A Prospective Open-label, Multicenter Clinical Investigation to Assess the Safety and Performance of ARGOS-IO System in Patients Undergoing Implantation of a Boston Keratoprosthesis (BKPro)
Phase: NA
Conditions: Graft vs Host Disease, Congenital Aniridia, Chemical Burns, Stevens-Johnson Syndrome, Congenital Glaucoma
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 REPORT 
A prospective, open-label, multicenter clinical investigation to assess the 
safety and performance of ARGOS-IO system in patients undergoing 
implantation of a Boston Keratoprosthesis (BKPro) 
Reference Number: ARGOS-KP01 
 
Investigational Medical Device: 
ARGOS-IO Intraocular Pressure Sensor Implant 
Study Design: 
Open-label, multicenter, single-arm, safety and performance study 
EudaMed No.: 
CIV-14-09-012725 
Sponsor: 
Implandata Ophthalmic Products GmbH 
 
Kokenstrasse 5, 30169 Hannover, Germany 
 
Max G. Ostermeier, Managing Director 
Stefan Meyer, Chief Technical Officer 
 
Telephone: 
+49 (0) 511 2204 2580 
 
Fax: 
+49 (0) 511 2204 2589 
 
E-mail: 
mostermeier@implandata.com 
smeyer@implandata.com 
Coordinating Investigator: 
Prof. Dr. med. Thomas Neuhann 
 
MVZ Prof. Neuhann 
Helene-Weber-Allee 19, 80637 München 
Report Author: 
Janina Hadeler 
Clinical Study Manager, Implandata Ophthalmic Products GmbH 
Report Date: 
25-JUL-2018 
 
 
Statement of Compliance 
This investigation was conducted in compliance with the protocol, ISO 14155:2011, the Declaration of 
Helsinki, International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines and 
applicable local and regional laws and regulations. 
 
 

 
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Summary 
SPONSOR 
Implandata Ophthalmic Products GmbH 
INVESTIGATIONAL DEVICE 
ARGOS-IO Intraocular Pressure Sensor Implant and Reader 
STUDY TITLE 
A prospective, open-label, multicenter clinical investigation to assess the safety and performance of ARGOS-IO 
system in patients undergoing implantation of a Boston-Keratoprosthesis (BKPro) 
EudaMed No.: 
CIV-14-09-012725 
STUDY PERIOD 
Date of First Enrollment: 12 February 2015 
Date of Last Patient Last Visit: 14 June 2017 
DATE OF REPORT: 
25-JUL-2018 
INTRODUCTION 
The ARGOS-IO system combines an implantable intraocular pressure sensor ring (4 haptics at the outer edges of 
the implant; diameter is available in three sizes 11.3, 11.7 and 12.1 mm; inner diameter 7 mm, thickness 
0.5 mm on the edges of the device, tapering to a 0.1 mm rounded outer haptics) with a hand-held reading 
device (MESOGRAPH) to measure intraocular pressure (IOP). The ring, consisting of microelectromechanical 
system application specific integrated circuit (MEMS-ASIC) bonded to a gold micro-coil and encapsulated in 
silicone-rubber, is implanted during Boston-Keratoprosthesis surgery. The implant is introduced into the ciliary 
sulcus using an open sky approach (through trepanation). In case of inadequate or missing capsular or iris 
support, the implant may be sutured transsclerally. An electromagnetic inductive connection between the coil 
of the sensor and the activated reader powers the ASIC, thereby initiating a pressure reading and enabling 
telemetric data transfer.  
Even though the implant contains a complex application-specific integrated circuit (ASIC), from a risk 
management view-point this implant is a simple product with a potential for mainly mechanical risks to the 
patients. ARGOS-IO is a diagnostic device for measuring intraocular pressure in Boston-Keratoprosthesis 
patients. It is not a life-supporting or life-sustaining implant and its malfunction in the worst case scenario will 
merely result in a wrong pressure measurement value. The IOP measurements obtained by this device is 
intended as only one of the inputs used for IOP monitoring in Boston-Keratoprosthesis patients. The ARGOS-IO 
implant is intended for permanent implantation but can be explanted. The implant does not contain a software.  
12 patients received ARGOS-IO implants in this open-label clinical investigation. During the 12 months following 
surgery, the patients returned for 13 follow-up visits consisting of comprehensive ophthalmic examinations as 
well as IOP measurements with the ARGOS-IO system, finger palpation and surgical manometry at Visit 7, 9, 11 
and 15. 
OBJECTIVES 
PRIMARY:  
Safety 
To evaluate the safety and tolerability of the ARGOS-IO pressure sensor in the 12 months following 
implantation. 
 
Performance 
To evaluate the performance of the ARGOS-IO system compared to manometry in the 12 months following 
implantation. 
 
SECONDARY:  
Safety 
• 
To evaluate the safety and tolerability of ARGOS-IO pressure sensor use in the first 4, 16 and 28 weeks 
after implantation. 

 
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Performance 
• 
To compare the IOP measured with the ARGOS-IO system to that obtained with manometry at week 4, 
16 and 28 after implantation. 
 
ENDPOINTS 
PRIMARY: 
Safety 
- 
Number of subjects experiencing at any time during the first 12 months a device related SAE defined 
as any adverse event that both 
➢ Is considered by the Investigator to have a possible, probable or definite relationship to the 
device and  
➢ That leads to any of the following: 
▪ 
Death 
▪ 
A serious deterioration in the health of the subject that results in a life-threatening 
illness or injury or a permanent impairment of a body structure or function, or that 
requires medical/surgical intervention to prevent such 
▪ 
Hospitalization or prolongation of existing hospitalization 
▪ 
Fetal distress or death or a congenital abnormality or birth defect. 
Performance 
- 
Level of agreement between IOP measurements made using manometry and the ARGOS-IO system 
over the first 12 months following implantation 
 
SECONDARY: 
Safety 
- 
Incidence, nature, seriousness, severity and duration of adverse events and adverse device events in 
the first 4, 16 and 28 weeks and 12 months following implantation of the ARGOS-IO pressure sensor. 
Performance 
- 
Level of agreement between IOP measurements made using surgical manometry and the ARGOS-IO 
system at 4, 16, 28 and 52 weeks following implantation 
- 
Incidence of device deficiencies in the first 4, 16, 28 and 52 weeks 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 Questionnaires (investigators). 
- 
Daily IOP self-measurement profiles (patients). 
 
STUDY DESIGN AND METHODOLOGY 
DESIGN: Prospective, open-label, multicenter, single-arm, safety and performance study. 
TREATMENT ALLOCATION: non-randomized, open-label. 
TREATMENT: Implantation of an ARGOS-IO pressure sensor in the ciliary sulcus concomitantly to Boston 
Keratoprosthesis implantation. 
CONTROL: Comparison of IOP values obtained with the ARGOS-IO system to those with surgical manometry 
(V7, V9, V11, V15) at the same time point. 
FOLLOW-UP: 13 post-surgical visits over a 12-month period with comprehensive ophthalmic examinations and 

 
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IOP measurements with finger palpation, surgical manometry (V 7, 9, 11, 15) and ARGOS-IO system. 
STATISTICAL METHODS:  
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. The Per Protocol Set (PPS) will comprise all subjects in whom 
an ARGOS-IO pressure sensor was successfully implanted and for whom the full data set including IOP 
measurements made in the clinic and safety data according to protocol are available until 28 weeks (Visit 11) 
after surgery 
 
Statistical analysis 
Safety analysis 
AEs, SAEs, ADEs and SADEs will be listed. Incidence will be estimated with a 95% confidence interval (Pearson-
Clopper, two-sided).  
 
Performance analysis 
The Bland-Altman method will be used to assess the limits of agreement between the IOP measurements 
ARGOS-IO and surgical manometry. When appropriate, two-sided 95% CIs, for these limits 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. 
 
STUDY POPULATION 
INCLUSION CRITERIA 
Eligible subjects must meet all the following inclusion criteria: 
1. Male or female aged ≥ 18 and ≤ 80 years on the day of screening 
2. Keratoprosthesis surgery indicated, defined as having a severely opaque and vascularized cornea AND 
either a verifiable history of two or more prior failed corneal transplant procedures or a medical 
condition such as alkali burns or autoimmune disease that makes the success of a traditional corneal 
transplant procedure unlikely. Potential study subjects will be solicited for participation in the clinical 
trial only after they have consented to the keratoprosthesis operation. 
3. Axial length > 21 mm 
4. Ability and willingness 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. Reasonable chance of success with traditional keratoplasty 
2. Current retinal detachment 
3. Connective tissue diseases 
4. 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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5. History of ocular or periocular malignancy  
6. History of extensive keloid formation 
7. Any known intolerance or hypersensitivity to topical anesthetics, mydriatics, or silicone (component of 
the device) 
8. Presence of another active medical eye implant and/or other active medical implants in the head/neck 
region 
9. Signs of current infection, including fever and current treatment with antibiotics 
10. Severe generalized disease that results in a life expectancy shorter than a year  
11. Any clinical evidence that the investigator feels would place the subject at increased risk with the 
placement of the device 
12. Currently pregnant or breastfeeding 
13. 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 
14. Intraoperative complication that would preclude implantation of the study device  
15. 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. 
16. Previous or concurrent enrollment of the contralateral eye in this clinical study. 
 
NUMBER OF PATIENTS (PLANNED AND ANALYSED): This exploratory study was planned to enroll a minimum of 
10 and a maximum of 15 patients. The sample size was chosen pragmatically based on the number of patients 
expected to undergo BKPro implantation at the study sites during a 12 months period. It is anticipated to be 
large enough to provide an initial estimate of common safety events and assessment of performance. 
In this clinical trial a total of 14 patients with an indication for Boston-Keratoprosthesis implantation were 
screened and 13 patients initially enrolled, 12 of whom successfully received the ARGOS-IO implant.  
One of the screened patients (DE-3-01) was excluded due to a screening failure. Due to a detected capsular bag 
instability during surgery, an implantation of the ARGOS-IO pressure sensor was not attempted in a second 
patient (DE-2-03). 
Nine out of 12 patients completed the study with the sensor implanted. One patient voluntary withdrew with 
sensor left in place. In two patients, the ARGOS-IO sensor was explanted, either after dislocation of the sclera-
fixed implant (DE-1-07) or in the course of multiple additional surgeries (DE-1-05, corneal graft melt twice). 
RESULTS 
PERFORMANCE RESULTS:  
IOP estimation by finger palpation was grouped in four categories: normal (A), soft/hypotonic (B), borderline (C) 
and hypertonic (D). Mean telemetric IOP was 18.2±6.1 mmHg in category A, 8.9±2.8 mmHg in B, 22.4±4.9 
mmHg in C, 34.3±11.0 mmHg in D. In visits with manometry, mean manometric IOP was 19.0±8.4 mmHg, mean 
telemetric IOP was 22.8±11.7 mmHg. Excluding three presumed measuring errors, the two modalities had a 
correlation of r=0.874 (P<0.001). 
SAFETY RESULTS: 
Overall 168 AEs in 13 patients were reported during the ARGOS-KP01 study including 23 SAEs in 9 patients. Only 
15 AEs in four patients were possible related to the medical device: anterior chamber cell, cystoid macular 
edema, hypotony of the eye, iris adhesion, pigment dispersion, vitritis, increased intraocular pressure and 
retroprosthetic membrane, six thereof serious. 
However, all potential ADE’s can be caused by the stand-alone procedure and they are not of a higher 
percentage in this study than in other known publications.  

 
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CONCLUSIONS: 
The implantable ARGOS-IO pressure sensor in Boston-Keratoprosthesis patients was well tolerated. The 
observed adverse events constitute known complications of keratoprosthesis surgery. The implant does not 
appear to be associated with additional or more severe complications. The system showed a good and reliable 
performance in comparison to other IOP measuring modalities.  
 
 
 

 
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Table of Contents 
 
Summary ..................................................................................................................................... 3 
Table of Contents ......................................................................................................................... 8 
Abbreviations and Definitions..................................................................................................... 13 
1 
Introduction........................................................................................................................ 15 
1.1 
Keratoprosthesis Devices...................................................................................................... 15 
1.2 
Limitations of Existing Treatments ....................................................................................... 16 
1.3 
State of Device Development ............................................................................................... 16 
2 
Investigational Device and Methods .................................................................................... 19 
2.1 
IMD Classification and Intended Use .................................................................................... 19 
2.1.1 
 Accessoiries .......................................................................................................... 19 
2.2 
IMD Description .................................................................................................................... 19 
2.2.1 
ARGOS-IO pressure sensor ring............................................................................. 21 
2.2.2 
MESOGRAPH reading device ................................................................................. 24 
Data Transmission ............................................................................................................................. 25 
3 
Clinical Investigation Plan .................................................................................................... 25 
3.1 
Study Design and Objectives ................................................................................................ 25 
3.1.1 
Type of Investigation ............................................................................................ 25 
3.1.2 
Objectives ............................................................................................................. 25 
3.1.3 
Endpoints .............................................................................................................. 26 
3.2 
Study Population / Patient Selection .................................................................................... 27 
3.2.1 
Eligibility Criteria .................................................................................................. 27 
3.2.2 
Setting and Location ............................................................................................. 28 
3.2.3 
Sample Size and Enrollment ................................................................................. 28 
3.3 
Study Procedures .................................................................................................................. 29 
3.3.1 
Study Intervention and Control ............................................................................ 29 
3.3.2 
Treatment Schedule .............................................................................................. 30 
3.3.3 
Assessments .......................................................................................................... 33 

 
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3.3.4 
Study Visits ........................................................................................................... 38 
3.4 
Treatment Allocation ............................................................................................................ 39 
3.5 
Data Quality Assurance......................................................................................................... 40 
3.6 
Statistics ................................................................................................................................ 41 
4 
Results ................................................................................................................................ 43 
4.1 
Critical Study Dates, Disposition of Subjects and Investigational Devices ........................... 43 
4.2 
Protocol changes during the study ....................................................................................... 43 
4.3 
Subject Demographics and Other Baseline Characteristics ................................................. 45 
4.4 
Implantation Characteristics ................................................................................................. 50 
4.5 
CIP Compliance ..................................................................................................................... 52 
4.6 
Data Sets Analyzed ............................................................................................................... 53 
4.7 
Performance ......................................................................................................................... 53 
4.7.1 
Tonometry ............................................................................................................ 53 
4.7.2 
User acceptance of the ARGOS-IO system at home by evaluation of patient 
acceptance questionnaire ...................................................................................... 68 
4.8 
Safety .................................................................................................................................... 77 
4.8.1 
Adverse Events...................................................................................................... 77 
4.8.2 
Concomitant Medications ..................................................................................... 96 
4.8.3 
Device Deficiencies ............................................................................................... 96 
4.8.4 
Examination Results over Time ............................................................................. 97 
5 
Discussion ........................................................................................................................... 98 
5.1 
Limitations of the Study ........................................................................................................ 98 
5.2 
Safety and Tolerability .......................................................................................................... 98 
5.3 
Performance ......................................................................................................................... 99 
5.4 
Relevance of the Results in the Light of Previous / External Data ....................................... 99 
5.5 
Risk / Benefit Assessment ..................................................................................................... 99 
6 
Ethics and Regulatory Compliance ......................................................................................103 
6.1 
Independent Ethics Committee (IEC) and Competent Authority ....................................... 103 

 
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6.2 
Ethical and Legal Conduct of the Study .............................................................................. 103 
6.3 
Patient Information and Consent ....................................................................................... 103 
7 
Study Administrative Structure...........................................................................................104 
8 
References .........................................................................................................................105 
9 
Annexes to the Report .......................................................................................................113 
 
 
 

 
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List of Tables 
Table 1: Assessment Schedule .............................................................................................................. 31 
Table 2: Recommended ARGOS-IO Implant Sizes ................................................................................ 35 
Table 3: Protocol changes during the study ......................................................................................... 45 
Table 4: Ophthalmic primary underlying condition/disease/event leading to need for KPro........... 46 
Table 5: Summary of Disease Characteristics concerning the study eye ............................................ 46 
Table 6: Summary of Concomitant Diseases without any Relation to Study Eye ............................... 49 
Table 7: Summary of Surgical Approach ............................................................................................... 50 
Table 8: Summary of Protocol Deviations ............................................................................................ 52 
Table 9: Summary of all AEs .................................................................................................................. 78 
Table 10: AEs related to the Medical Procedure – Time of Occurrence and Outcome ...................... 81 
Table 11: ADEs – Time of Occurrence and Outcome ............................................................................ 85 
Table 12: SADEs – Time of Occurrence and Outcome .......................................................................... 89 
 
List of Figures 
Figure 1. ARGOS-IO implant (previous prototype) ............................................................................... 20 
Figure 2. ARGOS-IO Implant (second generation) ................................................................................ 21 
Figure 3. Pressure sensor cell in profile ................................................................................................ 22 
Figure 4. Depiction of a micro-plate capacitor for pressure measurement ........................................ 22 
Figure 5. Mesograph Reading Device ................................................................................................... 24 
Figure 6. Individual IOP follow-up during study period per patient measured with the ARGOS-IO 
system ..................................................................................................................................... 54 
Figure 7. ARGOS-IO Measurements versus Finger Palpation – Scatter Plot for each Post-Surgery 
Visit ......................................................................................................................................... 55 
Figure 8. Difference between Manometry and ARGOS-IO over the time – mean value plot; DE-1-01
 ................................................................................................................................................ 56 
Figure 9. Difference between Manometry and ARGOS-IO over the time – mean value plot; DE-1-03
 ................................................................................................................................................ 57 
Figure 10. Difference between Manometry and ARGOS-IO over the time – mean value plot;           
DE-1-04 ................................................................................................................................... 58 

 
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Figure 11. Difference between Manometry and ARGOS-IO over the time – mean value plot;          
DE-1-05 .............................................................................................................................. 59 
Figure 12. Difference between Manometry and ARGOS-IO over the time – mean value plot;          
DE-1-06 .............................................................................................................................. 60 
Figure 13. Difference between Manometry and ARGOS-IO over the time – mean value plot;          
DE-1-08 .............................................................................................................................. 61 
Figure 14. Difference between Manometry and ARGOS-IO over the time – mean value plot;          
DE-2-01 .............................................................................................................................. 62 
Figure 15. Difference between Manometry and ARGOS-IO over the time – mean value plot;           
DE-2-02 .............................................................................................................................. 63 
Figure 16. Difference between Manometry and ARGOS-IO over the time – mean value plot;           
DE-2-02 .............................................................................................................................. 64 
Figure 17. Difference between Manometry and ARGOS-IO over the time – mean value plot             
(all patients) ...................................................................................................................... 65 
Figure 18. Bland-Altman Plot: Level of Agreement between Manometry and ARGOS-IO by Visit ... 66 
Figure 19. Bland-Altman Plot: Overall Level of Agreement between Manometry and ARGOS-IO .... 67 
 
 
 

 
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Abbreviations and Definitions 
Abbreviation 
Definition 
ADE 
Adverse device effect 
AE 
Adverse event 
ASIC 
Application specific integrated circuit  
BfArM 
Bundesinstitut für Arzneimittel und Medizinprodukte 
CIP 
Clinical Investigation Plan 
CRF 
Case Report Form 
dB 
Decibel 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
EEPROM 
Electrically erasable programmable read-only memory 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
GAT 
Goldmann Applanation Tonometry 
GCP 
Good Clinical Practice 
GDD 
Glaucoma Drainage Device 
IB 
Investigator’s Brochure 
IEC 
Independent Ethic Committee 
IO 
Intraocular 
IOL 
Intraocular lens 
IOP 
Intraocular Pressure 
ISF 
Investigator Site File 
Max 
Maximum (highest observation) 
MD 
Macular degeneration 
MDN 
Median 
Min 
Minimum (smallest observation) 
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) 
MRI 
Magnetic resonance imaging 
N 
Sample number 
NCT 
Non-contact tonometry 
ND:YAG 
Neodymium doped yttrium aluminum garnet 
P 
Pressure  
P25% 
25% quartile 
P75% 
75% quartile 
PIC 
Patient informed consent 

