Evaluation of the 5-Year Safety and Performance of the Medtentia Annuloplasty Ring in Adults - Follow-Up to Clinical Investigation 2010-040
Conditions: Mitral Regurgitation, Mitral Insufficiency
Sponsor: Medtentia International Ltd Oy

 
Evaluation of the 5-year Safety and Performance of the 
Medtentia Annuloplasty Ring in Adults - Follow-up to 
Clinical Investigation 2010-040 
 
NCT04161079 
 
CIP Version: Final 1.0 
CIP Date: 08 May 2019 
 
 

 
Clinical Investigation Code: 2010-040FU5 
CIP Version: Final 1.0, 08-May-2019 
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CLINICAL INVESTIGATION PLAN 
 
 
 
 
Evaluation of the 5-year Safety and Performance of the 
Medtentia Annuloplasty Ring in Adults - Follow-up to 
Clinical Investigation 2010-040 
 
 
 
 
 
Clinical Investigation Code: 
2010-040FU5 
 
 
Version Number: 
Final 1.0 
 
 
Release Date: 
08-May-2019 
 
Investigational Medical Device: 
 
Medtentia Annuloplasty Ring (MAR) 
 
 
Sponsor: 
 
 
Medtentia International Ltd Oy 
xxxxxxxxxxxx xxx, xxxxx x 
xxxxx xxxxx, xxxxxxx 
 
 
 
 
Sponsor‘s Representative: 
Phone:   xxxx xx xxx xxxx 
Fax:       xxxx x xxx xxxx 
E-Mail:   xxxxxxxxxxxxxxxx 
 
xxxx xxxxxxx 
xxxxx xxxxxxxxx xxxxxxx 
 
 
 
 
CONFIDENTIAL 
This document contains confidential information. Acceptance of this document constitutes your 
agreement that the information contained herein will not be copied, referred to, released or 
published without written approval from the sponsor.  

 
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Sponsor Signature Page 
 
Clinical Investigation Code: 2010-040FU5 
 
 
 
 
Clinical Investigation Plan reviewed and approved by: 
 
 
Chief Executive Officer 
 
 
Name 
 
Signature  
 
Date 
 
 
Head of Quality Assurance 
 
 
Name 
 
Signature  
 
Date 
 
 

 
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Consultant Signature Page 
 
Clinical Investigation Code: 2010-040FU5 
 
 
 
Clinical Investigation Plan prepared by: 
 
 
Medical Writer 
 
  xxxxxx xxxxxxxxxx 
xxxxx xxx xx 
 
Signature  
 
Date 
 
 
Statistician 
 
  xxxxx xxxxxxx 
xxxxx xxx xx 
 
Signature  
 
Date 
 
 

 
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Clinical Investigation Plan Agreement Form 
 
Clinical Investigation Code: 2010-040FU5 
 
I agree to the terms of this Clinical Investigation Plan. I will conduct the investigation 
according to the procedures specified herein. 
 
 
Principal Investigator: 
 
 
xxx xxxxx xxxxx, xx 
 
 
Signature  
 
Date 
 
Site: 
 
Xxxxxxxxxx xxxxxxxx 
xxxxxxxxx xxxxxxxxxxxxx xx x 
xxxxx xxxxxxxx 
xxxxxxx 
 
 
 
 
 
 
 
 

 
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INVESTIGATION SITES 
 
Principal Investigator:  
xxx xxxxx xxxxx, xx 
 
Site name and address:  
xxxxxxxxxx xxxxxxxx, xxxxxxxxx xxxxxxxxxxxxx xx x, xxxxx xxxxxxxx, xxxxxxx 
 
 
 

 
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1. 
SYNOPSIS 
 
Title 
Evaluation of the 5-year Safety and Performance of the Medtentia 
Annuloplasty Ring in Adults - Follow-up to Clinical Investigation 2010-
040 
Sponsor 
Medtentia International Ltd Oy 
Name of IMD 
Medtentia Annuloplasty Ring (MAR)  
Indication 
Patients with mitral valve (MV) regurgitation requiring annuloplasty 
repair of their native MV with retention of the natural valve apparatus 
and normal valve orifice, remodeling of the annulus and prevention of 
secondary distension after valvuloplasties 
Purpose of the 
Investigation 
The purpose of this clinical investigation is to evaluate long-term 
safety and performance of the MAR in patients who underwent 
successful mitral valve surgery using Medtentia’s MAR system in 
clinical investigation 2010-040 performed during June 2011 - April 
2016 
Design 
Observational, single-center 
Subject 
Population 
11 subjects, who underwent MV repair operation with successful MAR 
implantation in clinical investigation 2010-040 
Objectives 
The primary objective of this clinical investigation is to evaluate long-
term performance and safety of MAR five years after mitral valve 
repair surgery 
Subject Selection 
Inclusion Criteria 
Subjects who participated in the clinical investigation 2010-040 and 
meet ALL of the following inclusion criteria are eligible for participation 

