In that case, the DSMB will be called, and
decides whether the enrollment can be continued or not. lf two or fewer of the total 22 patients
experience 
an SADE, 
a conclusion 
for safety will made at the 5% significance 
level. A corresponding
95% confidence interval for the SADE rate will be calculated according to the procedure of Koyoma
(2008).
All patients who receive an ARGOS-IO 
implant will return for 10 follow-up visits to the clinic (day 1, 3,
10, 30, 60, 90, 120, 180, 240, 360) during the 12-month post-surgical 
period (see Table 6: Assessment
Schedule). 
To allow comparison 
of the IOP measurement 
methods, IOP measurements 
will be made
at every visit with GAT and with the ARGOS-IO 
systems beginning 
at V5 (day 30).
Page 66, 8.3.3.1 Study stopping rules:
RevC
As described in section 9, the study will be conducted in two stages. In the first stage, 11 subjects will
receive ARGOS-IO 
implants, after which implantation will be halted. Once these subjects have
completed their 3 months follow-up visits, the interim results will be evaluated by the DSMB. The
study will be stopped for safety reasons if at the time of the interim analysis 
two or more of these 11
subjects have had SADEs or if the DSMB othenrvise determines that severe safety risks to the
subjects exist.
lf more than two patients in the first stage of the study experience SADEs, 
the study will be stopped
for safety reasons,
The study may be discontinued 
at any time for administrative 
reasons; 
if new negative data about
the investigational 
device resulting from this or any other studies becomes available; 
and/or on
advice of the DSMB, the sponsor, the investigators, 
and/or the EC or regulatory authorities.
lf the study is prematurely 
terminated or suspended, 
the sponsor will promptly inform the
investigators, 
the Regulatory 
Authorities and the ECs of the reason for termination or suspension. 
lf
the study is prematurely 
terminated for any reason, the investigator 
should promptly inform the
study subjects and assure they receive appropriate 
therapy and/or follow-up.
The study can be terminated at any time for any reason by the sponsor.

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Ammended
Enrollment 
will be stopped 
at the occurrence 
of a SADE. 
At this point, a DSMB 
meeting 
will be called.
The DSMB 
will then evaluate 
the SADE, 
and decides 
as to whether enrollment 
will be ended, and will
also decide on how to proceed 
further with the conduct 
of the study.
The study may be discontinued 
at any time for administrative 
reasons; 
if new negative 
data about
the investigational 
device resulting 
from this or any other studies 
becomes 
available; 
and/or on
advice 
of the DSMB, 
the sponsor, 
the investigators, 
and/or the EC or regulatory 
authorities.
lf the study is prematurely 
terminated 
or suspended, 
or enrollment 
is stopped, 
the sponsor 
will
promptly inform the investigators, 
the Regulatory 
Authorities 
and the ECs of the reason for
termination 
or suspension 
or stop of enrollment. 
lf the study is prematurely 
terminated 
for any
reason, 
the investigator 
should promptly 
inform the study subjects 
and assure 
they receive
appropriate 
therapy and/or follow-u 
p.
The study can be terminated 
at any time for any reason 
by the sponsor.
Page 84 9.1 Statistical design, method and analytical procedures:
RevC
The primary purpose of this investigation is to assess safety of the investigational device. This will be
judged statistically based on the number of individual patients experiencing 
serious device-related
adverse events (SADEs). 
The study will be implemented in a two-stage design equivalent to the
Simon optimum design to minimize the expected sample size (Simon, 1989). In the first stage,
enrollment will be halted after 11 patients have received ARGOS-IO 
implants. An interim analysis 
will
be conducted when these 11 patients have been followed-up for 3 months. lf two or more patients
experience 
SADEs 
in this time, the study will be stopped for safety reasons (Type I error rate = 0.05).
lf fewer than two have experienced 
SADEs, 
enrollment will be resumed and will be continued until a
total of 22 patients have received ARGOS-IO 
implants. A final decision for safety will be drawn, if
overalf two or fewer of the total22 patients have an SADE ISIMON optimum two stage design to
minimize expected sample sizes, parameters: q,=0.05, 9=0.20, po = 0.75 (proportion in stage 1
without SADE), pr = 0.94 (proportion overall .without SADE)]. A corresponding 95% confidence
interval for the proportion of the safety population with SADEs 
will be calculated using the method
proposed by Koyoma and Chen (2008).