 
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POAG 
Primary open angle glaucoma 
PP 
Per Protocol 
ppV 
Pars plana vitrectomy 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SDV  
Source Data Verification 
T 
Temperature (in °C) 
TMF 
Trial Master File 
WTW 
White-to-white 
 
 
 

 
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1 
INTRODUCTION 
1.1 
Keratoprosthesis Devices 
Approximately 8 million people are bilaterally blind (defined as visual acuity < 19/180) because of 
corneal disease or injury (Ament, et al., 2010). Corneal transplantation, otherwise known as 
penetrating keratoplasty (PKP), which involves removing a disc comprising the majority of the 
patient’s cornea and replacing it with a corresponding disc from a donor eye, can restore sight to 
many of these patients. In 2008, 41,652 corneal transplants were performed in the United States 
alone (Eye Bank Association of America, 2014).  
Although the procedure usually leads to positive results over the long-term, certain high-risk groups, 
such as patients with cicatrizing diseases like Stevens-Johnson syndrome, ocular cicatricial 
pemphigoid and other autoimmune diseases; alkali burns; herpetic neurotrophic keratopathy; and 
some pediatric corneal opacities have a low success rate and often experience repeat graft failures 
(Klufas & Starr, 2009). Artificial corneas, otherwise known as keratoprostheses, are a final alternative 
treatment to salvage the vision of these patients.  
There are presently many keratoprostheses in development, but only three are generally used in the 
normal clinical setting (Lam & Liu, 2011): 
• 
Boston Keratoprosthesis (KPro) (Massachusetts Eye and Ear Infirmary, Boston, MA),  
• 
AlphaCor artificial cornea (Addition Technology Inc., Des Plaines, IL), and  
• 
Osteo-odonto keratoprosthesis (originally described by Strampelli, modified by Falcinelli, 
optic available from Osteo-Odonto Keratoprosthesis Optics [Sussex Eye Hospital, Brighton, 
United Kingdom]) 
The Boston type 1 KPro used in this study is the most widely used keratoprosthesis. It consists of a 
polymethylmethacrylate (PMMA) collar-button-like front plate that houses a periscope-like central 
optical cylinder (aphakic and pseudophakic powers available) and a threadless, titanium back plate. 
Prior to implantation, the two plates are snapped together sandwiching a ring of donor corneal tissue 
between them, which is then used to suture the device to the eye. With the exception of the 
assembly of the device, the implantation of a BKPro, which employs 12 interrupted sutures, is quite 
similar to that used for PKP (Santaella & Afshari, 2011). 
Use of the BKPro has risen from 50 implantations in 2002 to 1188 in 2010 (Klufas & Starr, 2009). 
Various retrospective studies reported improvements in vision from preoperative best corrected 

 
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visual acuity (BCVA) of ≤20/400 in 86-95% of the eyes to BCVAs ≥ 20/200 in 57 – 89% at various time 
points following surgery (Greiner, Li, & Mannis, 2011), with some studies reporting BCVAs of better 
than 20/40 in 25% of the patients included (Klufas & Starr, 2009). Continued advances in the design 
of the BKPro and the post-operative care given its recipients have resulted in improved outcomes. 
However, a significant number of BKPro patients lose their initial visual gains permanently over the 
longer term as a result of glaucoma, which may affect up to 75% of patients awaiting BKPro 
implantation and up to 100% of patients post-operatively  (Nguyen & Chopra, 2014), (Greiner, Li, & 
Mannis, 2011) . 
 
1.2 
Limitations of Existing Treatments 
Glaucoma treatment generally aims to reduce damage to the optic nerve by reducing the elevated 
intraocular pressure (IOP) believed to cause it. IOP management in patients with a keratoprosthesis 
is challenging. Conventional tonometry methods typically used to measure IOP deduce it indirectly by 
measuring the pressure required to applanate the cornea or the response to pressure applied to the 
sclera. The rigid PMMA cylinder that replaces the central part of the donor corneal graft in BKPro 
recipients makes corneal applanation methods of IOP measurement such as Goldmann Applanation 
Tonometry impossible to use, while changes in the sclera caused by BKPro implantation also make 
alternatives that assess scleral pressure infeasible. In current clinical practice, finger palpation by a 
highly experienced specialist is seen as the only feasible option for routine monitoring of IOP in 
BKPro patients, but the values obtained are at best highly subjective estimations (Santaella & Afshari, 
2011). The only available method to accurately measure IOP in these patients is surgical manometry, 
which carries significant risks and should not be performed frequently. To further compound the 
situation, the rapid progression to end-stage glaucoma that is frequently observed in BKPro patients 
with apparently normal IOP has raised the hypothesis that these patients experience undetected 
transient IOP spikes (Greiner, Li, & Mannis, 2011).   
1.3 
State of Device Development 
The ARGOS-IO implant is an innovative ring-shaped intraocular pressure sensor consisting of a 
miniature application specific integrated circuit (ASIC) with integrated electromechanical pressure 
sensors that is bonded to a gold micro-coil and encased in silicon rubber material. The ARGOS-IO 
pressure sensor is intended to be permanently implanted in the eyes of glaucoma patients in 
conjunction with surgery for cataract removal and concurrent intraocular lens implantation, and is 

 
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anticipated to enable patients to make direct accurate IOP measurements by themselves, and quasi-
continuous IOP diurnal curves. This in turn will permit more frequent measurement of IOP, providing 
a more detailed and accurate basis for treatment decisions. Power for pressure measurement and 
data transmission is provided during the measurement process via magnetic coupling with a portable 
hand-held device, which also receives and stores the data. 
The accuracy of the device was initially demonstrated in direct comparison with manometry in 
enucleated porcine eyes. Long term implantation testing in rabbits confirmed biocompatibility and 
permitted comparison of measurements obtained in vivo with the ARGOS-IO pressure sensor to 
those of other tonometers in vivo over a period lasting up to 2.5 years.  
In 2012 in an initial first-in-human case study, a sensor was implanted in the ciliary sulcus of a 66 year 
old female glaucoma patient in Beirut Lebanon and her condition followed over 18 month period. No 
significant adverse events were noted (Melki, Todani, & Cherfan, An Implantable Intraocular Pressure 
Transducer: Initial Safety Outcomes, 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 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 

 
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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 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.  
In May 2017, the ARGOS-IO system got the CE approval as intraocular pressure sensor for 
measurement of intraocular pressure in patients with primary open angle glaucoma due to the 
ARGOS-02 study. This clinical trial investigated the safety and performance of the ARGOS-IO systems 
in patients with primary open angle glaucoma undergoing phacoemulsification and IOL implantation 
for cataract and received ARGOS-IO implants in an add-on procedure. 22 patients were enrolled and 
their eye condition and IOP were followed over a course of 12 months. The ARGOS-IO measurements 
showed an excellent level of concordance to the conventional Goldmann Applanation tonometry and 
no device related serious adverse events were recorded (Implandata, 2017).  
The ARGOS-KP01 study described in this report investigated the safety and performance of 
implantation of the ARGOS-IO in conjunction with keratoprosthesis implantation in a larger patient 
population. Over a one year period 12 patients underwent Boston-Keratoprosthesis implantation and 

 
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received ARGOS-IO implants. Their eye condition and IOP were followed over the course of 12 
months.  
This investigation was designed and conducted in accordance with ISO 14155:2011, European 
Medical Device Directive and German Medical Device Act and Medical Device Ordinance.  
2 
INVESTIGATIONAL DEVICE AND METHODS 
2.1 
IMD Classification and Intended Use 
The ARGOS-IO system is an investigational medical device developed for the wireless, contactless 
measurement of the hydrostatic pressure of the aqueous humor (IOP, intraocular pressure) in 
patients with Boston Keratoprosthesis (BKPRO). It is composed of the ARGOS-IO pressure sensor 
implant and the separate hand-held MESOGRAPH reading device.  
The ARGOS-IO implant is classified as active implantable medical device under the consolidated 
Active Implantable Medical Device Directive 90/385/EEC Annex IX and AIMDD as amended by 
directive 2007/47/EC. 
2.1.1  Accessoiries 
Both, the Injector with its constituent parts (hand-piece, cartridge and plunger tip) and the 
MESOGRAPH reader device are classified as accessories to an active implantable medical device 
under the consolidated Active Implantable Medical Device Directive 90/385/EEC Annex IX and 
AIMDD as amended by directive 2007/47/EC. 
2.2 
IMD Description 
The ARGOS-IO pressure sensor, which is intended for permanent implantation in the posterior 
chamber of the eye and implanted in conjunction with a Boston Keratoprosthesis, bears a 
microelectromechanical system-application specific integrated circuit (MEMS-ASIC) that integrates 
pressure and temperature sensors, identification and analog-to-digital encoders and a telemetry 
unit. The ASIC is bonded to a gold micro-coil and hermetically encapsulated in a ring of silicone 
rubber material. When the external reading device (Mesograph) is activated in the close proximity of 
the eye, an electromagnetic inductive connection is formed between it and the microcoil that 
provides the ASIC with power and enables the measurement and telemetric data transfer between 
the sensor and the reader. 

 
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An earlier version of the ARGOS-IO implant was used in the two described case studies and the 
ARGOS-01 study. This early ARGOS-IO implant prototype, shown in Figure 1, had an outer diameter 
size of 11.3 mm, an inner diameter size of 7 mm and an overall thickness of 0.9 mm. 
Figure 1. ARGOS-IO implant (previous prototype) 
 
 
a) Anterior view (side towards the iris) 
b) Posterior view (side toward the lens). 
 
 
Suboptimal safety and performance outcomes in the ARGOS-01 study made it apparent that 
modifications to the form of the ARGOS-IO implant were necessary before clinical investigation of 
the ARGOS-IO system could be continued. The design modifications made included: 
• 
Addition of 4 haptics at the outer edges of the implant 
• 
Reduction in device thickness from a uniform 0.9 mm to 0.5 mm overall, tapering to a 
0.1 mm rounded outer edge 
• 
Addition of two allantoid protrusions running on either side of the posterior surface from the 
middle of the ring to the ASIC. 
 
 

 
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Figure 2. ARGOS-IO Implant (second generation) 
 
 
a) Anterior view (side towards the iris) 
b) Posterior view (side toward the lens) 
In this clinical investigation, three ARGOS-IO implant sizes will be tested:  
 11.3 mm; 0.5 mm thickness 
 11.7 mm; 0.5 mm thickness 
 12.1 mm; 0.5 mm thickness. 
The implant contains four haptics to maintain positional and rotational 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 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. All three implant sizes 
have an inner diameter size of 7 mm. 
2.2.1 
ARGOS-IO pressure sensor ring 
2.2.1.1 
ASIC 
The ASIC comprises functional blocks dedicated to pressure and temperature sensing, sensor readout 
and analog-to-digital conversion, a digital state machine to control the sequence of operation such as 
computation of checksum for data transmission and timing of the ASIC operation, EEPROM memory 
to store unique serial number for implant identification, and a radio frequency front end for power 
supply and filtering, and data transmission.  
The miniature, highly reliable, and stable pressure sensor systems manufactured by surface 
micromachining techniques are similar to those used in automotive and other technical and 

 
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consumer applications. The ASIC incorporates an array of 8 capacitive pressure sensors, each 
comprised of a rigid base plate and a parallel flexible membrane (Figure 3 and  
Figure 4).  
When the membrane is deflected by pressure changes, its distance to the base plate changes, 
generating a change in the capacity of the sensor cell that is directly proportional to the pressure 
within the eye. The capacity change is digitalized by the integrated power-saving analog/digital 
converter circuit, which converts it to a numerical value and transmits it to the MESOGRAPH reader.  
The sensors are referenced internally to a vacuum to compensate for their pneumatic isolation from 
the ambient pressure when implanted. Computation of the actual IOP is made by comparing the 
pressure detected by the sensor in the eye to the atmospheric pressure read by the MESOGRAPH. 
The sensors have an absolute accuracy of 3σ at 2 mmHg over a range of 800 to 1.150 hPa (absolute). 
Extrapolations from long-term stability testing have estimated their lifespan to be > 35 years at room 
temperature. 
Figure 3. Pressure sensor cell in profile 
 
 
Figure 4. Depiction of a micro-plate capacitor for pressure measurement 
 

 
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The pressure sensing ASIC transfers data by means of absorption modulation via a passive 
transponder system that uses a pair of coupled coils to establish a radio frequency link between the 
reader and the transducer (implant). The RF field emitted by the Mesograph at a frequency of 
13.56 MHz, which is reserved for medical devices and similar applications, both provides power to 
the ASIC and enables it to transmit the digitalized data from the implant to the reader via absorption 
modulation. 
The implant contains no energy storage device and is electrically passive if not coupled to the 
external magnetic field. The ASIC acquires the external power below 250µA with a voltage of 3 V 
needed for the entire duration of a measurement from an electrical current induced in the micro-coil 
by exposure to the RF field generated by the activated MESOGRAPH. 
2.2.1.2 
Micro-coil and Bonding Process 
The The micro-coil is manufactured using photolithographic technics in a gold micro-galvanic thin 
film process to create gold structures of approximately 20µm thickness on a PI layer of approx. 7 – 10 
µm. It is bound to the ASIC in a thermocompression flip-chip process that requires no adhesives or 
other agents. All silicone-aluminum interfaces and metal surfaces of the ASIC are hermetically sealed 
with gold bumps, which are also required for the bonding process. The very thin structure of the coil 
facilitates a high flexibility and foldability, which is a prerequisite for a foldable implant for safe 
implantation process. 
2.2.1.3 
Encapsulation 
The sensor module (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 
• 
Protects the patient from substances that could potentially be washed out of the electronic 
module and leak 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. 
Because the encapsulation material is soft and transfers pressure to the pressure sensors, the ASIC’s 
measurement function remains preserved without restrictions.  

 
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The encapsulation is intended to permanently protect the electronic module against electrolytes 
dissolved in the aqueous humor. In the event that the silicone coating was to become breached, the 
patient may indirectly come into contact with the materials of the ASIC and the micro-coil as well. 
Detailed risk assessments determined that the materials used to manufacture the ARGOS-IO implant, 
which consists of silicon, and traces of silicon dioxide, silicon nitride, gold, aluminum, titanium, 
phosphorus, arsenic, borium, polyimide and tungsten-titanium, pose no risk of an adverse biological 
effect to the patient (Cao, M, 2010). The silicone encapsulation, which is composed of 
polydimethylsiloxanes and diphenylsiloxane-dimethylsiloxane copolymers, has recognized inert and 
biostable properties under physiological conditions and is a commonly used component of medical 
devices such as IOLs. Cytotoxicity and chemical analyses of extracts obtained from final sensors 
detected no organic or inorganic leachables above the lower limit of quantification and no evidence 
that the sensors contained or would release any residues/contaminants in toxicologically relevant 
concentrations during clinical application (Timme, 2015).  
See IFU ARGOS-IO Implant for further details about implantation and use. 
2.2.2 
MESOGRAPH reading device 
The Mesograph reading device (Figure 5) is a handheld device powered by a 2CR5 lithium battery. 
When activated approximately 5 cm from the eye, it provides the power required by the ASIC for the 
duration of a measurement by generating a high-frequency electromagnetic field that produces a 
current in the microcoil. 
Figure 5: Mesograph Reading Device 
 
Dimensions: width x length x height ca. 65 mm x 180 mm x 26 mm 
The implant measures IOP within the eye, isolated from the ambient atmospheric pressure. When 

 
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a reading is made, the Mesograph measures the atmospheric pressure and uses it to automatically 
compute the relative IOP (which is the metric comparable to commonly measured IOP values). 
Detailed reading device technical data for pressure measurement: 
• 
Storage capacity: ca. 3,000 measurements  
• 
Battery: type 2CR5 (lithium photo battery) 
• 
Battery capacity: ca. 3,000 measurements  
• 
Reading device dimensions: 180 mm x 65 mm x 25 mm 
• 
Reading device weight (incl. battery). ca. 160 g 
• 
Connection to PC: galvanically separated data transmission adapter 
The maximum range for the wireless operation of the pressure transponder is up to 50 mm or 
more (distance between micro-coil and reading device coil). 
Data Transmission  
In the normal operating mode, the site personnel or patient can take several measurements per 
day simply by holding the activated Mesograph up to his/her eye for a short moment. 
Measurements can be transmitted through the connected Multiline Connector to a secure 
database and are recorded in parallel by the Mesograph as back-up. The measurements taken 
from the patient at home can be read by the physician, whenever needed. 
3 
CLINICAL INVESTIGATION PLAN 
3.1 
Study Design and Objectives 
The purpose of the ARGOS-KP01 study is to evaluate the safety and performance of the ARGOS-IO 
system in patients with indicated Boston Keratoprosthesis surgery. 
3.1.1 
Type of Investigation 
The trial was conducted as an open, prospective, multicenter single-arm clinical trial. 
3.1.2 
Objectives 
The aim of this trial is to verify the safety and performance of the ARGOS-IO system in patients with 
indicated Boston Keratoprosthesis surgery over 12 months’ period following implantation. The 
measurements of intraocular pressure through the pressure sensor were compared with surgical 

 
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manometry (V7, V9, V11, V15) at the same time point. The ARGOS-IO pressure sensor was implanted 
during Boston Keratoprosthesis implantation and is to remain permanently in the eye. 
3.1.3 
Endpoints 
3.1.3.1 
Primary Endpoint 
Safety 
• 
Number of patients experiencing a device related SAE at any time during the first 12 months 
following implantation of the IMD. For the purpose of this analysis, a device-related SAE is 
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: 
1. Led to death 
2. Led to a serious deterioration in the health of a subject that: 
a. Resulted in a life-threatening illness or injury 
b. Resulted in a permanent impairment of a body structure or body 
function 
c. Required in-patient hospitalization or prolongation of existing 
hospitalization 
d. Resulted in medical or surgical intervention to prevent 
permanent impairment to body structure or a body function 
3. Led to fetal distress, fetal death or congenital abnormality or birth defect. 
Performance 
• 
Limits of agreement between IOP measurements made using GAT and the ARGOS-IO system 
from V05 (day 30) through V09 (day 180). 
3.1.3.2 
Secondary Endpoints 
Safety 
• 
Incidence, nature, seriousness, severity and duration of adverse events and adverse device 
events in the 4 weeks 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 16 weeks following implantation of the ARGOS-IO pressure sensor. 
• 
Incidence, nature, seriousness, severity and duration of adverse events and adverse device 
events in the 28 weeks 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 
• 
Level of agreement between IOP measurements made using surgical manometry and the 
ARGOS-IO system at 4, 16, 28 and 52 weeks following implantation 
• 
Incidence of device deficiencies in the first 4, 16, 28 and 52 weeks 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) 
• 
Daily IOP self-measurement profiles (patients). 
3.2 
Study Population / Patient Selection 
3.2.1 
Eligibility Criteria 
3.2.1.1 
Inclusion Criteria 
In order to ensure that the study population is representative of the eligible patient population, the 
Investigator had to ensure that all patients who met the following inclusion criteria were offered 
enrolment in the study. The investigator might not apply any additional eligibility criteria. Eligible 
subjects had to meet all the following inclusion criteria: 
1. Male or female aged ≥ 18 and ≤ 80 years on the day of screening 
2. Keratoprosthesis surgery indicated, defined as having a severely opaque and vascularized 
cornea AND either a verifiable history of two or more prior failed corneal transplant 
procedures or a medical condition such as alkali burns or autoimmune disease that makes 
the success of a traditional corneal transplant procedure unlikely. Potential study patients 
will be solicited for participation in the clinical trial only after they have consented to the 
keratoprosthesis operation. 
3. Axial length > 21 mm 
4. Ability and willingness to attend all scheduled visits and comply with all study procedures 
3.2.1.2 
Exclusion Criteria 
Eligible subjects had not meet any of the following exclusion criteria: 
 

 
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1. Reasonable chance of success with traditional keratoplasty 
2. Current retinal detachment 
3. Connective tissue diseases 
4. 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 
5. History of ocular or periocular malignancy  
6. History of extensive keloid formation 
7. Any known intolerance or hypersensitivity to topical anesthetics, mydriatics, or silicone 
(component of the device) 
8. Presence of another active medical eye implant and/or other active medical implants in the 
head/neck region 
9. Signs of current infection, including fever and current treatment with antibiotics 
10. Severe generalized disease that results in a life expectancy shorter than a year  
11. Any clinical evidence that the investigator feels would place the subject at increased risk with 
the placement of the device 
12. Currently pregnant or breastfeeding 
13. 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 
14. Intraoperative complication that would preclude implantation of the study device  
15. 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. 
16. Previous or concurrent enrollment of the contralateral eye in this clinical study. 
3.2.2 
Setting and Location 
The trial was conducted as an open, prospective, multicenter single-arm clinical trial at 3 sites in 
Germany. 
3.2.3 
Sample Size and Enrollment 
This prospective, open-label, multicenter, single-arm clinical investigation enrolled 12 consecutive 
patients. 