 
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in this investigation: 
1. Signed Informed Consent Form 
2. Subject had a successful MAR implantation in clinical 
investigation 2010-040  
3. Subject is willing to participate in the follow-up study and to comply 
with the requirements of the CIP 
Exclusion Criteria 
Subjects who participated in the clinical investigation 2010-040 but 
had the MAR replaced with another MV repair ring or system are not 
eligible for participation in this investigation 
Investigation 
Procedures 
Visit  
After signing the Informed Consent Form, the subjects will have the 
following assessments: 
• 
Demographics  
• 
Relevant medical history after the last follow-up visit (2 years 
after MAR implantation) of investigation 2010-040  
• 
Assessment for functional mitral regurgitation as defined by 
current American College of Cardiology/American Heart 
Association (ACC/AHA) guidelines  
• 
Vital signs (pulse, blood pressure, and body temperature) and 
weight  
• 
New York Heart Association (NYHA) rating 
• 
Electrocardiography (ECG) 
• 
Quality of Life Questionnaire (15D©) 
• 
Trans-thoracic echocardiography (TTE) 
Data Analysis and 
Statistics 
Definition of the analysis populations 
Long-term follow up data of 11 subjects, who underwent MV repair 
operation with successful MAR implantation in clinical investigation 
2010-040 performed during June 2011 - April 2016 

 
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Statistical methods  
A statistical analysis plan (SAP) detailing the statistical analyses will 
be written and finalized prior to final data analyses 
Qualitative and quantitative statistics will be used, as appropriate, to 
present and summarize the data collected in the clinical investigation 
Endpoints 
Primary safety endpoints 
The occurrence, nature and frequency of significant medical events 
since the last visit of clinical investigation 2010-040 as defined in 
section 8.4 of this Clinical Investigation Plan 
Primary performance endpoints 
Change in MR from the 2-year follow-up data point to the 5-year 
follow-up as measured by TTE. Success will be defined as no change 
or any improvement in MR class as described in the ACC/AHA 
Guidelines. 
Secondary endpoints 
Safety 
• All-cause mortality collected retrospectively since the last 
visit of clinical investigation 2010-040  
• The occurrence, nature and frequency of adverse device 
effects (ADEs) and/or device deficiencies (DDs) since the 
last visit of clinical investigation 2010-040 
• Number of cardiovascular admissions occurred since the last 
visit of clinical investigation 2010-040  
Other Safety 
• The number of subjects with clinically significant abnormal 
findings in TTE, ECG, or vital signs and type of abnormal 
findings will be listed and tabulated 

 
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Performance 
• Change from the clinical investigation 2010-040 2-year 
follow-up in the following MR parameters, as measured by 
TTE: 
- 
Left ventricle reverse remodeling (standard 
measurement points)  
- 
Coaptation height 
• 
Changes in NYHA classification when compared to the 
clinical investigation 2010-040 2-year follow-up visit. 
• 
Number of subjects with recurrence of MR defined as 
changing of MR to moderate or severe according to 
ACC/AHA classification determined by TTE. 
Other 
• 
Number of subjects with re-operation or MV reintervention 
due MAR performance failure or malfunction 
• 
Quality of life scores as measured by the 15D©questionnaire. 
Data Collection 
Data will be collected using Electronic Data Capture (EDC) system. 
Investigation 
Duration 
The investigation duration for each individual subject includes only 
one visit. Subjects will undergo interview and assessments specified 
in this CIP 
Estimated overall study duration from first subject first visit to last 
subject last visit May-June 2019 
 
 
 