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Table 1. Study design
Oteiäü
SADE-free Subjects
Proportion
Minimum 
number 
required
Po = 0'75
10
Pr = 0.94
20
Subjects 
with SADE
Proportion
Maximum number allowed
1- Po = 0.25
a
1- Pr = 0.06
2
Total Number of Subjects
L L
22
Ammended
The primary purpose of this investigation 
is to assess 
safety of the investigational 
device. This will be
judged statistically based on the number of individual patients experiencing 
serious device-related
adverse events (SADEs). 
Patients will be enrolled consecutively 
until a total of 22 patients have
received ARGOS-IO 
implants. A final decision for safety will be drawn, if overall two or fewer of the
total 22 patients have an SADE [parameters: p, = 0.94 (proportion overall without SADE)]. A
corresponding95% 
confidence 
interval for the proportion of the safety population with SADEs 
will be
calculated using the method proposed by Koyoma and Chen (2008).
Table 2. Study design
Page 87,9.2 Sample Size Calculation:
RevC
The sample size calculation 
was based on the study's purpose of establishing 
safety.
To minimize the required sample size and consequently 
the number of patients exposed to risk while
at the same time maximizing 
the chances 
of detecting safety events, a two-stage design based on the
rate of non-events 
was chosen (Simon, 1989). The event of interest was defined as a serious device-
related adveise events (SADEs). 
Based on a probability of non-events 
of p0=0.75 for the first stage
and an overäll acceptable 
probability of pL=0.94, a sample size of at least 11 evaluable patients in the
first stage and additional 11 patients in the second stage are required. This maintains a type 1 error
O\rärgll
SADE-free 
Subjects
Proportion
Minimum number required
Pr = 0.94
20
Subjects with SADE
Proportion
Maximum number allowed
1- Pr = 0.06
2
Total Number of Subjects
22

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probability of 5% and the power of 80% based on minimizing 
the maximal sample size and results in
an expected sample size of 13.2 patients.
Ammended
The primary aim of this study is to show "safety", which will be evaluated based on the percentage 
of
subjects who experience 
an SADE (= "non-safety), 
as defined in the primary endpoints.
The study will be declared a success if the final non-safety event rate is less than 6% (type ll error
rate of 0.20) The calculation 
is based on a design optimizing the minimum expected sample size with
parameters 
c=0.05, 9=0.20, Po= 0.75, Pr = 0.94. According 
to Table 7, those parameters 
will be
fulfilled if 2 or less SADE will occur in a sample of 22 patients.
Part 2: Interim Analysis
Page 16, Table: Synopsis, Row: Data Analysis and Statistics, ltem: Interim Analysis:
RevC
An interim analysis 
to assess 
SADE 
will be performed, 
when the first 11 patients have completed 
the
3 month follow-up 
visit.
Ammended
An interim analysis 
to assess 
Safety and Performance 
will be performed, 
when the all patients have
completed 
the 6 month follow-up 
visit or if an SADE 
occurs.
Page 87, 9.5 lnterim Analysis:
RevC
One interim analysis is planned for this study. lt will take place when all patients in the first stage
have completed the first 3 months of the follow-up period and will determine whether or not to
continue the study to the second stage based on the number of patients experiencing 
an SADE..
Ammended
An interim analysis is planned for this study. lt will take place when all patients have completed 6
month follow-up period, or each time an SADE occurs, prior to the regular DSMB meeting

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Part 3: lmplant size selection
Page 7 4, 8.4.4. 13 ARGOS-IO impla nt size assessment :
RevC
The ARGOS-IO 
implant size will be determined based on the horizontal White-to-White (WTW)
measurement obtained with the IOL Master. At least three WTW measurements 
will be taken and
the average calculated. The average in mm will then determine the right ARGOS-IO 
implant size
(Table 5).
Ammended
The recommended ARGOS-IO 
implant size will be determined based on the horizontal White-to-
White UffW) measurement obtained with the IOL Master. At least three WTW measurements will
be taken and the average calculated. The average in mm will be used for fitting the ARGOS-IO
implant size (Table 5). The investigator may re-assess 
this selection if intraoperative findings
prescribe a different implant size.

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CIP amendment reviewed and approved by:
Primory lnvestigotor of ARGOS02 
Clinicol lnvestigation:
Prof. Dr. med. Hagen Thieme
Institution
/f'u,,
Date
Sponso 
r Re prese 
ntative s :
Max Ostermeier
Managing 
Director, Sponsor
Stefan Meyer
Chief Technology Officer, Sponsor
University Eye Clinic Magdeburg
Leipziger Str. 44
39L2O Magdeburg
LL
Signature
s4=
Signature
April 13,2015
Date
April 13,2015