 
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The primary aim of this study is to show “safety”, which is evaluated based on the number of 
subjects who experience an SADE (= “non-safety), as defined in the primary endpoints. 
AEs, SAEs, ADEs and SADEs are listed. Incidence is estimated with a 95% confidence interval 
(Pearson-Clopper, two-sided). 
A data safety monitoring board (DSMB) was established prior to enrollment of the first patient. The 
DSMB reviewed the safety data on a regular basis and advised on any changes required in the 
conduct of this clinical investigation. 
3.3 
Study Procedures 
3.3.1 
Study Intervention and Control 
The ARGOS-IO pressure sensor is intended to be permanently implanted in the subject’s eye 
concomitantly with implantation of the BKPro. Once its safety and performance have been 
demonstrated through comparison to an established method of IOP measurement in a patient 
population, the frequency of measurements possible with the ARGOS-IO system is expected to 
provide a more accurate basis for physicians to use to make treatment decisions. The system consists 
of an IOP sensor that is implanted in the eye and a hand-held Mesograph reader that powers the 
sensor and downloads the data from it, simultaneously correcting the pressure reading for ambient 
air pressure and converting it to the format obtained with standard tonometers in clinical use. 
Conventional methods of measuring IOP typically used in the clinical setting all involve manipulation 
of the (preferably intact) cornea and cannot be used in eyes with keratoprostheses (Santaella & 
Afshari, 2011)(Sentinels et al 2011). Finger palpation remains the only method available for frequent 
assessment of IOP in these eyes. It is however not very precise or reproducible and its use is reserved 
to a few experts (Lin et al. 2014, Banat 2011). 
 All consenting patients who met all inclusion criteria and no exclusion criteria had an ARGOS-IO 
sensor implanted in combination with a Boston-Keratoprosthesis implantation. The condition of 
patients was followed up for 12 months after surgery. To assess the accuracy of IOP measurements 
obtained with the ARGOS-IO system in BKPro recipients, IOP values obtained with ARGOS were 
compared to the exact and reliable direct measurements obtained using surgical ocular manometry, 
in which a cannula was temporarily inserted into the eye, at visits 7, 9, 11, and 15. However, even 
though the IOP measured with this procedure is very exact, the surface of the eye was penetrated, 
which may cause the leak of small amounts of aqueous humor, leading to a pressure that differs from 
the true physiologic pressure. The actual physiologic pressure is of less importance in this 

 
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investigation because the measurement were used to verify or calibrate the measurement taken 
with the intraocular ARGOS sensor at the same time under the same conditions. 
The Bland-Altman method was used to assess the limits of agreement between the IOP 
measurements ARGOS-IO and surgical manometry. When appropriate, two-sided 95% Cis, for these 
limits were calculated accounting for repeated measurements based on the method proposed by Zou 
(2012). 
AEs, SAEs, ADEs and SADEs are listed. Incidence is estimated with a 95% confidence interval 
(Pearson-Clopper, two-sided). 
This exploratory study aims to estimate the agreement of IOP measurements obtained surgical 
manometry and the ARGOS-IO system at the same time point to allow assessment of the accuracy of 
the ARGOS-IO system and to collect further information on the occurrence of AEs and ADEs and 
about the reliability of the device in humans. 
3.3.2 
Treatment Schedule 
During the study, subjects attended 15 clinic visits, including 1 screening visit (up to 60 days prior to 
surgery), 1 surgery visit (day 0 = V2 surgery), and 13 follow-up visits (day 1, 5, 10, 15, week 4, 10, 16, 
22, 28, 34, 40, 46 and 52). The assessment schedule in Table 1 summarizes all visits and the 
assessments which were performed at each. The visit window given in the table should be adhered 
to as closely as possible. 

 
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Table 1: Assessment Schedule 
  
Screening 
Surgery 
Follow-up 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Day -60 to -0 
Day 0 
Day 1 
Day 5 
Day 10 
Day 15 
Wk4 
Wk10 
Wk16 
Wk 22 
Wk 28 
Wk 34 
Wk 40 
Wk 46 
Wk 52 
 Visit Window (in days) 
+/- 0 
+/- 1 
+/- 2 
+/- 2 
+/- 7 
+/- 7 
+/- 7 
+/- 7 
+/- 7 
+/- 7 
+/- 7 
+/- 7 
+/- 7 
Procedure 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Informed Consent  a 
X 
  
  
Demographics 
X 
  
  
Eligibility 
X 
X 
  
Enrollment 
X 
  
  
Medical History  b 
X 
X  
  
AE/ADE/SAE/SADE 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior treatments 
X 
  
  
Urine pregnancy test 
X 
X  
  
Device deficiency 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Implantation Surgery 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
BKPro 
  
X 
 
 
 
 
 
 
 
 
 
 
 
 
  
ARGOS-IO 
  
X 
  
Anterior Segment 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Slit-lamp biomicroscopy 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biometry (axial length) 
X 
  
  
White-to-white 
X 
  
  
External eye photography – slit lamp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

 
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Screening 
Surgery 
Follow-up 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Posterior Segment 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Biomicroscopy 
X 
  
  
  
  
  
X 
  
X 
  
X 
  
  
  
X 
Macula and Optic nerve OCT  c 
X 
  
X 
X 
X 
X 
Fundus photography  c 
  
  
X 
X 
X 
X 
IOP measurement 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Goldmann Applanation  
X 
  
  
Pneumotonometry 
X 
  
  
ARGOS-IO clinic 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ARGOS-IO home 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X e 
Surgical manometry 
  
  
X 
X 
X 
X 
Finger palpation  d 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Miscellaneous 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Questionnaire surgeon 
  
X  
  
Questionnaire site staff 
  
  
X 
Questionnaire patient 
  
  
X 
BCVA 
  
  
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Perimetry 
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
X 
a  Potential participants must have consented to BKPro surgery before undergoing informed consent process for ARGOS-IO study.  
b Medical history includes conditions and events up to ARGOS-IO implantation, and will include ophthalmic history, condition and pretreatments, as well as any ongoing or significant general conditions. 
c  If feasible 
d   Finger palpation will be used to estimate IOP according to the categories: soft/ hypotonic, definitely normal, borderline, definitely hypertonic. 
e  Collection of the Mesograph reader and Multiline Connector. 
.

 
 
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3.3.3 
Assessments 
Individual assessments, described in the following sections, were repeated regularly throughout the 
study period. A list of the assessments and procedures conducted at each visit is contained in the 
Assessment Schedule, Table 1. The assessments and procedures are described in more detail in the 
following sections. 
3.3.3.1 
Patient demographics/other baseline characteristics 
Patient demographic and baseline characteristic data to be collected on all subjects include: year of 
birth, age, sex, race, pre-treatments and source of subject referral. This information was collected at 
V01. 
3.3.3.2 
Medical history 
Relevant medical history/current medical condition data includes data regarding ongoing or 
significant previous ophthalmic and general medical conditions and procedures 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 were recorded. 
3.3.3.3 
Pregnancy test 
Urine dip stick test at screening (SC) and before surgery (V01) was performed in female subjects of 
childbearing potential. The test type and results were recorded in the subject’s source documents. A 
positive result necessitated the exclusion of the subject from the study.  
3.3.3.4 
Concomitant medication, treatments and devices 
There were no restrictions for the use of concomitant medications required for ophthalmologic or 
systemic diseases during this clinical investigation. All medications including non-prescription 
medications used by the subject during the trial and medications in use at enrollment, were 
documented in the subject’s file and in the eCRF, as well all diagnostic procedures and medical 
interventions.  
Concomitant medication and devices during surgical procedure  
Medication administered during surgery was recorded in the eCRF. Data were collected about the 
surgical techniques used to implant the ARGOS-IO and the keratoprosthesis as well as about any 
clinically significant differences from the expected course of the procedure.  

 
 
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Concomitant medication after implantation 
The use of concomitant medication was at the discretion of the Investigator. Prophylactic use of 
steroid therapy and antibiotics according to standard local procedure was recommended following 
surgery. 
Concomitant therapy in case of inflammatory events after implantation 
If the subject showed signs of an inflammatory reaction following implantation, treatment such as 
administration of local and/or systemic steroid and antibiotic therapy was recommended, according 
to the local procedure regimens. In the event a hypopyon developed, an anterior chamber biopsy 
was recommended to determine whether it was sterile or due to an infectious agent. 
3.3.3.5 
AEs/ADEs/SAEs/SADEs 
All AEs/ADEs/SAEs/SADEs were recorded starting with the implantation of the ARGOS-IO pressure 
sensor. 
3.3.3.6 
Device Malfunctions 
A device deficiency form was completed and sent to the sponsor for all observed device malfunctions 
or deficiencies, including defects in devices that had not been implanted in a subject or otherwise 
used. Starting with the implantation of the ARGOS-IO implant, all relevant malfunctions were also be 
recorded in the subject’s chart and eCRF. 
3.3.3.7 
Questionnaires 
In the study, three types of questionnaires were used to assess potential strength and weaknesses of 
the ARGOS-IO system. Surgeons were asked to complete an implantation procedure questionnaire 
after each implantation at V02 (D0). At V15 (Wk52), the site staff responsible for IOP measurement 
as well as the subjects were asked to complete a user acceptance questionnaires for the 
MESOGRAPH reading device and the general measurement procedure.  
The aim of these questionnaires was 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 is included in the analysis. Results provided 
the sponsor with data that could influence future device system improvements. 

 
 
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3.3.3.8 
External Eye Photography 
Standard external eye photography was performed in conjunction with a slit-lamp in order to 
document changes to the outer eye. 
3.3.3.9 
Anterior eye segment measurement 
Slit-lamp biomicroscopy (undilated, anterior segment) 
The external ocular structures and the front of the eye were assessed at every visit using the 
slit-lamp biomicroscopy according to standard site procedures and following removal of the bandage 
contact lens (BCL), if present. Particular attention was paid to the ocular surface and, during follow-
up, the posterior portion of the PMMA cylinder. Following structures were assessed: 
a) Lids 
b) Conjunctiva 
c) Cornea 
d) Anterior chamber 
e) Iris 
f) Pupil 
g) Lens 
h) Anterior vitreous 
Optical Biometry  
When permitted by the subject’s condition, the IOL Master (Carl Zeiss Meditec, Germany) was used 
during screening to measure the axial length of the globe and the horizontal white-to-white 
diameter.  
To determine the implant size, at least three WTW measurements were taken and the average 
calculated. The average in mm was then determine the right ARGOS-IO implant size (see Table 5).  
Table 2: 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 

 
 
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If optical biometry was not possible, for example due to opacity of the subject’s cornea, ultrasound 
biomicroscopy or corneal diameter measurement using an ophthalmosurgical caliper was used to 
assess the dimensions of the subject’s anterior chamber.  
3.3.3.10 Posterior eye segment measurement 
All posterior eye segment examinations were done as permitted by the condition of the subject’s 
cornea. 
Biomicroscopy (dilated, fundus)  
The posterior eye segment was examined using a slit lamp in combination with a 90D or “Superfield” 
or comparable lenses. The following parameters were assessed: 
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 (PS-OCT) was used to assess macular structures and the peripapillary nerve 
fiber layer. 
Fundus photography 
Standard fundus photography was performed at visits 7, 9, 11 and 15 to document potential changes 
to the interior surface of the eye, including the retina.  
3.3.3.11  Intraocular pressure (IOP) measurement 
Intraocular pressure (IOP) was measured using four techniques. To provide a baseline IOP 
measurement, both Goldmann Applanation Tonometry (GAT) and pneumotonometry were 
performed at V01 (screening) if possible. Beginning at V03 (first follow-up visit), IOP measurement 
was performed with the ARGOS-IO system, both by site personnel at clinic visits and after discharge 

 
 
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from hospital by the subject at home between visits. Direct manometry was performed at visits 07, 
09, 11 and 15 to allow assessment of the accuracy of the ARGOS-IO system.  
After surgery, treatment decisions was based on direct manometry, supplemented by finger 
palpation.  
IOP measurement in the clinic 
On the occasions when IOP was measured with both ARGOS-IO and manometry, it was measured as 
a series consisting of first with ARGOS-IO prior to positioning of the operating microscope, then 
manometry and followed again by ARGOS-IO. At the other follow-up visits IOP was measured with 
ARGOS-IO at least two times at every visit preferably at the beginning and end of the visit.  
The surgical manometry measurements was conducted in the surgical suite under an operating 
microscope. A manometry system utilizing sterile saline solution was implemented via a 21-gauge 
needle cannulated to the anterior chamber. A standard procedure was followed both during the 
preparation of the system and the measurement in order to minimize the possibility of leaks or 
trapped air in the system.  
At follow-up visits where manometry was not performed, the physician also estimated IOP using 
finger palpation, categorizing pressure as soft/hypotonic, definitely normal, borderline or definitely 
hypertonic. 
ARGOS-IO system measurement by the subject at home 
While in the clinic following surgery, subjects received detailed instruction in the use of the 
Mesograph reading device. Upon discharge from the clinic, they received an individual Mesograph 
reading device, a copy of the instructions for use and the Multiline Connector to perform self-
tonometry at home. Subjects were requested to perform at least 4 IOP measurements with the 
Mesograph daily, evenly spread throughout the day.  
No manual recording of data by the subject was required. The MESOGRAPH is capable of storing up 
to 3,000 measurements. Subjects were instructed to bring the Mesograph reading device to every 
visit, at which time site staff checked its functionality, access and downloaded the recorded readings 
and then deleted the measured IOP data from the device.  

 
 
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3.3.4 
Study Visits 
3.3.4.1 
Screening 
Only patients who had already independently agreed to undergo BKPro surgery were approached by 
the trial team about participation in the study.  
At V01, the Investigator conducted the informed consent process (Section 12.1), ensuring that the 
subject’s signature had been obtained on the patient informed consent (PIC) form and that the 
subject had received a copy before any study specific procedures are conducted. Once the PIC was 
signed, the subject was assigned a patient number (Section 8.2) and the Investigator determined if 
the subject met the eligibility criteria, surgery (V02) was scheduled and the screening fax form 
completed and faxed to the sponsor.  
In addition, the following procedures were performed at the screening visit: 
• 
Collection of background information about the subject including: demographics, medical 
history with prior treatments and current medications. 
• 
Pregnancy test, when applicable 
• 
External eye photography 
• 
Anterior Segment assessments (slit-lamp biomicroscopy) 
• 
Optical biometry, including ARGOS-IO implant size assessment 
• 
Posterior Segment assessments (biomicroscopy, PS-OCT if feasible) 
• 
IOP measurement with GAT and pneumotonometry 
• 
Instruction of subjects on the need to report as soon as possible any SAEs occurring at any 
time during the study (starting from Visit 02 surgery) 
• 
Completion the screening fax form and send to sponsor 
• 
Completion of the eCRF.  
3.3.4.2 
Surgery 
The following procedures might be carried out one day before surgery (in subjects already 
hospitalized for the surgery) or on the day of surgery: 
• 
Verification that the subject continues to meet eligibility criteria 

 
 
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• 
For female subjects of childbearing potential: collection of urine for pregnancy test. A test 
done within 24 hours prior to surgery had to be negative 
• 
Performance of external eye photography prior to surgery. 
The following procedures were performed on the day of the surgery: 
• 
BKPro and ARGOS-IO pressure sensor implantations, including the updating medical history 
(up to surgery) and recording of concomitant medications, device deficiencies or 
malfunctions (including those detected during device preparation) and any AEs (starting from 
implantation of the ARGOS-IO pressure sensor) 
• 
Completion of the implantation procedure questionnaire (surgeon) and the eCRF  
• 
Completion of the patient inclusion form and fax it to the sponsor 
• 
Instruction of subjects on the need to promptly report any SAE that may occur at any time 
during the study. 
• 
Schedule Visit 2 (V02). 
The duration of the subject’s hospitalization was at the discretion of the Investigator. Durations of up 
to 7 days were not considered in themselves to be SAEs.  
3.3.4.3 
Follow-up, including duration 
Following surgery, patients attended a total of 13 follow-up visits (Day 1 until Week 52). The main 
purpose of the follow-up visits was to assess eye condition and to determine if the patients had 
experienced any AEs. In addition, IOP was measured with the ARGOS-IO system beginning on Day 1 
(V2) at the clinic to permit assessment of the performance of the ARGOS-IO pressure sensor and 
from week 4 (V7) ARGOS-IO home measurements were performed as well. V7, V9, V11 and V15 
surgical manometry and ARGOS-IO measurements were performed at the same time point. 
A detailed listing of the visit schedule and main activities conducted at each can be found in the 
assessment schedule in Table 1.  
3.4 
Treatment Allocation 
This was a single-arm open-label study. No randomization and blinding/masking procedures were 
used in this study. To avoid bias resulting from patient selection, all consecutive patients potentially 
meeting the eligibility requirements were informed of the study and asked to participate. Those 
agreeing underwent the informed consent procedure and if they consented, was screened. All 
eligible patients were enrolled.  