 
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TABLE OF CONTENTS 
INVESTIGATION SITES ........................................................................................................ 5 
1. SYNOPSIS ...................................................................................................................... 6 
TABLE OF CONTENTS ....................................................................................................... 10 
2. ABBREVIATIONS AND DEFINITIONS ......................................................................... 13 
3. BACKGROUND AND RATIONALE .............................................................................. 14 
3.1 
Background Information ......................................................................................... 14 
3.2 
Summary of Clinical Data Preceding the Follow-up Clinical Investigation (2010-040)
 .............................................................................................................................. 15 
3.3 
Risks and Anticipated Adverse Device Effects to Be Assessed .............................. 17 
4. INVESTIGATIONAL MEDICAL DEVICE INFORMATION ............................................. 17 
5. RISK EVALUATION ...................................................................................................... 18 
5.1 
Risks Associated with the Participation in the Clinical Investigation ........................ 18 
5.2 
Risk/Benefit Assessment ........................................................................................ 18 
6. DESIGN OF THE CLINICAL INVESTIGATION ............................................................. 18 
6.1 
Purpose .................................................................................................................. 18 
6.2 
A description of the study design including justification based on clinical evaluation
 .............................................................................................................................. 18 
6.3 
Randomization and Blinding/Masking ..................................................................... 19 
6.4 
Objectives and Endpoints ....................................................................................... 19 
6.4.1 
Primary Objectives ..........................................................................................19 
6.4.2 
Secondary Objectives .....................................................................................20 
6.4.3 
Primary Endpoints ...........................................................................................20 
6.4.4 
Secondary Endpoints ......................................................................................20 
6.5 
Anticipated AEs to be Assessed ............................................................................. 21 
6.6 
Clinical Investigation Materials and Equipment ....................................................... 21 
6.7 
Subject Enrollment ................................................................................................. 21 
6.8 
Control ................................................................................................................... 22 
6.9 
Duration of Participation ......................................................................................... 22 

 
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6.10 
Time Schedule ....................................................................................................... 22 
7. INVESTIGATION POPULATION ................................................................................... 22 
7.1 
Inclusion and Exclusion Criteria .............................................................................. 22 
7.2 
Discontinuation or Withdrawal Criteria .................................................................... 23 
8. STUDY PROCEDURES ................................................................................................. 23 
8.1 
Informed Consent ................................................................................................... 23 
8.2 
Subject Number ..................................................................................................... 23 
8.3 
Visit Schedule and Assessments ............................................................................ 23 
8.3.1.1 Demographics .................................................................................................24 
8.3.1.2 Medical history ................................................................................................24 
8.3.1.3 Assessment for functional mitral regurgitation .................................................24 
8.3.1.4 Vital signs ........................................................................................................24 
8.3.1.5 Assessment of heart failure status ...................................................................24 
8.3.1.6 Electrocardiography (ECG) .............................................................................24 
8.3.1.7 Transthoracic echocardiography (TTE) ...........................................................24 
8.4 
Adverse Events, Adverse Device Effects and Device Deficiencies ......................... 25 
8.4.1 
Significant Medical Events...............................................................................26 
8.4.2 
Medical Care ...................................................................................................28 
9. STATISTICS .................................................................................................................. 29 
9.1 
General Statistical Considerations .......................................................................... 29 
9.2 
Statistical Methods ................................................................................................. 29 
9.2.1 
Primary Endpoints ...........................................................................................29 
9.2.2 
Secondary Endpoints ......................................................................................29 
9.3 
Reporting of Deviations .......................................................................................... 30 
9.4 
Missing, Unused and Spurious Data....................................................................... 30 
9.5 
Datasets to Be Analyzed ........................................................................................ 31 
9.6 
Demographic and Baseline Characteristics ............................................................ 31 
9.7 
Number of Subjects ................................................................................................ 31 
10. DATA AND QUALITY MANAGEMENT ......................................................................... 31 
10.1 
Site Monitoring ....................................................................................................... 31 

 
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10.2 
Data Collection ....................................................................................................... 31 
10.3 
Access to Source Data and Documentation ........................................................... 32 
10.4 
Database Management and Quality Control ........................................................... 32 
10.5 
Data Retention and Retention Period ..................................................................... 33 
10.5.1 
Investigator Records Retention .......................................................................33 
10.5.2 
Sponsor Records Retention ............................................................................33 
10.6 
Quality Assurance .................................................................................................. 34 
11. ADMINSTRATIVE PROCEDURES AND RESPONSIBILITIES ..................................... 35 
11.1 
Informed Consent ................................................................................................... 35 
11.2 
Statement of Compliance ....................................................................................... 35 
11.3 
Approval from Ethics Committee or Regulatory Authority ....................................... 36 
11.4 
Subject Data Protection .......................................................................................... 36 
11.5 
Investigator Responsibilities for EC and Regulatory Authority ................................ 36 
11.6 
Imposed Additional Requirements .......................................................................... 37 
11.7 
Reporting Responsibilities ...................................................................................... 37 
11.7.1 
Investigator Reporting Responsibilities ............................................................37 
11.7.2 
Sponsor Reporting Responsibilities .................................................................37 
11.8 
Insurance ............................................................................................................... 37 
11.9 
Amendments to the Clinical Investigation Plan ....................................................... 37 
11.10 Deviations from the Clinical Investigation Plan ....................................................... 37 
11.11 Corrective and Preventive Action and Principal Investigator Disqualification Criteria
 .............................................................................................................................. 38 
11.12 Suspension or Premature Termination ................................................................... 38 
11.13 Investigator and Site Selection ............................................................................... 38 
12. PUBLICATION POLICY ................................................................................................ 39 
13. REFERENCES .............................................................................................................. 40 
14. APPENDICES ............................................................................................................... 44 
14.1 
New York Heart Association Functional Classification ............................................ 44 
 

 
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2. 
ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definition 
ACC 
American College of Cardiology 
ADE 
Adverse device effect 
AE 
Adverse event 
AHA 
American Heart Association 
ASADE 
Anticipated serious adverse device effect 
CE 
Conformite Europenne (Conformity Mark for products marketed in the European 
Economic Area) 
CI 
Confidence interval 
CIP 
Clinical Investigation Plan 
CRA 
Clinical Research Associate 
EC 
Ethics Committee 
ECHO 
Echocardiography 
ECG 
Electrocardiography 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ERO 
Effective regurgitant orifice area 
ESC 
European Society of Cardiology 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ID 
Identification 
IMD 
Investigational medical device 
ISF 
Investigator Site File 
ISO 
International Organization for Standardization 
LV 
Left ventricle 
LVEF 
Left ventricle ejection fraction 
MAR 
Medtentia Annuloplasty Ring 
MEDDEV 
Medical Device Directive 
MedDRA 
Medical Dictionary for Regulatory Authorities 
MR 
Mitral regurgitation 
MV 
Mitral valve 
NYHA 
RA 
New York Heart Association 
Regulatory authority 
SADE 
Serious adverse device effect 
SAE 
Serious adverse event 
TTE 
Trans-thoracic echocardiography 
 
 

 
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3. 
BACKGROUND AND RATIONALE 
3.1 
Background Information 
Mitral regurgitation (MR) is an abnormal flow of blood in the heart from the left ventricle back 
to the left atrium caused by an incomplete closure of the mitral valve (MV) (Cooper et al., 1998). 
MR can result either from a structural or degenerative abnormality of the MV itself, or a 
distortion of the architecture or function of the left ventricle. With an estimated global 
prevalence of 1.7% and over 10% in people aged ≥75, MR is the most common heart valve 
disease (Nkomo et al., 2006; Mozaffarian et al., 2016; Nishimura et al., 2016). 
Initially patients with MR may have no symptoms because of compensatory changes to the 
heart. If MR is left untreated, compensatory changes to the heart become irreversible 
(Nishimura et al., 2016). The severity of MR usually worsens gradually, and severe MR 
eventually leads to left ventricular failure, various cardiac morbidities, and death if left untreated 
(Pozzoli et al., 2016). 90% of patients with severe MR end up dying or requiring cardiac surgery 
within 10 years of diagnosis (Enriquez-Sarano et al., 2009).  
There are currently no generally accepted pharmacological treatments for MR. Surgery has 
been the only treatment truly improving patient outcomes, especially over the long term 
(Vahanian et al., 2012). Therefore, the surgery is strongly recommended in the case of severe 
or moderate MR, as well as in asymptomatic patients in the case of progressive cardiac 
enlargement visible by ECHO (Falk et al., 2017; Iung et al., 2002). Surgical intervention aims 
either at repairing the MV or at replacing it with an artificial valve (Nishimura et al., 2016). 
Surgical MV repair, or MV annuloplasty, involves an annuloplasty ring that is implanted around 
the MV annulus, thus supporting the coaptation of the leaflets. Timely MV annuloplasty often 
associates with a good clinical outcome and normalized lifetime expectancy (De Bonis et al., 
2016; Pozzoli et al., 2016). MV repair has been estimated to be clinically superior to valve 
replacement surgery and is therefore the preferred option (Jokinen et al., 2007; Nishimura et 
al., 2016; Pedrazzini et al., 2010; Shang et al., 2017; Zhou et al., 2010). 
The MV repair process, however, is both technically demanding and time-consuming: it usually 
requires careful placement of more than ten sutures, and experienced and multidisciplinary 
operators are required to obtain good outcomes (LaPar et al., 2014; Nishimura et al., 2016). 
The Medtentia Annuloplasty Ring (MAR) was designed to provide a simpler alternative for the 
current technically demanding mitral repair processes. In preclinical safety and efficacy studies 
conducted in sheep, the new MAR system has proven to be easy to use, well tolerated, and to 
have a functional outcome comparable to that of a certified annuloplasty ring. MAR was also 