 
 
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Measurements of IOP with the ARGOS-IO sensor was compared to IOP measured with surgical 
manometry in the same subject at the same time point to allow assessment of performance.  
3.5 
Data Quality Assurance 
The study was 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 were 
conducted by trained and qualified monitors, who documented each individual monitoring visit. In 
general, during monitoring visits the monitor ensured 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 compared the CRF entries to original source data. He/she also 
made sure the informed consent procedure had been appropriately carried out and ensured that all 
SAEs had been reported within applicable timeframes. He/she also ensured that investigational 
device accountability had been maintained and, after completion of the study, performed final 
accountability and arranged return or destruction of investigational products. Detailed monitoring 
procedures are described in a separate monitoring plan. 
Data were collected through an electronic Case Report Form (eCRF) provided by the sponsor or its 
designee to the centers prior to study start. The site entered study data directly into the eCRF during 
or as soon after the visit as possible. 
The investigator was 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 had to be maintained. The sites maintained a list of the subjects´ names and 
the Patient ID assigned to each individual patient. Documents that identifed the subject beyond the 
Patient ID were not submitted to the sponsor (e.g. the signed informed consent document) and had 
to 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 had promptly reviewed the completed eCRFs for each subject promptly and had to 
confirm the accuracy of all data entered with his/her signature at the end of each documented 
subject’s visit in the eCRF. Any corrections made to data entries were GCP conform. 
During data review, data management generated queries for any missing, out of range or 
questionable data and sent these to the investigator for resolution. The physician answered the 
query and this answer was documented. All queries had to be answered and the database locked 
before any (interim) analysis of the data.  

 
 
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It had been verified by the sponsor that only validated and secure electronic data systems were used 
in this clinical investigation. Electronic data systems included the clinical data management database 
and the ARGOS-IO system measurement database. Database validation and security followed the 
respective national and international requirements. 
3.6 
Statistics 
Statistical design, method and analytical procedures 
The primary purpose of this investigation is to assess safety of the investigational device.  
Demographic and baseline characteristics 
Demographic characteristics (age, sex, educational level), pre-existing glaucoma, secondary glaucoma 
to BKPro, pressure lowering surgeries incl. GDD prior to BKPro, GDD post BKPro, anti-glaucoma 
medication, and other previous and concurrent treatments are tabulated for the safety set. 
Patient Disposition 
The number and percentage of screened, enrolled and implanted subjects, as well as those who 
completed the follow-up are tabulated for the safety set. The number and percentage of screen 
failures and early withdrawals is also tabulated, along with the reason for the screen failure or drop-
out. 
Safety Analysis 
The incidence within the safety population was estimated with a 95% confidence interval 
(Pearson-Clopper, two-sided). 
Performance Analysis 
The Bland-Altman method, which compares the mean of paired measurements to their difference, 
was used to determine the upper and lower limits of agreement expected to contain 95% of the IOP 
value pairs obtained with ARGOS-IO and surgical manometry. The two-sided 95% confidence 
intervals for each of these limits were calculated using the Mover method (Zou, Confidence interval 
estimation for the Bland-Altman limits of agreement with multiple observations per individual, 2011) 
to account for repeated observations of a changing value in individuals. IOP values were plotted both 
as Bland-Altman plots of individual measurement pairs, and by measurement technique as time plots 
of both population means and individual participant values. 

 
 
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The level of agreement was calculated to provide an estimate of the agreement, and eventually a 
correction factor to allow direct comparison of values obtained with different methods. 

 
 
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4 
RESULTS  
4.1 
Critical Study Dates, Disposition of Subjects and Investigational Devices 
Patients were recruited from prior patients and referrals from other physicians requiring and 
consenting to surgery for Boston-Keratoprosthesis implantation at 3 sites in Germany between 
December 2014 and June 2016. In this clinical trial a total of 14 patients with indication for a Boston-
Keratoprosthesis implantation were screened and 13 patients initially enrolled, 12 of whom 
successfully received the ARGOS-IO implant.  
One of the 14 screened patients (DE-3-01) was excluded due to a screening failure based on inclusion 
criterion 1 (Male or female aged ≥ 18 and ≤ 80 years on the day of screening). The patient was 83 
years old. Due to a capsular bag instability detected during surgery, an implantation of the ARGOS-IO 
pressure sensor was not attempted in the second patient (DE-02-03). Thus, exclusion of this patient 
was unrelated to the ARGOS-IO device or procedures.  
The capsular bag instability for DE-02-03 is, however, included in the overall safety data for the trial. 
All patients underwent Boston-Keratoprosthesis and ARGOS-IO pressure sensor implantation 
between 15-FEB-2015 and 15-JUN-2016 and were followed up for approximately 12 months. The last 
patient visit took place on 14-JUN-2017. 
A total of 12 sensors were used for this study. 9 patients completed the study with the implanted 
sensors. One patient (DE-1-02) voluntary withdrew from the study after visit 10. In patient DE-1-05 
the ARGOS-IO sensor was explanted on 13-JUN-16 (last Visit V10) after two SAEs of corneal graft melt 
which had, however, no causal relationship with the ARGOS-IO sensor. And in patient DE-1-07 sensor 
explantation was done on 31-MAY-16 (last Visit V7) after a dislocation of the ARGOS-IO implant 
(SAE). 
4.2 
Protocol changes during the study 
The trial started out with revision B (Approval December 9th, 2014) of the clinical investigation plan. 
On March 30th, 2015 CIP Rev. C was approved with change from a paper-based Case Report Form to 
an electronic CRF. Rev. D resulted from an additional study center (change from monocenter to 
multicenter study) and from previous experiences within the trial (Approval August 5th, 2015). This 
clinical trial was finished with CIP Rev. E approved on April 13th, 2016. The most important changes to 
the protocol where as follows: 

 
 
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CIP Rev. D: Changes in Determination of ARGOS-IO Implant Size 
CIP 8.4.4.9, p. 68 “Anterior eye segment measurement, Optical Biometry” 
• 
“If optical biometry is not possible, for example due to opacity of the subject’s cornea, 
ultrasound biomicroscopy or corneal diameter measurement using an ophthalmosurgical 
caliper will be used to assess the dimension of the subject’s anterior chamber.” 
This method has been shown to be a feasible approach during the first implantation by 
Professor Neuhann. 
 
CIP Rev. E: Changes in Sample Size Considerations and Usage of the ARGOS-IO injector during 
implantation (optional) 
CIP Synopsis, p. 6 “Sample Size Considerations”, CIP 8.3.7, p. 68 “Number of subjects required”, CIP 
8.38, p. 68 “Estimated time needed to select the planned number of subjects” and CIP 9.2, p. 83 
“Sample Size Calculation” 
• 
The enrollment from a minimum of 6 and a maximum of 10 patients was increased to a 
minimum of 10 and a maximum of 15 patients. Due to very different baseline parameters of 
the patients and a good tolerance of the ARGOS-IO implant until then, the enrollment 
number was increased to gain more experience. 
 
CIP 4.7, p. 35 “Description of any specific medical or surgical procedures involved in the use of the 
investigational device”, CIP 5.1.1.3, p. 38 “Sterilization Verification”, CIP 6.5, p. 54 “Possible 
Interactions with concomitant Medical Treatments” and CIP 8.4.5.2, p. 75 “ARGOS-IO pressure 
sensor implantation” 
• 
The surgeons was given the option to use the ARGOS-IO Implant Injector as in the ARGOS-02 
study for an easier access to the posterior chamber by an intact narrow pupil. 
In the following table is listed which Revision of the Clinical Investigation Plan was valid for. 
 
 
 

 
 
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Table 3: Protocol changes during the study  
 
4.3 
Subject Demographics and Other Baseline Characteristics 
At enrollment, the patients (6 women and 7 men) were between 18 and 62 years of age (mean 39.4 
years, SD 15.4 years). All patients had a verifiable history of two or more prior failed corneal 
transplant procedures or a medical condition such as alkali burns or autoimmune disease that makes 
the success of a traditional corneal transplant procedure unlikely (Table 4 and Table 5). Seven 
subjects were already treated for elevated IOP or glaucoma.  
The patients had a mean axis length of 23.46 (SD 1.54) mm. 
Previous general illnesses of interest included myocardial infarction in one patient. All other reported 
Medical History are related to the eyes. Concomitant diseases besides eye disorders are related to 
endocrine disorders (5 patients), nervous system disorders (5 patients), metabolism and nutrition 
disorder (2 patients), vascular disorders (2 patients), the blood and lymphatic system (1 patient), 
gastrointestinal disorder (1 patient), and asthma, renal failure and leukemia (1 patient). 
 Medical History and Baseline medical conditions related to the study eye are summarized in Table 4 
and Table 5. 
Patient 
Date of Screening 
Date of Implantation 
Relevant CIP Version 
DE-1-01 
12-Feb-15 
12-Feb-15 
Rev. B 
DE-1-02 
29-Jul-15 
30-Jul-15 
Rev. C 
DE-1-03 
10-Sep-15 
10-Sep-15 
Rev. D 
DE-1-04 
29-Oct-15 
29-Oct-15 
Rev. D 
DE-1-05 
10-Dec-15 
10-Dec-15 
Rev. D 
DE-1-06 
14-Dec-15 
21-Jan-16 
Rev. D 
DE-1-07 
28-Apr-16 
28-Apr-16 
Rev. E 
DE-1-08 
02-Jun-16 
02-Jun-16 
Rev. E 
DE-2-01 
21-Oct-15 
22-Oct-15 
Rev. D 
DE-2-02 
10-Mar-16 
11-Mar-16 
Rev. D 
DE-2-03 
18-Apr-16 
(19-Apr-16, ARGOS-IO 
Implantation not done) 
Rev. E 
DE-2-04 
23-May-16 
24-May-16 
Rev. E 
DE-2-05 
15-Jun-16 
16-Jun-16 
Rev. E 
DE-3-01 
06-Jun-16 
n. a. 
Rev. E 

 
 
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Concomitant diseases are listed in Table 6. 
Table 4: Ophthalmic primary underlying condition/disease/event leading to need for KPro 
 
 
Table 5: Summary of Disease Characteristics concerning the study eye 
Parameter 
Total (N=13) 
 
 
 
 
Disease Characteristics concerning Study Eye 
 
 
Study Eye 
n 
% 
 
OD 
4  
30.8 
 
OS 
9 
69.2 
 
 
 
 
Ophthalmic primary underlying condition 
n 
% 
 
Autoimmune disease 
2 
15.4 
Chemical injury 
 2 
15.4 
Mechanical injury 
 1 
7.7 
Patient 
Need for keratoprosthesis 
Date of 
Onset 
Result of 
Current or previous 
treated for elevated 
IOP or glaucoma? 
DE-1-01 
Aniridia syndrome,  
Limbal stem cell insufficiency, 
Failed keratoplasty,  
Secundary glaucoma 
26-May-1996 
Aniridia syndrome 
(genetic) 
Yes 
DE-1-02 
Corneal decompensation 
22-Aug-2014 
Congenital glaucoma 
Yes 
DE-1-03 
Limbal stem cell insufficiency,  
Aniridia 
23-Apr-1983 
Genetic condition 
No 
DE-1-04 
Graft versus Host Disease 
2005 
Autoimmune disease 
No 
DE-1-05 
Explosion injury 
2005 
Injury, mechanical 
No 
DE-1-06 
Chemical burn 
28-Jul-1995 
Injury, chemical 
Yes 
DE-1-07 
Congenital aniridia syndrome 
05-Jan-1975 
Congenital disease 
Yes 
DE-1-08 
Congenital aniridia syndrome 
23-May-1995 
Congenital disease 
Yes 
DE-2-01 
Corneal opacity with 
vascularization 
22-May-2006 
Injury, chemical 
No 
DE-2-02 
Corneal decompensation after 
keratoplasty in complicated 
secondary glaucoma 
06-Jan-2016 
Aniridia 
Yes 
DE-2-03 
Corneal transplant failure, 
Chronic keratocinjunctivitis 
18-Jun-2015 
Atopic dermatitis 
No 
DE-2-04 
Aniridia, 
Corneal graft failure 
16-Dec-2015 
Hereditary disease 
Yes 
DE-2-05 
Corneal decompensation after 
corneal ulcer 
09-Dec-2011 
Autoimmune disease 
No 

 
 
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Other 
 8 
61.5 
 
 
Time since onset at surgery (in years) 
Mean 
SD 
Min 
Max 
14.2 
12.9 
1 
42 
 
 
 
 
Treated for elevated IOP or glaucoma* 
n 
% 
No 
6 
46.2 
Yes 
7 
53.8 
 
 
 
Axial length (mm) 
Mean 
SD 
Min 
Max 
23 
1.54 
21.23 
27 
 
 
 
IOP Measurements at Screening Visit 
 
GAT 
(mmHg) 
Pneumotonometry 
(mmHg) 
Beginning of Visit 
n 
Mean 
SD 
Min 
Max 
8 
12.9 
5 
7 
22 
4 
12.3 
6.2 
7 
12 
 
 
 
 
End of Visit 
n 
Mean 
SD 
Min 
Max 
5 
15 
4.6 
8 
20 
4 
14.5 
5.6 
7 
20 
 
Medical History Related to Study Eye 
n1 
% 
Any System Organ Class 
11 
84.6 
Congenital, Familial and Genetic Disorders 
1 
7.7 
Cataract congenital 
1 
7.7 
Eye Disorders 
6 
46.2 
Conjunctivalisation 
2 
15.4 
Corneal disorder 
1 
7.7 
Corneal erosion 
1 
7.7 
Retinal detachment 
1 
7.7 
Symblepharon 
1 
7.7 
Trichiasis 
1 
7.7 
Injury, Poisoning and Procedural Complications 
2 
15.4 
Blast injury 
1 
7.7 
Chemical burns of eye 
1 
7.7 
Surgical and Medical Procedures 
9 
69.2 
Keratoplasty 
4 
30.8 
Cataract operation 
3 
23.1 
Photocoagulation 
3 
23.1 
Amniotic membrane graft 
2 
15.4 

 
 
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Eye operation 
2 
15.4 
Stem cell transplant 
2 
15.4 
Corneal sutures removal 
1 
7.7 
Cryotherapy 
1 
7.7 
Depilation 
1 
7.7 
Eye prosthesis insertion 
1 
7.7 
Eyelid operation 
1 
7.7 
Intraocular lens implant 
1 
7.7 
Vitrectomy 
1 
7.7 
 
 
 
Concomitant Diseases Related to Study Eye 
n1 
% 
Any System Organ Class 
11 
84.6 
Congenital, Familial and Genetic Disorders 
6 
46.2 
Aniridia 
5 
38.5 
Developmental glaucoma 
1 
7.7 
Eye Disorders 
8 
61.5 
Glaucoma 
4 
30.8 
Limbal stem cell deficiency 
4 
30.8 
Amblyopia 
3 
23.1 
Ulcerative keratitis 
2 
15.4 
Aphakia 
1 
7.7 
Corneal neovascularisation 
1 
7.7 
Corneal edema 
1 
7.7 
Keratitis 
1 
7.7 
Keratoconus 
1 
7.7 
Symblepahron 
1 
7.7 
Xerophthalmia 
1 
7.7 
Immune System Disorders 
1 
7.7 
Graft versus Host Disease 
1 
7.7 
Nervous System Disorders 
4 
30.8 
Nystagmus 
4 
30.8 
Skin and Subcutaneous Tissue Disorders  
1 
7.7 
Toxic epidermal necrolysis 
1 
7.7 
Surgical and Medical Procedures 
7 
53.8 
Eye operation 
3 
23.1 
Keratoplasty 
3 
23.1 
Photocoagulation 
2 
15.4 
Trabeculectomy 
2 
15.4 
Amniotic membrane graft 
1 
7.7 
Cataract operation 
1 
7.7 
Corneal transplant 
1 
7.7 
Phacocystectomy 
1 
7.7 
 
 
 
Source: Final Statistical Output – Tables 
Table 14.1.4.2.1 – Disease Characteristics concerning Study Eye 
Table 14.1.4.7.1 – IOP Measurements at Screening Visit 

 
 
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Table 14.1.5.2.1 – Medical History Related to Study Eye by SOC and PT 
Table 14.1.5.4.1 – Concomitant Diseases Related to Study Eye by SOC and PT 
%: Percentage based on N 
n: Number of subjects with data available 
N: Number of subjects in total (Safety Set) 
(*): Previously or currently treated 
n1: Number of patients reporting at least one past diagnosis/procedure 
 
 
Table 6: Summary of Concomitant Diseases without any Relation to Study Eye 
Concomitant diseases 
Total (N=13) 
n1 
% 
Any System Organ Class 
12 
92.3 
Blood and Lymphatic System Disorders 
1 
7.7 
Anaemia 
1 
7.7 
Congenital, Familial and Genetic Disorders 
1 
7.7 
Cataract congenital 
1 
7.7 
Endocrine Disorders 
5 
38.5 
Hypothyroidism 
4 
30.8 
Cushing’s syndrome 
1 
7.7 
Eye Disorders 
2 
15.4 
Atrophy of globe 
2 
15.4 
Conjunctivalisationl 
1 
7.7 
Macular edema 
1 
7.7 
Retinal detachment 
1 
7.7 
Gastrointestinal Disorders 
1 
7.7 
Hyperchlorhydria 
1 
7.7 
Pancreatic failure 
1 
7.7 
General Disorders and Administration Site Conditions 
1 
7.7 
Pain 
1 
7.7 
Metabolism and Nutrition Disorders 
2 
15.4 
Diabetes Mellitus 
2 
15.4 
Vitamin B12 Deficiency 
1 
7.7 
Neoplasms Benign, Malignant and Unspecified 
1 
7.7 
Leukaemia 
1 
7.7 
Nervous System Disorders 
1 
7.7 
Epilepsy 
1 
7.7 
Psychiatric Disorders 
1 
7.7 
Psychotic disorder 
1 
7.7 
Renal Failure and Urinary Disorders 
1 
7.7 
Renal failure 
1 
7.7 

 
 
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Respiratory, Thoracic and Mediastinal Disorders 
1 
7.7 
Asthma 
1 
7.7 
Skin and Subcutaneous Tissue Disorders  
1 
7.7 
Dermatitis atopic 
1 
7.7 
Surgical and Medical Procedures 
1 
7.7 
Intraocular lens implant 
1 
7.7 
Vascular Disorders 
2 
15.4 
Hypertension 
2 
15.4 
 
 
 
Source: Final Statistical Output – Tables 
Table 14.1.5.3.1 – Concomitant Diseases by SOC and PT 
%: Percentage based on N 
N: Number of subjects in total (Safety Set) 
n1: Number of patients reporting at least one past diagnosis/procedure 
 
4.4 
Implantation Characteristics 
The surgical approach involved a typical trephination of adequate size of the central cornea of the 
recipient. Phakic subjects underwent cataract extraction by an open sky approach. If the subject was 
pseudophakic, the IOl was dealt with according to the site’s customary keratoprosthesis implantation 
procedure. A posterior chamber IOL implanted in the capsular bag could remain in the eye. 
 
Table 7: Summary of Surgical Approach 
Patient 
Was the patient 
pseudophacik? 
Location/Disposition 
Iridectomy 
Glaucoma Drainage Device 
Fixation of  
ARGOS-IO sensor 
DE-1-01 
Yes 
Posterior chamber, sulcus 
ciliaris/remained in eye 
No 
Yes, already at start of KPro 
surgery/left in place 
ukn 
DE-1-02 
Yes 
Posterior chamber, capsular 
bag/removed 
Yes 
Yes, already at start of KPro 
surgery/left in place 
Supported by sulcus 
Sutured to sclera 
DE-1-03 
No 
No 
No 
Sutured to sclera 
DE-1-04 
Yes 
Posterior chamber, capsular 
bag/remained in eye 
Yes 
No 
Supported by sulcus 
DE-1-05 
No 
No 
No 
Supported by sulcus 
DE-1-06 
Yes 
Yes 
No 
Supported by sulcus 

 
 
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Most frequently the ARGOS-IO sensor with a diameter of 11.7 mm was implanted (58.3%). In three 
patients (25.0%) was the smallest sensor implanted (11.3 mm) and two patients got (16.7%) got the 
ARGOS-IO sensor with a diameter of 12.1 mm. The implant was fixated in the ciliary sulcus in seven 
patients (58.3%), in four patients it was sutured to the sclera (33.3%) and in one case the fixation of 
the ARGOS-IO sensor was not documented. 
Intraoperative complications were reported in 3 patients (23.1%). In patient DE-1-02, a retinal hole 
occurred prior to the ARGOS-IO implantation. The other two complications occurred during the 
placement of the ARGOS-IO sensor, in patient DE-1-04 pigment dispersion and in patient DE-2-03 a 
posterior capsular tear so that the investigator decided to do no further attempts to implant the 
ARGOS-IO sensor in this patient. All these AEs have a causal relationship to the medical procedure 
and can also occur in a stand-alone implantation of a Boston-Keratoprosthesis. Pigment dispersion 
was rated as possible related to the medical device as well as to the medical procedure. It is known 
possible risk and is described in the CIP (7.4 Risks and anticipated adverse device effects to be 
assessed). All intraoperative complications were documented as AE (see 4.8 Safety). 
Posterior chamber, capsular 
bag/remained in eye 
DE-1-07 
No 
No 
No 
Sutured to sclera 
DE-1-08 
Yes 
Posterior chamber, capsular 
bag/removed  
No 
No 
Supported by sulcus 
DE-2-01 
Yes 
Posterior chamber, sulcus 
ciliaris/remained in eye 
Yes 
No 
Supported by sulcus 
DE-2-02 
Yes 
Posterior chamber, capsular 
bag/remained in eye 
No 
Yes, already at start of KPro 
surgery/left in place 
Sutured to sclera 
DE-2-03 
Yes 
Posterior chamber, capsular 
bag/remained in eye 
No 
No 
No Implantation of 
ARGOS-IO sensor 
DE-2-04 
No 
No 
No 
Sutured to sclera 
DE-2-05 
Yes 
Posterior chamber, capsular 
bag/remained in eye 
Yes 
No 
Supported by sulcus 
Source: Final Statistical Output – Listings 
Listing 16.2.5.1 – Implantation Surgery Data 
Listing 16.2.5.2 – ARGOS-IO Implantation 

 
 
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4.5 
CIP Compliance 
A summary of the protocol deviations is given by Table 8. 
Table 8: Summary of Protocol Deviations 
Parameter 
Total (N=13) 
n 
% 
 
At least one deviation 
12 
92.3 
 
Deviation related to 
 
 
 
Patient rights/welfare 
0 
0.0 
 
Patient safety 
1 
7.7 
 
Integrity of research data 
0 
0.0 
 
Other 
11 
84.6 
 
Involvement of deviation 
 
 
 
Consent process 
1 
7.7 
 
Patient eligibility 
0 
0.0 
 
AE/SAE reporting 
0 
0.0 
 
Assessments 
10 
76.9 
 
Device implantation 
0 
0.0 
 
Visit window/missed visit 
12 
92.3 
 
Audit finding that require corrective action 
0 
0.0 
 
Other 
4 
30.8 
 
Source: Final Statistical Output – Tables 
Table 14.1.3 – Summary of Protocol Deviations 
%: Percentage based on N 
N: Number of subjects in total (Treated patients) 
 
Patient rights and welfare were not affected by the protocol deviations. The deviation related to the 
patient safety was a missed signature on the Informed Consent Form by the investigator. For this 
issue, the investigator stated with actual date that the patient was informed about the study, agreed 
to participate, signed and got a copy of the patient information and Informed Consent Form.  
Most protocol deviations include visits out of the time window and assessments which were not 
completed as described in the CIP. The most frequent violation of the assessments was missing the 
external eye photography. This was only a minor deviation because these photos were not included 
in the evaluation. Missed surgical manometries were not performed due to medical reasons 
(hypotony of eye, Site DE-02 did no further surgical manometry in aniridia patients after SAEs (see 
4.8.1.1 Serious Adverse Events in the follow-up period)). 
 

 
 
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4.6 
Data Sets Analyzed 
Safety Population 
The safety population comprises all subjects for whom ARGOS-IO pressure sensor implantation was 
attempted, defined as introduction of the ARGOS-IO pressure sensor into the eye, whether or not the 
implantation was successful. 
The Per-Protocol-Set (PPS) population 
The Per Protocol Set (PPS) will comprise all subjects in whom ARGOS-IO pressure sensor was 
successfully implanted and for whom the full data set including IOP measurements made in the clinic 
and safety data according to protocol are available until 28 weeks (Visit 11) after surgery. Because 
IOP measurements conducted outside the clinic will made at varying times under varying conditions, 
they are not anticipated to be comparable to those made in the clinic and will not be included in the 
Per-Protocol evaluation of agreement. 
Additional information about the drop-outs: all subjects who revoke their consent and agreement 
preoperatively will be regarded as screen failures and will not be included in the statistical 
evaluation. All subjects who revoke their consent and agreement postoperatively will be considered 
withdrawals. Unless the subject also withdrew consent to use their data, they will be evaluated in the 
safety analysis. 
4.7 
Performance 
4.7.1 
Tonometry 
4.7.1.1 
ARGOS-IO System 
Telemetric IOP assessments by the ARGOS-IO implant was conducted at every study visit of every 
patient. 
In the following line graphs (Figure 6) display the individual ARGOS-IO measurements over per 
patient at scheduled visits. Post-operative study visits were at Day 1, 5, 10, 15 and week 4, 10, 16, 22, 
28, 34, 40, 46 and 52. 
 

 
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Figure 6. Individual IOP follow-up during study period per patient measured with the ARGOS-IO system 
 

 
 
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4.7.1.2 
Comparison of ARGOS-IO system compared to finger palpation and surgical manometry 
Comparison to finger palpation 
IOP by finger palpation was assessed at every study visit. Figure 7 shows the average of the within 
subjects ARGOS-IO measurements at the beginning of the visit. Concerning Visit V07, V09, V11 and 
V15, ARGOS-IO measurements were taken before surgical manometry. Categories for the outcome of 
the finger palpation were normal, soft hypotonic, borderline and hypertonic. Measurements were 
not always performed. 
 
Figure 7. ARGOS-IO Measurements versus Finger Palpation – Scatter Plot for each Post-Surgery Visit 
Population: Safety Set 
 
Figure 14.2.6.1; Reference Table 14.2.6.1 
 
 
IOP by finger palpation was assessed at every study visit. In 82 visits IOP by finger palpation was seen 
“normal”, mean telemetric IOP in these visits was 18.2 ± 6.1 mmHg, ranging from 7.3 to 52.0 mmHg. 
In 16 visits, patients’ eyes were rated soft/hypotonic in finger palpation, while mean ARGOS-IO 
measurement was 8.9 ± 2.8 mmHg (range, 4.1 – 14.9 mmHg). In 9 visits, palpated IOP was classified 
as borderline, mean IOP assessed by the ARGOS-IO system was 22.4 ± 4.9 mmHg (range, 15.2 – 27.9 
mmHg). In 8 visits, eyes were seen hypertonic in palpation. In these cases, mean telemetric IOP was 
34.3 ± 11.0 mmHg, ranging from 23.4 to 58.0 mmHg. Kruskal Wallis test showed a statistically 

 
 
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significant difference of telemetric IOP measurements between finger palpation categories with P < 
0.001. 
Comparison to surgical manometry 
The following figures show the ARGOS-IO measurements within subject average of ARGOS-IO 
measurements during surgical manometry of the visit. The difference between surgical manometry 
and ARGOS-IO measurements is plotted as well. The difference was only derived when the time 
points of measurements differed for at most 2 min. Measurements were not always performed 
(Surgical Manometry in patients DE-1-02, DE-1-07 and DE-2-05 was never done). 
 
Figure 8. Difference between Manometry and ARGOS-IO over the time – mean value plot; DE-1-01 
 
Figure 14.2.1.3; Reference: Subject Data Listing 16.2.6.1 
 
 
 
Visit 
Surgical Manometry 
Average of 3 consecutive ARGOS-IO measurements 
Time 
IOP 
(mmHg) 
Before Manometry 
During Manometry 
Following Manometry 
Time 
IOP 
(mmHg) 
Time 
IOP 
(mmHg) 
Time 
IOP 
(mmHg) 
V07 
12:40 
17.0 
12:30 
18.7 
Not done 
14:18 
16.9 
V09 
14:30 
21.0 
08:34 
27.8 
14:30 
27.0 
Not done 
V11 
Not done 
17:04 
25.2 
Not done 
Not done 
V15 
Not done 
Not done 
Not done 
Not done 
 
 

 
 
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Figure 9. Difference between Manometry and ARGOS-IO over the time – mean value plot; DE-1-03 
 
Figure 14.2.1.3; Reference: Subject Data Listing 16.2.6.1 
 
 
 
Visit 
Surgical Manometry 
Average of 3 consecutive ARGOS-IO measurements 
Time 
IOP 
(mmHg) 
Before Manometry 
During Manometry 
Following Manometry 
Time 
IOP 
(mmHg) 
Time 
IOP 
(mmHg) 
Time 
IOP 
(mmHg) 
V07 
09:40 
18.0 
Not done 
09:40 
14.4 
10:40 
18.5 
V09 
11:45 
19.0 
09:41 
20.3 
11:45 
24.3 
13:25 
11.8 
V11 
12:05 
11 
11:33 
20.7 
12:05 
16.7 
13:31 
14.9 
V15 
13:16 
18 
12:45 
11.7 
12:48 
13.9 
Not done 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Figure 10. Difference between Manometry and ARGOS-IO over the time – mean value plot; DE-1-04 
 
Figure 14.2.1.3; Reference: Subject Data Listing 16.2.6.1 
 
 
 
Visit 
Surgical Manometry 
Average of 3 consecutive ARGOS-IO measurements 
Time 
IOP 
(mmHg) 
Before Manometry 
During Manometry 
Following Manometry 
Time 
IOP 
(mmHg) 
Time 
IOP 
(mmHg) 
Time 
IOP 
(mmHg) 
V07 
11:03 
32.0 
09:02 
16.4 
11:04 
20.8 
12:57 
30.3 
V09 
12:48 
11 
12:45 
11.7 
12:48 
13.9 
Not done 
V11 
Not done 
Not done 
Not done 
Not done 
V15 
13:25 
19 
10:44 
27.6 
13:25 
27.7 
Not done 
 
There is no explanation for the discrepancy of more than 10 mmHg between ARGOS-IO and surgical 
manometry in V07. 
 
 
 
 
 
 

 
 
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Figure 11. Difference between Manometry and ARGOS-IO over the time – mean value plot; DE-1-05 
 
Figure 14.2.1.3; Reference: Subject Data Listing 16.2.6.1 
 
 
 
Visit 
Surgical Manometry 
Average of 3 consecutive ARGOS-IO measurements 
Time 
IOP 
(mmHg) 
Before Manometry 
During Manometry 
Following Manometry 
Time 
IOP 
(mmHg) 
Time 
IOP 
(mmHg) 
Time 
IOP 
(mmHg) 
V07 
12:30 
19.0 
10:48 
40.1 
12:30 
23.7 
Not done 
V09 
10:50 
18.0 
08:40 
23.7 
10:50 
21.6 
12:36 
21.9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Figure 12. Difference between Manometry and ARGOS-IO over the time – mean value plot; DE-1-06 
 
Figure 14.2.1.3; Reference: Subject Data Listing 16.2.6.1 
 
 
 
Visit 
Surgical Manometry 
Average of 3 consecutive ARGOS-IO measurements 
Time 
IOP 
(mmHg) 
Before Manometry 
During Manometry 
Following Manometry 
Time 
IOP 
(mmHg) 
Time 
IOP 
(mmHg) 
Time 
IOP 
(mmHg) 
V07 
14:45 
30.0 
12:08 
18.8 
14:45 
25.6 
14:48 
20.4 
V09 
Not done 
12:42 
34.5 
Not done 
Not done 
V11 
18:09 
39.0 
Not done 
18:09 
40.3 
18:26 
17.5 
V15 
Not done 
Not done 
Not done 
Not done 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Figure 13. Difference between Manometry and ARGOS-IO over the time – mean value plot; DE-1-08 
 
Figure 14.2.1.3; Reference: Subject Data Listing 16.2.6.1 
 
 
 
Visit 
Surgical Manometry 
Average of 3 consecutive ARGOS-IO measurements 
Time 
IOP 
(mmHg) 
Before Manometry 
During Manometry 
Following Manometry 
Time 
IOP 
(mmHg) 
Time 
IOP 
(mmHg) 
Time 
IOP 
(mmHg) 
V07 
10:09 
10.0 
Not done 
10:09 
17.7 
15:33 
18.6 
V09 
14:59 
12.0 
09:38 
18.7 
14:59 
11.8 
15:16 
2.4 
V11 
11:00 
25.0 
08:29 
21.6 
11:00 
61.0 
11:01 
1.4 
V15 
11:05 
30.0 
09:52 
28.1 
11:05 
44.8 
Not done 
 
Almost certainly, a measurement error is existent for the ARGOS-IO measurements during surgical manometry 
at V11 and V15 in this patient. ARGOS-IO measurements which were obtained before surgical manometry 
correspond well with the manometric values. Patient DE-1-08 has a congenital aniridia syndrome. The IOL was 
removed during the BkPro and ARGOS-IO implantation. The ARGOS-IO sensor is supported by the sulcus. It 
cannot be excluded that the sensor was touched during the manometry which could explain this high values.  
 
 
 
 
 
 
 

 
 
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Figure 14. Difference between Manometry and ARGOS-IO over the time – mean value plot; DE-2-01 
 
Figure 14.2.1.3; Reference: Subject Data Listing 16.2.6.1 
 
 
 
Visit 
Surgical Manometry 
Average of 3 consecutive ARGOS-IO measurements 
Time 
IOP 
(mmHg) 
Before Manometry 
During Manometry 
Following Manometry 
Time 
IOP 
(mmHg) 
Time 
IOP 
(mmHg) 
Time 
IOP 
(mmHg) 
V07 
16:01 
20.0 
11:14 
20.8 
16:20 
19.0 
16:45 
16.3 
V09 
15:55 
17.0 
15:00 
19.9 
15:56 
17.6 
16:30 
17.1 
V11 
17:15 
24 
12:30 
19.8 
Not done 
17:30 
23.8 
V15 
15:36 
14 
12:00 
20.1 
15:32 
22.8 
Not done 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Figure 15. Difference between Manometry and ARGOS-IO over the time – mean value plot; DE-2-02 
 
Figure 14.2.1.3; Reference: Subject Data Listing 16.2.6.1 
 
 
 
Visit 
Surgical Manometry 
Average of 3 consecutive ARGOS-IO measurements 
Time 
IOP 
(mmHg) 
Before Manometry 
During Manometry 
Following Manometry 
Time 
IOP 
(mmHg) 
Time 
IOP 
(mmHg) 
Time 
IOP 
(mmHg) 
V07 
15:46 
23.0 
15:40 
19.1 
15:46 
16.1 
15:52 
16.0 
V09 
14:05 
5.0 
12:16 
7.8 
14:05 
5.7 
Not done 
V11 
Not done 
11:15 
7.3 
Not done 
Not done 
V15 
Not done 
12:00 
8.3 
Not done 
13:00 
8.5 
 
In this patient with aniridia, PVR with consecutive tractive retinal detachment developed in timely 
connection to surgical manometry (see 4.8.1.1 Serious adverse events in the follow-up period; DE-2-
02: Proliferative vitreoretinopathy (PVR) with retinal detachment). Therefore, the investigator 
decided against assessing a manometry in this patient at V11 and V15. 
 
 
 
 
 
 
 
 
 
 

 
 
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Figure 16. Difference between Manometry and ARGOS-IO over the time – mean value plot; DE-2-02 
 
Figure 14.2.1.3; Reference: Subject Data Listing 16.2.6.1 
 
 
 
Visit 
Surgical Manometry 
Average of 3 consecutive ARGOS-IO measurments 
Time 
IOP 
(mmHg) 
Before Manometry 
During Manometry 
Following Manometry 
Time 
IOP 
(mmHg) 
Time 
IOP 
(mmHg) 
Time 
IOP 
(mmHg) 
V07 
14:30 
03 
12:17 
12.3 
14:30 
11.1 
Not done 
V09 
Not done 
11:00 
7.7 
Not done 
Not done 
V11 
Not done 
14:25 
11.1 
Not done 
Not done 
V15 
Not done 
09:31 
14.0 
Not done 
Not done 
 
In this patient with aniridia, PVR with consecutive tractive retinal detachment developed in timely 
connection to surgical manometry (see 4.8.1.1 Serious adverse events in the follow-up period; DE-2-
04: Proliferative vitreoretinopath). Therefore, the investigator decided against assessing a 
manometry in this patient at V09, V11 and V15. 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Figure 17. Difference between Manometry and ARGOS-IO over the time – mean value plot (all patients) 
Population: Safety Set 
 
 
Figure 14.2.1.2; Reference Table 14.2.1.2 
 
 
Surgical intracameral manometry was performed in a total of 24 visits in nine patients. The study 
protocol entailed manometry in four visits in every patient, when the investigators rated the study 
eye sufficiently stable to undergo surgical manometry. In these visits, the mean telemetric IOP, 
representing the averaged value of three repeated measurements, was 22.8 ± 11.7 mmHg. The mean 
invasive IOP by manometry was 19.0 ± 8.4 mmHg. In nine of 24 events (37.5%), both IOP 
measurements deviated by less than 10%, and in 14 of 24 by less than 20% (58.3%). In three visits, 
telemetric and manometric IOP measurements showed a discrepancy of more than 10 mmHg, 
suggesting measurement errors. In these cases, a major discrepancy was noted between 
preoperative and intraoperative telemetric IOP measurements. Two of the three outliers occurred in 
the same patient (DE-1-08). While intraoperative telemetric measurements obtained by the ARGOS-
IO system showed high values of 45 mmHg and 60 mmHg respectively, manometric values 
corresponded well with telemetric values obtained one hour preoperatively. In the first visit, the 
preoperative mean telemetric IOP was 28.1 mmHg with a manometric measurement of 30 mmHg. In 
the second visit, a manometric IOP of 25 mmHg compared to a preoperative mean telemetric IOP of 
21.6 mmHg. In the third outlier (DE-1-04), preoperative telemetric IOP measurements showed a 
consistent discrepancy. When these three cases of outliers were excluded, IOP measurements by 
both modalities had a correlation of r = 0.874 (P < 0.001).  

 
 
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Figure 18 and 19 are a Bland-Altman plot of all acquired events in this study for graphical display of 
the congruence between both modalities to measure IOP. 
 
 
Figure 18. Bland-Altman Plot: Level of Agreement between Manometry and ARGOS-IO by Visit  
Population: Safety Set 
 
Figure 14.2.3.1; Reference: Table 14.2.3.1 
 
ARGOS-IO measurements: within subject average of ARGOS-IO measurements during surgical manometry of the visit. 
NOTE: Measurements were not always performed. The difference between surgical manometry and ARGOS-IO measurements is plotted 
against the average of the two values by visit. The solid line represents the level of agreements the broken lines display the lower 95% and 
the upper 95% bound for the level of agreement. 
 
 
 

 
 
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Figure 19. Bland-Altman Plot: Overall Level of Agreement between Manometry and ARGOS-IO  
Population: Safety Set 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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4.7.2 
User acceptance of the ARGOS-IO system at home by evaluation of patient 
acceptance questionnaire 
In all patients who completed the patient acceptance questionnaire was a very high overall 
acceptance in using the ARGOS-IO system in their daily routine. The instruction for use for the 
Mesograph reader device was easily to understand, the implant did not cause them any problems 
and the patients were less concerned about unidentified high IOP.  
Patients could give an estimate on a scale of 1 to 7 how strongly they agree with the following 
questions. 1 means totally disagree and 7 stands for totally agree. 
 