 
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proven to effectively stop MR without causing thrombus formation or hemolysis (Jensen et al., 
2010; Konerding et al., 2013). Furthermore, MAR rings were temporarily positioned in 18 
patients undergoing otherwise conventional annuloplasty and then removed without incident 
before the annuloplasty continued (Medtentia International Ltd Oy, 2011). No safety issues 
were seen when annuloplasty using the MAR was performed in these studies.  
During the years 2011-2014, MAR was implanted to 11 patients needing mitral valve 
regurgitation correction (investigation code: 2010-040) at two study stages. The outcomes of 
the study are presented in detail in the Clinical Investigation Report, dated 14-Feb-2019. As a 
conclusion this clinical investigation showed the first clinical evidence on MAR being an 
effective and well-tolerated method for the treatment of MR.  
This follow-up study to evaluate the 5-year performance and safety of the MAR in the current 
subject population is expected to provide valuable insight into the longer-term performance 
and safety of the MAR. 
3.2 
Summary of Clinical Data Preceding the Follow-up Clinical Investigation 
(2010-040) 
The prospective, single-arm clinical investigation was conducted between 2011–2014 (clinical 
investigation code: 2010-040), which aimed at investigating the safety and performance of 
MAR in subjects with MR requiring mitral valve annuloplasty. 
A total of 11 subjects with severe MR underwent successful mitral valve annuloplasty with 
MAR during two stages of this clinical investigation and were regularly followed up to 2 years 
after the surgery. At Stage 1 MAR Classic sizes available were 28-36 mm in 2 mm increments. 
At Stage 2, MAR Regular and Expanded sizes available were 26-40 mm diameters in 2 mm 
increments; Regular and Expanded corresponded to mitral leaflet’s thicknesses. 
During the first stage 17 subjects requiring mitral valve repair surgery were screened between 
June 2011 and August 2012. Implantation of the MAR was not attempted for one of these 
subjects, whose anterior leaflet was determined to be too large. MAR implantation was 
attempted but not completed for 9 subjects. Of these, three had thickened leaflets, two in 
addition to thick leaflets also had myxomatous mitral valve, one had annulus too small for the 
ring sizes defined in clinical investigation plan and available at that time, three had other 
anatomical features that made implantation unfeasible. Annuloplasty was completed using the 
MAR in the remaining 8 subjects, for one of these unsuccessfully leading to the replacement 
of MAR with a smaller Physio Ring. For one subject re-operation had to be done after few days 
due to continuous moderate-to-severe regurgitation and the MAR was replaced with a smaller 
Physio Ring. In total, the successful annuloplasty was completed using MAR (Classic) for 6 