 

 
 
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Q2 - To what extend do you agree with the following statements: 
Based on my experience with the ARGOS-IO system in this study, I would seriously consider 
 
…permanently using ARGOS-IO system at home. 
 
 
…using ARGOS-IO system at workplace. 
 
 
 
Answer 
Frequency (N=6) 
n 
% 
Completely agree 
6 
100.0 
Answer 
Frequency (N=6) 
n 
% 
Completely disagree 
1 
16.7 
Somewhat agree 
1 
16.7 
Completely agree 
2 
33.3 
Missing 
2 
33.3 

 
 
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…using the ARGOS-IO system while travelling. 
 
 
 
…recommending the ARGOS-IO system to other glaucoma patients. 
 
 
 
Answer 
Frequency (N=6) 
n 
% 
Strongly agree 
1 
16.7 
Completely agree 
5 
83.3 
Answer 
Frequency (N=6) 
n 
% 
Somewhat disagree 
1 
16.7 
Indifferent 
2 
33.3 
Strongly agree 
1 
16.7 
Completely agree 
2 
33.3 

 
 
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Q3 – How do you normally have your IOP measured (outside of the study)? 
 
 
 
Q4 – To what extend do you agree with the following statements regarding the user instructions 
…user instructions for the Mesograph reader device can easily be understood. 
 
 
 
Answer 
Frequency (N=6) 
n 
% 
Monthly 
4 
66.7 
Every 2 months 
1 
16.7 
Every 3 months 
1 
16.7 
Answer 
Frequency (N=6) 
n 
% 
Indifferent 
1 
16.7 
Strongly agree 
2 
33.3 
Completely agree 
2 
33.3 
Missing 
1 
16.7 

 
 
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…user instructions for the Multiline connector can easily be understood. 
 
 
Q5 – To what extend do you agree with the following statements about the Mesograph reader 
device? 
The Mesograph reader device fits well in the hand… 
 
 
 
Answer 
Frequency (N=6) 
n 
% 
Indifferent 
1 
16.7 
Strongly agree 
1 
16.7 
Completely agree 
1 
16.7 
Missing 
3 
50.0 
Answer 
Frequency (N=6) 
n 
% 
Somewhat agree 
1 
16.7 
Strongly agree 
1 
16.7 
Completely agree 
4 
66.7 

 
 
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The display of the Mesograph reader is large enough… 
 
 
 
The battery of the MESOGRAPH reader lasts long and can be easily exchanged… 
 
 
 
 
 
 
Answer 
Frequency (N=6) 
n 
% 
Strongly agree 
3 
50.0 
Completely agree 
3 
50.0 
Answer 
Frequency (N=6) 
n 
% 
Indifferent 
1 
16.7 
Strongly agree 
2 
33.3 
Completely agree 
2 
33.3 
Missing 
1 
16.7 

 
 
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Q6 – To what extend do you agree with the following statements about the implant: 
The implant does not cause me any problems… 
 
 
 
I feel the implant as a foreign body… 
 
 
 
 
 
Answer 
Frequency 
(N=6) 
n 
% 
Strongly agree 
1 
16.7 
Completely agree 
5 
83.3 
Answer 
Frequency (N=6) 
n 
% 
Completely disagree 
4 
66.7 
Strongly disagree 
2 
33.3 

 
 
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The implant affects my visual field… 
 
 
 
Q7 – To what extend do you agree the following statements: 
Pressure measurements at home do not disturb my daily routine… 
 
 
 
 
 
 
Answer 
Frequency (N=6) 
n 
% 
Completely disagree 
6 
100.0 
Answer 
Frequency (N=6) 
n 
% 
Completely disagree 
1 
16.7 
Strongly agree 
1 
16.7 
Completely agree 
4 
66.7 

 
 
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Pressure measurements at home reduced my worries about unidentified high ocular pressure… 
 
 
 
Pressure measurements at home increased my motivation to regularly take my pressure lowering 
medication… 
 
 
 
 
Answer 
Frequency (N=6) 
n 
% 
Indifferent 
1 
16.7 
Strongly agree 
2 
33.3 
Completely agree 
3 
50.0 
Answer 
Frequency (N=6) 
n 
% 
Somewhat disagree 
1 
16.7 
Indifferent 
2 
33.3 
Strongly agree 
1 
16.7 
Completely agree 
1 
16.7 
Missing 
1 
16.7 

 
 
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4.8 
Safety  
4.8.1 
Adverse Events 
Information about all untoward medical occurrences occurring during a subject’s study participation 
was collected at study visits through examination by the Investigator. Information about events 
occurring between visits was obtained by asking the patient non-leading questions. 
Particular attention was paid to ophthalmic AEs, for which increased risks are considered possible 
(CIP 7.4 Risks and anticipated adverse device effects to be assed): 
• 
Retroprosthetic membrane formation 
• 
Increased intraocular pressure 
• 
Glaucoma progression 
• 
Endophthalmitis  
• 
Angle narrowing or angle closure 
• 
Sterile keratolysis 
• 
Fungal infections 
• 
Choroidal effusions/hemorrhage 
• 
Vitritis 
• 
Vitreous hemorrhage 
• 
Retina detachments 
• 
Corneal melt/necrosis 
• 
Loss of implant, disintegration of implant, implant dislocation or extrusion 
• 
Need for GDD implantation (pars plana vitrectomy) 
• 
Cystoid macular edema 
• 
Fibrin reactions 
• 
Hypopyons 
• 
Pigment dispersion during surgery 
• 
Postsurgical pigment dispersion 
Overall 168 AEs were reported during the ARGOS-KP01 study. 12 months after implantation were 
reported 168 AEs in 13 patients, including 23 SAEs in 9 patients. 92 AEs in 5 patients were rated as 
unlikely to the medical device and 61 AEs in patients have no relationship to the ARGOS-IO sensor. 
Only 15 AEs in four patients were possible related to the medical device: anterior chamber cell, 

 
 
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cystoid macular edema, hypotony of the eye, iris adhesion, pigment dispersion, vitritis, increased 
intraocular pressure and retroprosthetic membrane. 
Table 9 lists all adverse events including SAEs. 
Table 9: Summary of all AEs  
Adverse Events 
Total (N=13) 
       n 
% 
AE 
Any System Organ Class 
13 
100 
168 
Ear and Labyrinth Disorders 
1 
7.7 
 
Tinnitus 
1 
7.7 
 
Eye Disorders 
11 
84.6 
79 
Eye pain 
6 
46.2 
7 
Hypotony of eye 
6 
46.2 
8 
Vitritis 
4 
30.8 
5 
Cystoid macular edema 
3 
23.1 
7 
Retinal detachment 
3 
23.1 
3 
Choroidal detachment 
2 
15.4 
2 
Corneal infiltrates 
2 
15.4 
2 
Iris adhesion 
2 
15.4 
4 
Keratitis 
2 
15.4 
3 
Retinopathy proliferative 
2 
15.4 
4 
Visual acuity reduced 
2 
15.4 
2 
Anterior chamber cell 
1 
7.7 
1 
Anterior chamber fibrin 
1 
7.7 
1 
Blepharitis 
1 
7.7 
1 
Choroidal haemorrhage 
1 
7.7 
1 
Conjunctival disorder 
1 
7.7 
1 
Conjunctival haemorrhage 
1 
7.7 
1 
Conjunctival hyperaemia 
1 
7.7 
1 
Corneal epithelium defect 
1 
7.7 
3 
Corneal neovascualrisation 
1 
7.7 
1 
Corneal perforation 
1 
7.7 
1 
Erythema of eyelid 
1 
7.7 
1 
Eye inflammation 
1 
7.7 
1 
Eye pruritus 
1 
7.7 
1 
Keratic precipitates 
1 
7.7 
1 
Lacrimation increased 
1 
7.7 
1 
Lens disorder 
1 
7.7 
1 
Ocular discomfort 
1 
7.7 
2 
Pigment dispersion  
1 
7.7 
1 
Retinal disorder 
1 
7.7 
1 
Retinal haemorrhage 
1 
7.7 
1 
Retinal scar 
1 
7.7 
1 
Retinal tear 
1 
7.7 
1 

 
 
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Retinal thickening 
1 
7.7 
1 
Subretinal fibrosis 
1 
7.7 
1 
Trichiasis 
1 
7.7 
2 
Visual impairment 
1 
7.7 
1 
Vitreous haemorrhage 
1 
7.7 
1 
Vitreous opacities 
1 
7.7 
1 
Gastrointestinal Disorders 
2 
15.4 
2 
Constipation 
1 
7.7 
1 
Nausea 
1 
7.7 
1 
General Disorders and Administration Site 
Conditions 
3 
23.1 
4 
Atrophy of the donor cornea 
1 
7.7 
1 
Leakage between keratoprosthesis and 
keratoplasty 
1 
7.7 
1 
Subjectively worse impression 
1 
7.7 
1 
Drug intolerance 
1 
7.7 
1 
Infections and Infestations 
3 
23.1 
3 
Bacterial disease carrier 
1 
7.7 
1 
Gastroenteritis 
1 
7.7 
1 
Urinary tract infection 
1 
7.7 
1 
Injury, Poisoning and Procedural Complications 
4 
30.8 
8 
Procedural Pain  
3 
23.1 
3 
Hyphaema 
1 
7.7 
1 
Post procedural complication 
1 
7.7 
1 
Post procedural haemorrhage 
1 
7.7 
1 
Suture related complication 
1 
7.7 
1 
Corneal graft melt 
1 
7.7 
1 
Investigations 
8 
61.5 
35 
Intraocular pressure increased 
8 
61.5 
30 
Intraocular pressure decreased 
3 
23.1 
4 
Seidel Test positive 
1 
7.7 
1 
Musculoskeletal and Connective Tissue Disorders 
1 
7.7 
3 
Back pain 
1 
7.7 
1 
Bone pain 
1 
7.7 
1 
Fibromyalgia 
1 
7.7 
1 
Nervous System Disorders 
3 
23.1 
4 
Dizziness 
1 
7.7 
1 
Headache 
1 
7.7 
1 
Paraesthesia 
1 
7.7 
1 
Syncope 
1 
7.7 
1 
Product Issues 
8 
61.5 
13 
Retroprosthetic membrane 
6 
46.2 
7 
Device material opacification  
(BkPro and IOL)* 
3 
23.1 
5 
Dislocation of ARGOS-IO sensor 
1 
7.7 
1 

 
 
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Psychiatric Disorders 
1 
7.7 
1 
Panic attack 
1 
7.7 
1 
Renal and Urinary Disorders 
1 
7.7 
2 
Renal failure 
1 
7.7 
2 
Surgical and Medical Procedures 
6 
46.2 
12 
Corneal sutures removal 
5 
38.5 
8 
Corneal transplant 
2 
15.4 
4 
Vascular Disorders 
1 
7.7 
1 
Hypertension 
1 
7.7 
1 
 
 
 
 
Source: Final Statistical Output – Tables 
Table 14.3.1.3 – Adverse Events by SOC and PT: first 4 weeks, 16 weeks, 28 weeks, 12 months following implantation 
surgery 
%: Percentage based on N 
N: Number of subjects in total (Safety Set) 
n: Number of patients reporting at least one adverse event with the specification 
*: 3x opacification of BkPro’s rear surface/1x milky optic of KPro/1x hazy IOL 
 
 
The majority of the AEs (116 of 168) has a relationship to the medical procedure which implements 
both the implantation of the ARGOS-IO sensor and the Boston-Keratoprosthesis surgery (Table 10). 
Often, an AE cannot be assigned definitely to one procedure as the two implantations were 
performed in one surgery and many of the AEs are already known as complications for a stand-alone 
BkPro procedure. 
 

 
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Table 10: AEs related to the Medical Procedure – Time of Occurrence and Outcome 
 
Total (N=13) 
Adverse Event 
First 4 weeks 
First 16 weeks 
First 28 weeks 
First 12 months 
Outcome 
n 
% 
AE 
n 
% 
AE 
n 
% 
AE 
n 
% 
AE 
Any System Organ Class 
5 
38.5 
32 
10 
76.9 
62 
13 
100 
80 
13 
100 
116 
 
Eye Disorders 
9 
69.2 
16 
11 
84.6 
36 
11 
84.6 
44 
11 
84.6 
61 
 
Hypotony of eye 
1 
7.7 
2 
4 
30.8 
5 
5 
38.5 
6 
6 
46.2 
7 
6 recovered 
1 recovering 
Eye Pain 
2 
15.4 
2 
3 
23.1 
3 
3 
23.1 
4 
4 
30.8 
5 
recovered 
Cystoid macular edema 
0 
0.0 
0 
2 
15.4 
3 
3 
23.1 
4 
3 
23.1 
6 
4 recovered 
1 recovering 
1 recurrent 
Vitritis 
0 
0.0 
0 
1 
7.7 
1 
1 
7.7 
1 
3 
23.1 
4 
recovered 
Choroidal detachment 
0 
0.0 
0 
2 
15.4 
2 
2 
15.4 
2 
2 
15.4 
2 
recovered 
Corneal infiltrates 
0 
0.0 
0 
0 
0.0 
0 
1 
7.7 
1 
2 
15.4 
2 
1 recovered 
1 recovered 
with sequelae 
Retinal detachment 
0 
0.0 
0 
1 
7.7 
1 
1 
7.7 
1 
2 
15.4 
2 
1 recovered 
1 recovered 
with sequelae 
Retinopathy proliferative 
0 
0.0 
0 
1 
7.7 
2 
1 
7.7 
2 
2 
15.4 
4 
recovered 
Visual acuity reduced 
0 
0.0 
0 
2 
15.4 
2 
2 
15.4 
2 
2 
15.4 
2 
1 recovered 
1 recovering 
Anterior chamber cell 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
recovered 
Anterior chamber fibrin 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
recovered 
Blepharitis 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
recovering 

 
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Choroidal haemorrhage 
0 
0.0 
0 
0 
0.0 
0 
0 
0.0 
0 
1 
7.7 
1 
not recovered 
Conjunctival disorder 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
recovered 
Conjunctival haemorrhage 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
recovered 
Conjunctival hyperaemia 
0 
0.0 
0 
0 
0.0 
0 
0 
0.0 
0 
1 
7.7 
1 
recovering 
Corneal epithelium defect 
0 
0.0 
0 
0 
0.0 
0 
0 
0.0 
0 
1 
7.7 
1 
recovered 
Corneal neovascularisation 
0 
0.0 
0 
0 
0.0 
0 
1 
7.7 
1 
1 
7.7 
1 
not recovered 
Eye inflammation 
0 
0.0 
0 
0 
0.0 
0 
0 
0.0 
0 
1 
7.7 
1 
recovered 
Eye pruritus 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
recovered 
Iris adhesion 
0 
0.0 
0 
1 
7.7 
1 
1 
7.7 
2 
1 
7.7 
2 
recovered 
Keratic precipitates 
0 
0.0 
 
0 
0.0 
0 
0 
0.0 
0 
1 
7.7 
1 
recovered 
Keratitis 
0 
0.0 
0 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
recovered 
Lacrimation increased 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
recovered 
Capsular bag instability 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
unknown 
Ocular discomfort 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
2 
1 
7.7 
2 
recovered 
Pigment dispersion 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
recovered 
Retinal disorder 
0 
0.0 
0 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
recovered 
Retinal haemorrhage 
0 
0.0 
0 
0 
0.0 
0 
0 
0.0 
0 
1 
7.7 
1 
recovered 
Retinal scar 
0 
0.0 
0 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
recovered 
Retinal tear 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
recovered 
Retinal thickening 
0 
0.0 
0 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
not recovered 
Vitreous haemorrhage 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
recovered 
Vitreous opacities 
0 
0.0 
0 
0 
0.0 
0 
1 
7.7 
1 
1 
7.7 
1 
recovered 
General Disorder and Administration 
Site Conditions 
0 
0.0 
0 
0 
0.0 
0 
1 
7.7 
1 
2 
15.4 
2 
 
Atrophy of the donor cornea 
0 
0.0 
0 
0 
0.0 
0 
1 
7.7 
1 
1 
7.7 
1 
not recovered 
Subjectively worse impression 
0 
0.0 
0 
0 
0.0 
0 
0 
0.0 
0 
1 
7.7 
1 
recovered 
Injury, Poisoning and Procedural 
Complications 
4 
30.8 
6 
4 
30.8 
7 
4 
30.8 
7 
4 
30.8 
7 
 
Procedural pain 
3 
23.1 
3 
3 
23.1 
3 
3 
23.1 
3 
3 
23.1 
3 
recovered 
Hyphaema 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
recovered 
Post procedural complication 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
recovered 
Post procedural haemorrhage 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
recovered 

 
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Suture related complication 
0 
0.0 
0 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
recovered 
Investigations 
6 
46.2 
7 
6 
46.2 
10 
7 
53.8 
16 
7 
53.8 
25 
 
Intraocular pressure increased 
6 
46.2 
7 
6 
46.2 
10 
7 
53.8 
16 
7 
53.8 
24 
recovered 
Intraocular pressure decreased 
0 
0.0 
0 
0 
0.0 
0 
0 
0.0 
0 
1 
7.7 
1 
not recovered 
Nervous System Disorders 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
 
Headache 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
recovered 
Product Issue 
1 
7.7 
1 
5 
38.5 
6 
6 
46.2 
7 
7 
53.8 
11 
 
Retroprosthetic membrane 
1 
7.7 
1 
4 
30.8 
4 
4 
30.8 
4 
5 
38.5 
5 
3 recovered 
2 not 
recovered 
Device material opacification 
(BKPro and IOL)* 
0 
0.0 
0 
2 
15.4 
2 
2 
15.4 
2 
3 
23.1 
5 
recovered 
Dislocation of ARGOS-IO sensor 
0 
0.0 
0 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
recovered 
Surgical and Medical Procedures 
1 
7.7 
1 
2 
15.4 
2 
3 
23.1 
4 
6 
46.2 
9 
 
Corneal suture removal 
1 
7.7 
1 
1 
7.7 
1 
2 
15.4 
2 
5 
38.5 
7 
recovered 
Corneal graft melt 
0 
0.0 
0 
1 
7.7 
1 
1 
7.7 
2 
1 
7.7 
2 
recovered 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Final Statistical Output – Tables 
Table 14.3.1.7 – Adverse Events Related to Procedure by SOC and PT – periods first 4 weeks, 16 weeks, 28 weeks, 12 months following implantation surgery 
%: Percentage based on N 
N: Number of subjects in total (Safety Set) 
n: Number of patients reporting at least one adverse event with the specification 
AE: Number of individual adverse events which occurred among the n patients 
*: 3x opacification of BKPro’s rear surface/1x milky optic of KPro/1x hazy IOL 
 

 
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The most common adverse event was an increased intraocular pressure (30 AEs in eight patients) 
which was related to the medical procedure 24 times in seven patients. It is a common complication 
in patients with Boston-Keratoprothesis and an expected event. Seven patients were already treated 
for glaucoma previous and/or in the study for glaucoma. Retroprostethic membrane was seen in five 
study eyes and hypotony in six patients. All of these AEs are also well known to occur in a standalone 
Boston-Keratoprosthesis implantation procedure and were in line with the expected prevalence of 
complications after BkPro surgery (Lee WB, 2015) (Ahmad S, 2016). 
Visual acuity reduced was seen in two patients (DE-2-02 and DE-2-04) and was caused by a 
retroprosthetic membrane and other AEs of these patients. 
The choroidal hemorrhage in patient DE-2-02 occurred after a complicated retina surgery due to an 
amotio (retinopathy proliferative (PVR)). The resorption of this bleeding takes a long time why it was 
not recovered to the end of the study. 
PVR with consecutive tractive retinal detachment developed in two patients (DE-2-02 and DE-2-04) 
with congenital aniridia in timely connection to surgical manometry. As a causal relationship – while 
unlikely – could not be excluded by the investigators with certainty, a decision to undergo manomety 
was weighted carefully by the investigators. A causal relationship between PVR formation and the 
sensor implant was not obsereved. 
 
In the following Table are listed the adverse device effects. All these ADEs were documented with a 
possible causal relationship to the ARGOS-IO sensor by the investigators. 
 
 
 

 
 
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Table 11: ADEs – Time of Occurrence and Outcome 
 
Total (N=13) 
Adverse Device Defect 
First 4 weeks 
First 16 weeks 
First 28 weeks 
First 12 months 
Outcome 
n 
% 
AE 
n 
% 
AE 
n 
% 
AE 
n 
% 
AE 
Any System Organ Class 
1 
7.7 
3 
3 
23.1 
8 
4 
30.8 
11 
4 
30.8 
15 
 
Eye Disorders 
2 
15.4 
2 
4 
30.8 
6 
4 
30.8 
9 
4 
30.8 
13 
 
Cystoid macular edema 
0 
0.0 
0 
2 
15.4 
3 
3 
23.1 
4 
3 
23.1 
6 
4 recovered 
1 recovering 
1 recurrent 
Hypotony of eye 
0 
0.0 
0 
0 
0.0 
0 
1 
7.7 
1 
2 
15.4 
2 
recovered 
Anterior chamber cell 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
recovered 
Iris adhesion 
0 
0.0 
0 
1 
7.7 
1 
1 
7.7 
2 
1 
7.7 
2 
recovered 
Pigment dispersion 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
recovered 
Vitritis 
0 
0.0 
0 
0 
0.0 
0 
0 
0.0 
0 
1 
7.7 
1 
recovered 
Investigations 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
 
Intraocular pressure increased 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
recovered 
Product Issue 
0 
0.0 
0 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
 
Retroprosthetic membrane 
0 
0.0 
0 
1 
7.7 
1 
1 
7.7 
1 
1 
7.7 
1 
not recovered 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Final Statistical Output – Tables 
Table 14.3.1.6 – Adverse Device Effects by SOC and PT – periods first 4 weeks, 16 weeks, 28 weeks, 12 months following implantation surgery 
%: Percentage based on N 
N: Number of subjects in total (Safety Set) 
n: Number of patients reporting at least one adverse event with the specification 
AE: Number of individual adverse events which occurred among the n patients 
 

 
 
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Of the 15 ADEs, three were classified as mild, six as moderate and six as severe.  
- 
Anterior chamber cell: moderate 
➢ Inflammation is a normal and common response to any trauma of the eye, including 
intraocular surgery. A moderate intraocular inflammation after surgery is expected and 
can be caused by the implantation of the Boston keratoprothesis as well as by the 
manipulation of the iris caused by the implantation of the ARGOS-IO sensor. A self-
resolving, sterile anterior chamber inflammation after surgery is not expected to 
negatively impact device functioning, healing or functional recovery. 
- Cystoid macular edema: 3 moderate, 3 severe  
➢ 
A cystoid macular edema is a known complication of all intraocular surgeries and has in 
most times a self-limiting nature. In stand-alone BK-Pro surgery, CME is with up to 27% 
also a frequent complication (Moshin H. Ali, 2018). However, a causal relationship with 
the ARGOS-IO sensor can never be excluded.  
- 
Hypotony of eye: 1 moderate, 1 severe 
➢ Boston keratoprothesis represents a second line surgical treatment in eyes, where 
primary keratoplasty has a low chance of success. In many cases, eyes scheduled for 
keratoprothesis surgery experienced ocular trauma or condition after multiple surgical 
interventions. Due to a lack of aqueous humor production and/or leckage because of 
insufficient corneal sutures, hypotony of the eye is an expected event after surgery. 
Therefore it is unlikely, that the device itself caused hypotony of the eye. 
- 
Iris adhesion: severe 
➢ Iris adhesions can occur between the iris and the sensor and as anterior synechiae 
between iris and cornea. Both phenomena can be caused as a consequence of Boston 
keratoprothesis surgery. The additional volume in the posterior chamber related to the 
ARGOS sensor might have an impact on formation of adhesions. However, as this ADE 
only occurred in one case, the significance may be questioned.  
 
 

 
 
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- 
Pigment dispersion: mild 
➢ Manipulation of the iris may lead to disruption of cells of the pigmented layer of the iris 
and dispersion of pigment granula into the anterior chamber. The pigment can settle 
anywhere in the anterior chamber, frequently showing as non-symptomatic small 
deposits on the posterior surface of the cornea or anterior surface of the IOL. This is not 
limited to the implantation of the ARGOS-IO sensor but to any anterior chamber surgery 
during which there is accidental or initial manipulation the iris. A second potential cause 
of pigment release after initial surgery can be posterior iris chafing on the sensor placed 
in the ciliary sulcus. 
- 
Vitritis: moderate 
➢ Vitritis in the posterior chamber is the equivalent intraocular inflammation in the 
anterior chamber. A moderate vitritis after surgery is expected with a frequency of up to 
23% in stand-alone BK-Pro of aniridia patients (Salima I. Hassanaly, 2014) and can be 
caused by the implantation of the Boston keratoprothesis as well as by manipulation of 
caused by the implantation of the ARGOS-IO sensor. A self-resolving, sterile posterior 
chamber inflammation after surgery is not expected to negatively impact device 
functioning, healing or functional recovery. 
- 
Intraocular pressure increased: mild 
➢ A postoperative increase in intraocular pressure can be considered as an expected event, 
not only in this study, but highly frequently after intraocular surgery.  
- 
Retroprosthetic membrane: moderate 
➢ Formation of a retroprosthetic membrane is a key adverse event after stand-alone 
Boston keratoprothesis surgery and represents with >50% the most frequent 
complication after BKPro surgery (Lee WB, 2015). Therefore, the occurrence in this 
study is not surprising. An additional impact of the ARGOS sensor on formation of the 
membrane cannot be fully ruled out excluded. But giving the extent and the 
frequency of membrane formation after stand-alone keratoprothesis surgery, it 
seems more likely to be caused by the procedure itself.  

 
 
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To summarize, all potential ADE’s can be caused by the stand-alone procedure and they are not of a 
higher percentage in this study than in other known publications. The overall benefit to offer IOP 
measurement in a situation where - without implantable device - only palpatory IOP would be 
possible outweighs a possibly increased likelihood of occurrence of theses ADE’s. 
 
4.8.1.1 
Serious adverse events in the follow-up period 
23 out of 168 AEs in 9 Patients fulfilled at least one criterion for “serious adverse event” (SAE) and 
were reported as such.  
10 of these SAEs were unrelated to the IMD or implantation procedure of which seven occurred in 
the non-study eye:  
• 
Corneal melting non-study eye (twice) 
• 
Corneal perforation non-study eye 
• 
High intraocular pressure study eye 
• 
High intraocular pressure non-study eye 
• 
Leakage between keratoprosthesis and keratoplasty non-study eye 
• 
Renal failure 
• 
Sterile vitritis non-study eye 
• 
Surface defect of graft (non-study eye) 
• 
Tractive retinal detachment study eye 
13 SAEs were at least possibly related to the implant (6 initial SADEs) and/or the implantation 
procedure in the initial SAE report. Table 12 shows an overview of time, occurrence and outcome of 
the SADEs. 
 
 

 
 
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Table 12: SADEs – Time of Occurrence and Outcome 
 
Total (N=13) 
Adverse Device Defect 
First 4 weeks 
First 16 weeks 
First 28 weeks 
First 12 months 
Outcome 
n 
% 
AE 
n 
% 
AE 
n 
% 
AE 
n 
% 
AE 
Any System Organ Class 
0 
0.0 
0 
1 
7.7 
2 
2 
15.4 
4 
3 
23.1 
6 
 
Eye Disorders 
0 
0.0 
0 
1 
7.7 
2 
2 
15.4 
4 
3 
23.1 
6 
 
Cystoid macular edema 
0 
0.0 
0 
1 
7.7 
1 
2 
15.4 
2 
2 
15.4 
3 
2 recovered 
1 recovering 
Hypotony of eye 
0 
0.0 
0 
0 
0.0 
0 
0 
0.0 
0 
1 
7.7 
1 
recovered 
Iris adhesion 
0 
0.0 
0 
1 
7.7 
1 
1 
7.7 
2 
1 
7.7 
2 
recovered 
Source: Final Statistical Output – Tables 
Table 14.3.6 – Serious Adverse Device Effects by SOC and PT – periods first 4 weeks, 16 weeks, 28 weeks, 12 months following implantation surgery 
%: Percentage based on N 
N: Number of subjects in total (Safety Set) 
n: Number of patients reporting at least one adverse event with the specification 
AE: Number of individual adverse events which occurred among the n patients 
 
 

 
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The investigations of the SAEs with a causal relationship to the medical device and/or medical 
procedure resulted in the following: 
DE-1-01 
Hypotony of eye: 
Description of the event: Patient DE-1-01 was hospitalized for a bulbus hypotony and sterile vitritis. 
Remedial action taken by the investigation site: The first remedial action was a bulbus tonification 
with BSS on January 26th, 2016. A tonification was repeated with Healon on February 2nd, 2016. On 
March 6th, 2016 the patient was hospitalized again for pars-plana-vitrectomy and silicone oil 
tamponade (07-MAR-2016). 
Rationale for the classification as expected or unexpected: The sterile vitritis was rated as expected 
by the site. The bulbus hyptony was unexpected in this case. 
Investigation results and rationale for the above root cause classification taking all SAEs into 
consideration: Both events were classified as possibly related to the medical device and to the 
medical procedure. The cause of the bulbus hypotony could not be determined. Sterile vitritis is a 
known complication in patients with Boston-Keratoprosthesis implantation (Dokey, et al., 2012) and 
has no relationship to the ARGOS-IO implant. This adverse event therefore is concluded to be 
unrelated to the ARGOS-IO Implant. 
 
Corneal infiltrates: 
Description of the event: The site became aware of corneal infiltrates on January 26th, 2016. The 
severity was rated as “severe”. 
Remedial action taken by the investigation site: The patient was treated with medication and the 
infiltrates regressed to February 17th, 2016. 
Rationale for the classification as expected or unexpected: This adverse event was rated as definite 
related to the medical procedure. It is a known complication and therefore an expected event.  
Investigation results and rationale for the above root cause classification taking all SAEs into 
consideration: No causal relationship with the implant could be established. Corneal infiltrates occur 
in 10-20% of patients with Boston-Keratoprosthesis (Aravena, Bozkurt, Yu, & Aldave, 2016).  
 

 
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DE-1-04: 
Cystoid macular edema (two events):  
Description of the event: A severe cystoid macular edema was detected on April 8th, 2016. 
Remedial action taken by the investigation site: The patient was treated with an intravitreal 
Ozurdex-Injection on April 21st,2016. 
Rationale for the classification as expected or unexpected: It is an expected adverse event described 
in section 7.4 “Risks and anticipated adverse device effects to be assessed” in the Clinical 
Investigation Plan. 
Investigation results and rationale for the above root cause classification taking all SAEs into 
consideration: The cystoid macular edema was recovered on May 24th, 2016. It cannot definitely 
excluded that there is no relationship to the medical device. Most likely, the cystoid macular edema 
is due to the underlying autoimmune disease. Furthermore, cystoid macular edemas are one of the 
most common complications in intraocular surgeries.  
On August 17th, 2016, the site became aware of a further cystoid macular edema, treated with an 
additional intravitreal Ozurdex-Injection. 
 
DE-1-05 
Corneal graft melt (two events):  
Description of the event: On March 19th, 2016, three months after Boston-Keratoprosthesis and 
ARGOS-IO implantation, the site became aware of corneal graft melt in patient DE-1-05. 
Remedial action taken by the investigation site: The patient was hospitalized with following surgical 
intervention in peribulbar anaesthesia: renewal of the corneal graft and bulbus tonification. 
Discharge was on March 24th, 2016. 
Rationale for the classification as expected or unexpected: It is an expected adverse event described 
in section 7.4 “Risks and anticipated adverse device effects to be assessed” in the Clinical 
Investigation Plan. 
Investigation results and rationale for the above root cause classification taking all SAEs into 
consideration: No causal relationship to the medical device could be established. It is a known 
“classic” complication in Boston-Keratoprosthesis implantation and occurs in 10% of these patients 
by experience of the site. Another three months later (June 11th, 2016), corneal graft melt occurred 

 
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again with hospitalization and renewal of the corneal graft in combination with explantation of the 
ARGOS-IO sensor (June 13th, 2016). 
 
DE-1-06 
Cystoid macular edema: 
Description of the event: Patient DE-1-06 experienced a macular edema in the first three months 
after implantation (April 5th, 2016). 
Remedial action taken by the investigation site: The patient was treated with an intravitreal 
injection of 10 mg Triamcinolone. 
Rationale for the classification as expected or unexpected: This event was expected as described in 
section 7.4 of the clinical investigation plan. It was documented as possible related to the medical 
device and has a probable relationship to the medical procedure. 
Investigation results and rationale for the above root cause classification taking all SAEs into 
consideration: A cystoid macular edema is a known complication of all intraocular surgeries. In this 
case, it is almost certainly due to the underlying disease. However, a causal relationship with the 
ARGOS-IO sensor can never be excluded.  
The cystoid macular edema was recovered on May 9th, 2016. 
 
Anterior synechiae (two events): 
Description of the event: Patient DE-1-06 experienced anterior synechiae in the first three months 
after implantation (April 5th, 2016). 
Remedial action taken by the investigation site: The anterior synechiae were resolved by surgical 
lysis. 
Rationale for the classification as expected or unexpected: This event was rated as possible related 
to the medical device and as probable related to the medical procedure. It is a known complication 
and therefore an expected event. 
Investigation results and rationale for the above root cause classification taking all SAEs into 
consideration: Anterior synechiaes are a known complication in Boston-Keratoprosthesis patient. 
However, a causal relationship with the ARGOS-IO sensor can never be definitely excluded.  

 
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Anterior synechiae reoccurred on July 21st, 2016 and the patient got a surgical lysis again. 
 
Detachment of retina and choroid membrane: 
Description of the event: A retinal and choroidal detachment was detected by during ultrasound 
examination one year after surgery (January 13th, 2017). 
Remedial action taken by the investigation site: The remedial action taken by the site was the 
exchange of the Boston-Keratoprosthesis, explantation of the IOL and of the ARGOS-IO sensor and a 
pars-plana vitrectomy (January 23rd, 2017 at site). Additional, a membrane peeling, retinotomy, 
endolaser and endotamponade was done on January 26th, 2017, extern. 
Rationale for the classification as expected or unexpected: It is an expected adverse event described 
in section 7.4 “Risks and anticipated adverse device effects to be assessed” in the Clinical 
Investigation Plan. 
Investigation results and rationale for the above root cause classification taking all SAEs into 
consideration: Retinal detachment is a known complication in patients with Boston-Keratoprosthesis. 
It occurs in 7,69% of Boston-Keratoprosthesis patients up to 42% in patients with an additional 
autoimmune disease (Schaub, et al., 2016) (Neuhann, Koller, & Neuhann, 2015) (Jardeleza, Rheaume, 
Chodosh, Lane, & Dohlman, 2015). This adverse event is concluded therefore to be unrelated to the 
ARGOS-IO implant. 
 
DE-1-07 
Dislocation of ARGOS-IO sensor: 
Description of the event: At visit 5 (May 30th, 2016), a dislocation of the ARGOS-IO sensor was 
noticed in patient DE-1-07. 
Remedial action taken by the investigation site: The site immediately hospitalized the patient and 
explanted the sensor the next day. 
Rationale for the classification as expected or unexpected: It is an expected potential risk of 
implantation of the ARGOS-IO sensor described in section 6.3 “Anticipated Adverse Device Effects 
associated with the ARGOS-IO sensor device and their control”. 
Investigation results and rationale for the above root cause classification taking all SAEs into 
consideration: Because of a congenital aniridia syndrome, the sensor was sutured to the sclera. The 

 
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temporal suture dissolved. Due to the underlying conditions as aphakia, no intact iris and a severe 
hypotony during the surgery, the implantation of the Boston-Keratoprosthesis after ARGOS-IO 
implantation was a challenge. After implantation of the Boston-Keratoprosthesis a slightly rotation of 
the sensor was already recognized. The implantation of the ARGOS-IO sensor harbors not a huge risk 
per se and is easy to handle. However, the condition of these eyes is really difficult to evaluate. 
Mostly, no examination to look insight the eye is possible. 
 
DE-2-02 
Proliferative vitreoretinopathy (PVR) with retinal detachment 
Description of the event: On August 22th, 2016 the patient was hospitalized with the diagnosis of 
proliferative vitreoretinopathy and suspicion of PVR-related retinal detachment in the study eye.  
Remedial action taken by the investigation site: A diagnostic pars plana vitrectomy was performed 
and following interventions were done: an intraoperative retinonotomy,  retinopexy by photo and 
kryocoagulation,  membrane peeling and endotamponade of the eye with silicone oil.  
Rationale for the classification as expected or unexpected: It was an unexpected event for the site.  
Investigation results and rationale for the above root cause classification taking all SAEs into 
consideration: After implantation of the Boston-Keratoprosthesis and ARGOS-IO implantation, the 
patient with genetic aniridia had a normal postoperative healing process and increase of visual 
acuity. On June 27th, 2016 the second surgical manometry was performed according to CIP. Due to a 
loss of visual acuity in the study eye from 0.02 to hand movements, the patient has consulted the 
hospital twice per month in unscheduled visits. The formation of a retroprosthethic membrane was 
diagnosed and the patient was treated with YAG-membranotomy on Aug 18th, 2016. One week after 
this treatment, the patient experienced progressive loss of visual acuity and increased formation of 
retroprosthetic membranes. Therefore the decision for diagnostic vitrectomy was made. 
Intraoperatively, a PVR retinal detachment required surgical treatment. Several factors could have 
contributed to the development of this PVR retinal detachment. First the congenital anridia of the 
patient is followed by an increased risk for retinal detachment. Second, both the intraocular 
manometry and the YAG capsulotomy could be responsible for the occurrence of a retinal 
detachment. Also it cannot be fully ruled out, that the PVR detachment is associated with the BKPro 
implant or the ARGOS sensor.  
 

 
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PVR-Amotio under oil tamponade 
Description of the event: On November 20th, 2016 the patient was hospitalized again due to a 
recurring PVR related retinal detachment under oil tamponade. 
Remedial action taken by the investigation site: A pars plana vitrectomy was performed and 
following interventions were done: an intraoperative cerclage and retinotomy, closure of the 
Baerveldt implant, silicone oil change. 
Rationale for the classification as expected or unexpected: It was an unexpected event for the site.  
Investigation results and rationale for the above root cause classification taking all SAEs into 
consideration: The recurring retinal detachment is most likely due to the primary retinal detachment 
and the proliferative vitreoretinopathy. As it is well documented in literature, occurrence of PVR 
increases the risk for recurring detachment significantly (Enders et al, Retina 2017). Therefore it is 
highly unlikely, that the ARGOS IO implant has a causal relationship with this serious adverse event.   
 