 
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subjects during the Stage 1. As planned in the CIP, enrollment was then halted to allow a 
safety review by an independent data safety monitoring board (DSMB) composed of two 
clinicians with expertise in MV repair surgery and a biostatistician after the 6-month follow-up 
of the last of these subjects.  
On 04-Feb-2013 DSMB reviewed the Stage 1 data and found no safety concerns thus 
concluding that it was ethical and feasible to continue the study as planned (Lauer et al., 2013). 
As a consequence of the unexpectedly high number of patients with thickened leaflets, slight 
modifications were made to the ring design before the Stage 2 was opened for recruitment. A 
greater diversity of MAR sizes and an additional version of the MAR with a wider distance 
between the loops allowing implantation in patients with thicker mitral leaflets became available 
for Stage 2. Stage 2 started in July 2013, and the first implantation occurred on 10-Jul-2013. 
By May 2014, 5 subjects were successfully implanted with MAR and 2 were withdrawn due to 
anatomical anomalies. In August 2014 the project development was put on hold for a year. 
The company decided to terminate the study in September 2015 due to company’s focus shift 
towards the development of a transcatheter technology for mitral regurgitation and strategical 
reasons. No new subjects were enrolled after June 2014. 
Due to the limited number of subjects, the decision was made to use only descriptive statistics 
for data analysis. 
MAR performance results showed that at the 3-month time point, MAR implantation had 
induced a 2-degree MR status improvement in 10 out of 11 subjects (90.9%; 95% CI 58.7–
99.8%). Two years after surgery, MR status had improved by at least 2 degrees in all 11 
subjects (100%; 95% CI 71.5–100). Improved score according to NYHA classification also 
confirmed that all subjects with MAR had benefited from the operation: all had normal mitral 
leaflet motion and diminished size of the left ventricle two years after the MAR implantation. 
Reverse remodeling of the left ventricle after MAR implantation led to recovery of the 
anatomical features of the MV in all subjects who underwent a successful surgery. Hence, after 
the two-year follow-up period defined by the 2010-040 study design, all MAR subjects had 
diminished left ventricle size. The improved MR result was further supported by the NYHA 
assessment of subjects’ heart failure status that is based on an interview evaluating how much 
the potential heart condition limits the study subject’s physical activity. Two years after MAR 
implantation, all subjects had reached class I functional classification and thus had no 
limitations of physical activity caused by their heart condition. 
No deaths occurred in the hospital or during the 24-month follow-up. No device-related adverse 
events (ADEs) were detected in the subjects eligible for the study. 

 
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Regarding the safety of MAR and the implantation procedure, total number of non-device 
related AEs was 31. Of these, one event was major adverse cardiac event (MACE) - residual 
regurgitation leading to reoperation was observed on a 75-year-old female subject who had 
been excluded from the MAR population due to the concomitant annular decalcification. The 
MACE was deemed to be due to the small size and overall fragility of the subject’s mitral 
annulus, for which the MAR size used (32mm) could have been suboptimal, and it led to 
reoperation of the subject and MAR removal four days after the operation. No increases in the 
subjects’ mean thrombocyte values were detected during the study, indicating low 
thrombogenicity of the MAR. 
Thirteen serious adverse events (SAE) were reported: 11 SAEs had occurred after the MAR 
operation and two occurred post operation before the subject was released from the hospital 
– all resolved during the investigation; 6 of 14 SAEs were cardiology related (including MACE). 
Two SAEs were both severe and classified as MAR procedure related (one related and one 
possibly related).  
This clinical investigation results showed that mitral valve annuloplasty with the MAR is a well-
tolerated and efficient method to treat patients suffering from severe mitral regurgitation. 
3.3 
Risks and Anticipated Adverse Device Effects to Be Assessed 
This is an observational follow-up clinical investigation.  
There were no adverse device effects (ADEs) nor serious ADEs (SADEs) in previous clinical 
investigation 2010-040. 
4. 
INVESTIGATIONAL MEDICAL DEVICE INFORMATION 
Medtentia Annuloplasty Ring (Classic, Regular, and Expanded) and its accessories for 
selecting and implanting an appropriate mitral annuloplasty ring were used during the clinical 
investigation 2010-040.  
The following disposition of investigational device type and ring sizes were during the clinical 
investigation 2010-040: 
- At Stage 1 (year period 2011-2012), MAR Classic sizes were 28-36 mm in 2 mm increments.  
- At Stage 2 (year period 2013-2016), MAR Regular and Expanded sizes were 26-40 mm 
diameters in 2 mm increments; Regular and Expanded corresponded to mitral leaflet’s 
thicknesses. 