DE-2-04 
Proliferative vitreoretinopathy 
Description of the event: Patient DE-2-04 was hospitalized because of a decreased visual acuity, 
retroprosthetic membrane and vitritis on August 18th, 2016. 
Remedial action taken by the investigation site: A diagnostic ppV (pars plana vitrectomy) was 
performed. Intraooperative appeared an older tractive retinal detachment which was treated 
surgical with retinotomy, oil-tamponade, kryopexy and laser retinopexy. 
Rationale for the classification as expected or unexpected: The site rated this event as unexpected. 
Investigation results and rationale for the above root cause classification taking all SAEs into 
consideration: After implantation of the Boston-Keratoprosthesis and ARGOS-IO implantation, the 
patient had a normal postoperative healing process. The visual acuity increased from finger counting 
to 0.05 (distance 1m). On June 30th, 2016 the first surgical manometry was performed according to 
CIP. On July 20th, 2016 the patient was scheduled for an unscheduled visit because of loss of her 
therapeutic contact lens. At this visit, the decreased visual acuity, retroprosthetic membrane and 
vitritis were observed. According to the subjective description of the patient, the decrease of visual 
acuity decreased followed after manometry. A leakage could not be detected. The IOP was normoton 

 
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according to palpation and ARGOS-IO sensor. After no improvement, the diagnostic ppV was 
performed on August 17th, 2016. Due to the time context of this serious adverse event and the 
surgical manometries, a causality by the surgical manometry could not be excluded (see also DE-2-02 
“Proliferative vitreoretinopathy (PVR) with retinal detachment”). However, a direct relationship 
between the ARGOS sensor and this SAE is unlikely.  
 
4.8.2 
Concomitant Medications 
No restrictions were placed on patients’ use of concomitant medications during study participation.  
Antiglaucoma preparations and miotics were used in 12 patients.  
 
4.8.3 
Device Deficiencies 
In the ARGOS-KP01 trial did not occur any device deficiency which affected (potentially) the safety 
and well-being of a patient. 
ARGOS-IO sensor: 
During the trial two sensors had to be recalibrated after an offset occurred. In patient DE-1-01, the 
ARGOS-IO sensor was adjusted to surgical manometry after a minimal offset was detected at Visit 9. 
The IOP measured by surgical manometry was 21 mmHg, the ARGOS-IO sensor measured 27.3 
mmHg. The ARGOS-IO sensor was recalibrated to the value of 21 mmHg of the surgical manometry. 
The recalibration was requested by the site. In patient DE-1-02, measurements were outside limits 
caused by external manipulation/application of high energy densities to the eye (YAG-capsulotomy). 
This was necessary due to retroprosthetic opacification (a common occurrence in patients with 
Boston-Keratoprosthesis). 
No safety issues arose from these two incidences, the devices remained in place and no surgery was 
necessary.  
Mesograph reader device: 
There were several device deficiencies of the Mesograph reader device, all of which could be fixed by 
replacing the device itself. The deficiencies were limited to storage space due to a software failure, 
no data transfer possible and a defect button. 
 

 
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4.8.4 
Examination Results over Time 
All relevant and clinical significant findings of the anterior and posterior segment following surgery 
were documented as adverse events. 
4.8.4.1 
Visual Acuity  
Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. 
There was no measurement scheduled for the baseline visit but for Visit 07 (4 weeks post surgery) 
and V15 (52 weeks post surgery). The mean number of letters correctly read by 12 patients at V07 
was 1.7 (SD 2.7) (range 0-9). For V15, the visual acuity was measured in 7 patients. The mean number 
of letters correctly read was 7.7 (SD 13.8) (range 0-34). 
 
 

 
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5 
DISCUSSION  
5.1 
Limitations of the Study  
Several aspects of the study limited its conclusiveness. 
1. Only 12 patients were included and only 9 patients finished the study, which is sufficient to 
detect problematic design features that lead to common adverse events and still limits the 
number of patients that could potentially be harmed due to unforeseen events. However, 
with this low number of patients it is unlikely to detect rare negative effects particularly with 
regard to the different underlying diseases of these patients and different indications for the 
Boston-Keratoprosthesis implantation. 
2. 12 months follow-up for a device intended for permanent implantation are too short to 
detect any long-term complications or late device deficiencies in patients with Boston 
Keraprosthesis. Since the device itself is technical identical to the CE approved EYEMATE-IO 
device, to be placed into the posterior chamber/ciliary sulcus of the eye during cataract 
surgery and this device performs well for more than several years, no main device related 
issues are to be expected.  
3. Although surgical manometry is the only available method to accurately measure IOP in 
BKPro patients, it carries problems in the performance and therefore some limitations for the 
comparability with ARGOS-IO measurements: 
a. Due to the puncture of the bulbus and following removal of the needle, aqueous 
humor can be lost which lead to a decrease of the intraocular pressure. 
b. The quality of the measurements can be strongly influenced by experience of the 
investigator. 
5.2 
Safety and Tolerability 
The overall outcome of the ARGOS-KP01 clinical trial provide sufficient evidence that the ARGOS-IO 
system is safe and well tolerated in to support its implantation in patients with an indication for a 
BKPro. Adverse events and serious adverse events in this study were in line with the expected 
complications after BKPro surgery (Lee WB S. R., 2015) (Ahmad S M. P., 2016). Most frequent 
complications were formation of a retroprosthetic membrane and hypertonic or hypotonic IOP. The 
study investigators saw the causality of most adverse events linked to the implantation of both the 
BKPro and the ARGOS-IO sensor. While it is not possible to clearly differentiate causality between 

 
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those two potential causes, all observed complications are also well known to occur in stand-alone 
BKPro implantation. 
5.3 
Performance 
Performance data acquired in this study showed overall good consistency between manometric and 
telemetric IOP results and between ARGOS-IO and finger palpation. There was not seen a trend for 
increasing discrepancies between modalities during the follow-up. 
The technical performance of the components of the ARGOS-IO system during the ARGOS-KP01 trial 
was good. There were no major device deficiencies of any of its components that compromised the 
safety of the patients in the trial. None of the adverse events reported for the trial where a direct or 
indirect result of a device deficiency. 
5.4 
Relevance of the Results in the Light of Previous / External Data 
The ARGOS-IO device performed well in patients with a Boston Keraprosthesis and showed an overall 
good consistency between the telemetric IOP and finder palpation/manometry. Though the 
implantation of the ARGOS-IO device in conjunction with the BKPro might pose additional risks 
compared to stand-alone BKPro implantation, the complications observed where found to be in the 
range of the occurrences reported in the literature. Considering the high prevalence of preexisting 
glaucoma in patients undergoing the Boston Keratoprosthesis surgery (Ahmad S. M. P., 2016) and the 
Glaucoma progression after implantation of the BKPro (de Oliveira L. A., 2014) (Samarawickrama C., 
2018), the implantation of a monitoring device (ARGOS-IO) clearly outweighs the risks induced by 
implantation of an additional device within the same surgical procedure. 
5.5 
Risk / Benefit Assessment  
Glaucoma is the most significant cause of the loss of regained vision in keratoprosthesis recipients.   
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, Glaucoma, 2013).  
The presence of BI-KPro does not allow conventional tonometric IOP measurement, as this requires a 
normal cornea. Patient self-monitoring or home measurement is also not possible, as available 
devices are also using tonometric IOP measurement methods. Currently, surgical manometry – if 
properply performed - is the only accurate means of measuring IOP in BKPro recipients. But due to its 
invasiveness and risk for complications, most ophthalmologists don’t perform surgical manometry at 
BI-KPro patients. Equipment for surgical manometry is in general not available either, which is 
another reason why invasive IOP measurements are performed only in very rare cases. Usually finger 

 
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palpation is applied to estimate IOP, but is highly dependent on the skill of the individual examiner, 
provides highly subjective values and thus prone to error.  
 
IOP in BI-KPro patients can be extremely high, potentially causing severe glaucomatous damage in 
unusually short periods of time. Even a comprehensive follow-up schedule may not be appropriate. 
This problem is compounded if no physician experienced in the finger palpation technique is 
available to perform IOP estimation. 
 
The ARGOS-IO device allows frequent, reproducible IOP monitoring in both the clinical and home 
setting, facilitating the management of IOP in this vulnerable patient group. In addition, because of 
the ease of its use, it will also permit detection of fluctuations in IOP resulting from the patient’s 
daily activities and circadian rhythm. 
One objective of this study was to verify the device’s accuracy in the patient population. Patients will 
benefit from a continual long-term monitoring of IOP independent from visits to the 
ophthalmologist. 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 by the 
treating physician between office visits. This will permit a more rapid response to changes in IOP and 
a better fine-tuning of treatment protocols. 
Because of the high risk of critically IOP values possible in BKPro patients, glaucoma may progress 
more rapidly as at open angle glaucoma patients, which requires an even closer monitoring regimen. 
An additional effect may be improved adherence to prescribed treatment regimens. The potential 
consequences of poor IOP control are serious and can lead to irreversible loss of vision and 
accompanying handicap. Patient self-measurement is expected to motivate better compliance with 
the treatment regimen, thereby facilitating improved IOP control and optimizing long-term outcome. 
 
The ARGOS-KP01 clinical trial was conducted to address these questions: 
Compatibility with Boston-Keratoprosthesis 
The ARGOS-KP01 study confirmed that it possible to implant a BKPro and ARGOS-IO sensor without 
mutual interference. 
Irritation, Inflammation of Eye, Iris Pigment Abrasion 
Does the implant cause irritation, inflammation and pigment abrasion?  

 
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• 
Implant surface material has history as IOL material for ocular implantation, with well-known 
biocompatibility properties; material surface is soft, edges are rounded and smooth, possible 
small material flashes are soft and atraumatic 
• 
In ARGOS-KP01 trial, the ARGOS-IO device was found to be safe and well tolerated within the 
eye. No higher levels of irritation, inflammation and pigment abrasion were observed 
compared to standard Boston Keratoprosthesis implantation and were manageable under 
standard of care.  
Accuracy, precision and sensor drift 
Does the ARGOS-IO device exhibit acceptable levels of accuracy and precision? 
• 
Accuracy, precision and sensor drift have been tested and validated in bench tests and in 
animal trials 
• 
The ARGOS-IO device was compared to finger palpation (the current gold standard in BI-KPro 
patients) within this clinical trial and showed a positive statistically significant difference of 
telemetric IOP measurements between the finger palpation categories (soft hypertonic, 
normal, borderline, hypertonic). 
• 
ARGOS-KP01 trial has shown that the human anatomy does not have an impact on the 
accuracy of the device. It is recommended to re-calibrate the device once a year and 
following ocular surgery. 
Usability 
The patient acceptance of the ARGOS-IO system at home was very good, showing a very high overall 
acceptance in using the ARGOS-IO system in their daily routine. The instruction for use for the 
Mesograph reader device was easily to understand, the implant did not cause them any problems 
and the patients were less concerned about unidentified high IOP. 
 
Compatibility of the ARGOS-IO implant with Glaucoma drainage devices (GDD) 
Compatibility of the ARGOS-IO implant with Glaucoma drainage devices (GDD) was an issue that was 
long discussed within the risk analysis team. This clinical trial showed if the GDD is placed in the 
anterior chamber, there is no physical contact with the ARGOS-IO implant, which is located in the 
ciliary sulcus, and consequently no interference occurs between the two devices. 
 
 
 
 

 
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Overall Summary: Based on the clinical study results, risk management effort and user information, 
it is concluded that the benefits for a patient from the implantation of an ARGOS-IO implant device 
outweighs the risk. Predicate implantable ophthalmic medical devices, like Boston-Keratoprosthesis, 
show that there is also residual risk with regard to the surgical procedure in general. The adverse 
event rate by combining BKPro implantation with EYEMATE-IO/KP insertion is similar to BKPro 
implantation alone and adverse events were in general manageable under standard of care. The 
medical benefit of the implantation of the device, and resulting possibility of direct IOP 
measurement and frequent self-tonometry by the patients at home clearly outweighs the 
identified residual risks of the device. The residual risks and their probability of occurrence are 
within the acceptable range, compared to similar marketed devices in the ophthalmic field. 
Being able to monitor IOP quasi-continuously over extended periods of time will give the treating 
ophthalmologists valuable information about the individual disease of a patient and the effectiveness 
of the medication regimen. Most importantly, it will alert the ophthalmologist early on in case of a 
critically elevated IOP. Patients treated with BKPro for corneal blindness face a significant risk to 
consecutively loose vision due to progressive glaucomatous damage. Continual and reliable IOP 
monitoring, as only possible with a telemetric sensor system, is an indispensable prerequisite for 
adequate glaucoma management at BKPro patients to reduce post-surgical BKPro complications and 
to improve chances of these patients to maintain vision. 
 
 

 
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6 
ETHICS AND REGULATORY COMPLIANCE 
6.1 
Independent Ethics Committee (IEC) and Competent Authority 
In compliance with ICH-GCP, the European Medical Device Directives, the German Medical Device 
Act and its Ordinance on Clinical Trials with Medical Devices (MPKPV), the study approved by the 
responsible Ethics Committee in Munich (Ethik-Kommission der Medizinischen Fakultät der 
Technischen Unversität München) on November 14th, 2014, and by the German Federal Institute for 
Drugs and Medical Devices [Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM)] on 
December 09th, 2014, and before any potential patient underwent any study-specific procedures. 
6.2 
Ethical and Legal Conduct of the Study 
This investigation was conducted in compliance with the ethical standards having their origin in the 
Declaration of Helsinki, with ICH-GCP, ISO 14155:2011 and with all relevant German and European 
laws and regulations governing medical devices and clinical trials on humans. 
6.3 
Patient Information and Consent 
To avoid any possible effect of the study on a patient’s decision to undergo necessary Boston 
keratoprosthesis surgery, only patients who had already been scheduled for surgery with Boston 
keratoprosthesis implantation were approached about the possibility of participating in the ARGOS-
KP01 clinical investigation. 
Each potential patient was thoroughly informed about the device and the aims and procedures of the 
investigation through appropriate EC approved written patient information material and in an 
individual discussion with an investigator. Information given included the potential risks and benefits 
associated with the implantation and use of the ARGOS-IO pressure sensor and study participation, 
as well as the explicit statement that the patient’s participation was voluntary and could be ended by 
the patient at any time. The investigator answered any study-related questions the potential patient 
may have had. Prior to undergoing any study related procedure all patients signed and dated Patient 
Informed Consent forms, which were then countersigned and dated by the informing investigator. 
Patients were given one copy for their own records. The second copy was filed in the Investigational 
Site File. 
Copies of the informed consent form and patient information are included in Annex D. 

 
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7 
STUDY ADMINISTRATIVE STRUCTURE 
The study was financed and managed by the Sponsor Implandata Ophthalmic Products GmbH, which 
is the developer and manufacturer of the ARGOS-IO system. 
The study was conducted at 3 sites in Germany with Prof. Dr. med. Thomas Neuhann, MVZ Prof. 
Neuhann, Helene-Weber-Allee 19, 80637 Munich, Germany as Coordinating Investigator. 
The additional sites included: 
Prof. Dr. med. Claus Cursiefen  
Universität zu Köln, Zentrum für Augenheilkunde 
 
 
Kerpenerstr. 62, 50924 Cologne, Germany 
Prof. Dr. med. Gerd Geerling 
 
Universitäts-Augenklinik Düsseldorf 
 
Moorenstr. 5, 40225 Dusseldorf, Germany 
The following functional areas were outsourced to third parties: 
Safety Reporting 
MDSS GmbH 
Schiffgraben 41 
30175 Hanover, Germany 
Data Management 
X-act Cologne, Clinical Research GmbH 
Hansaring 97 
50670 Cologne, Germany 
Statistics 
X-act Cologne, Clinical Research GmbH 
Hansaring 97 
50670 Cologne, Germany 
Clinical Monitoring 
Dr. Gerlinde Lang 
Dienstleistungen für klinische Prüfungen 
Blumenstr. 3 
91094 Langensendelbach 
 
The Data Safety Monitoring Board was composed of the following member: 
Member 
PD Dr. med. Konrad Hille 
Wolgang Dachstein Str. 28 
77654 Offenburg, Germany 
 
 
 

 
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Suzuki, S., Oshika, T., Sakabe, I., Iwase, A., Amano, S., & Araie, M. (kein Datum). Corneal thickness 
measurements: scanning-slit corneal topography and noncontact specular microscopy versus 
ultrasonic pachymetry. J Cataract Refract Surg(29), 1313-1318. 
Timme, M. (2015). Biological safety-toxicology evaluation of the ARGOS-IO implant (second 
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Zou, G. (2011). Confidence interval estimation for the Bland-Altman limits of agreement with 
multiple observations per individual. Stat Methods Med Res, 0(0), pp. 1-13. 
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Zou, G. (2011). Confidence interval estimation for the Bland-Altman limits of agreement with 
multiple observations per individual. Stat Methods Med Res, 0(0), pp. 1-13. 
 
 

 
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9 
ANNEXES TO THE REPORT 
Annexes to the report are provided separately. They include: 
Annex A: Clinical Investigation Plan ARGOS-KP01  
Reference Number: ARGOS-KP01 
Revision B, 03-OCT-2014 
A prospective, open-label, monocenter clinical investigation to assess the safety and 
performance of ARGOS-IO system in patients undergoing implantation of a Boston 
Keratoprosthesis (BKPro) 
Clinical Investigation Plan ARGOS-KP01  
Reference Number: ARGOS-KP01 
Revision C, 17-MAR-2015 
A prospective, open-label, monocenter clinical investigation to assess the safety and 
performance of ARGOS-IO system in patients undergoing implantation of a Boston 
Keratoprosthesis (BKPro) 
Clinical Investigation Plan ARGOS-KP01  
Reference Number: ARGOS-KP01 
Revision D, 05-MAY-2015 
A prospective, open-label, mullticenter clinical investigation to assess the safety and 
performance of ARGOS-IO system in patients undergoing implantation of a Boston 
Keratoprosthesis (BKPro) 
Clinical Investigation Plan ARGOS-KP01  
Reference Number: ARGOS-KP01 
Revision E, 29-JAN-2016 
A prospective, open-label, mullticenter clinical investigation to assess the safety and 
performance of ARGOS-IO system in patients undergoing implantation of a Boston 
Keratoprosthesis (BKPro) 
Annex B: Investigator’s Brochure 
Reference Number: ARGOS-KP01  
Rev. A, 15-SEP-2014 

 
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Investigator’s Brochure 
Reference Number: ARGOS-KP01  
Rev. B, 29-JAN-2016 
Annex C: Instructions for Use 
Annex D: Patient Informed Consents 
Patienten-Information und –Einwilligung, Version 2.1, 24-FEB-2015 
Patienten-Information und –Einwilligung, Version 3.0, 18-SEP-2015 
Patienten-Information und –Einwilligung, Version 4.0, 02-FEB-2016 
Annex E: Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
A prospective, open-label, multicenter clinical investigation to assess the safety and 
performance of ARGOS-IO system in patients undergoing implantation of a Boston 
Keratoprosthesis 
Reference Number: ARGOS-KP01 
Version 1.0, 09-JAN-2018 
Annex F: Relevant Data Sets 
Final Statistical Output – Listings 
Version 2.0 (21FEB2018) 
Reference Number: ARGOS-KP01 
Final Statistical Output – Tables 
Version 2.0 (21FEB2018) 
Reference Number: ARGOS-KP01