 
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Details on the device and its manufacturing process of the MAR can be found in the most 
recent Investigator’s Brochure (IB) (Medtentia International Oy, 2019). 
5. 
RISK EVALUATION 
5.1 
Risks Associated with the Participation in the Clinical Investigation 
Medtentia International Ltd Oy does not foresee any risks associated with this investigation. 
5.2 
Risk/Benefit Assessment  
This is an observational follow-up clinical investigation. There are no additional risks 
anticipated, specific to participating in this study for the subjects. The investigation is not 
examining any experimental procedures and participation in the investigation is not predicted 
to affect the medical treatment received by enrolled subjects. 
There is minimal potential for direct benefit to subjects as the investigation does not involve 
any change to their standard monitoring and treatment. However, there may be a benefit in the 
special attention paid to the subjects' cardiac function and picking up additional information 
from the subjects’ assessment. 
6. 
DESIGN OF THE CLINICAL INVESTIGATION 
6.1 
Purpose 
This clinical investigation is a continuation of the clinical investigation 2010-040 aiming to 
assess the long-term outcomes of the surgical therapy of MR using MAR. The purpose of this 
clinical investigation is to evaluate 5-year safety and performance of the MAR in patients who 
underwent successful mitral valve surgery using Medtentia’s MAR system in the clinical 
investigation 2010-040 performed during June 2011 - April 2016.   
6.2 
A description of the study design including justification based on 
clinical evaluation 
A pilot clinical investigation 2010-040 was conducted at the Helsinki University Central Hospital 
between June 2011 and April 2014. During two study stages of this clinical investigation MAR 
was implanted for 12 subjects. 11 of 24 consented subjects did not receive the device due to 
non-anatomical fit, mainly at Stage 1, therefore after sizing adjustment of the implant (Regular 
and Expanded) the enrolment rate improved significantly. For 1 subject MAR was replaced 

 
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before the operation was completed. For 1 subject the implantation was successful, but four 
days post-operation, MAR had to be replaced with another ring type due to the mismatch of 
the ring size. This emphasizes the importance of various ring sizes, as well as careful 
evaluation of patient’s mitral valve anatomy before a MAR operation. 
11 of 12 of the MAR population recovered from operation with improved mitral regurgitation 
and were regularly followed up to 2 years of ring implantation. The primary safety endpoints of 
the clinical investigation were met with no device-related safety issues and 100% survival. The 
primary performance endpoints were met with mitral regurgitation improvement of at least 2 
degrees in mitral regurgitation class.  
The limitations of clinical investigation 2010-040 include relatively small subject population, as 
well as the relatively short follow-up time for a surgical product. Therefore, an observational 
follow-up study to evaluate the 5-year performance and safety of the MAR in the current subject 
population was planned. 
This follow-up study, 2010-040FU5, aims to include 11 MAR subjects for one follow-up visit in 
order to evaluate whether MAR has been able to keep the mitral regurgitation trivial or mild. 
Subjects are planned to enter this follow-up clinical investigation at least 5 years after MAR 
implantation. 
The sponsor selected xxxxxxxxxx hospital as a follow-up clinical investigation site based upon 
a site assessment considering appropriate facilities, qualifications of the investigators’ 
experience with the intended procedures, and ability to conduct the study according to the 
clinical investigation plan. 
6.3 
Randomization and Blinding/Masking 
This section is not applicable. 
6.4 
Objectives and Endpoints 
6.4.1 
Primary Objectives 
Safety 
• To evaluate the safety of the MAR in terms of longstanding complications and adverse 
events 
Performance 
• To evaluate the performance of the MAR 5 years post MV repair surgery 

 
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6.4.2 
Secondary Objectives 
Safety 
• To evaluate the safety of the MAR in terms of survival since the last visit of clinical 
investigation 2010-040  
Performance 
• To obtain additional performance information 
6.4.3 
Primary Endpoints 
Safety 
• The occurrence, nature and frequency of significant medical events since the last visit 
of clinical investigation 2010-040 as defined in section 8.4 
 
Performance 
• Change in MR from the 2-year follow-up data point to the 5-year follow-up as measured 
by TTE. Success will be defined as no change or any improvement in MR class as 
described in the American College of Cardiology/ American Heart Association 
(ACC/AHA) Guidelines 
6.4.4 
Secondary Endpoints 
Safety 
• All-cause mortality collected retrospectively since the last visit of clinical investigation 
2010-040  
• The occurrence, nature and frequency of adverse device effects (ADEs) and/or device 
deficiencies (DDs) since the last visit of clinical investigation 2010-040 
• Number of cardiovascular admissions occurred since the last visit of clinical 
investigation 2010-040  
Other Safety 
• The number of subjects with clinically significant abnormal findings in TTE, ECG, or 
vital signs and type of abnormal findings will be listed and tabulated 
Performance 
• Change from the clinical investigation 2010-040 2-year follow-up in the following MR 
parameters, as measured by TTE: 

 
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- 
Left ventricle reverse remodeling (standard measurement points)  
- 
Coaptation height 
• 
Changes in NYHA classification when compared to the clinical investigation 2010-040 
2-year follow-up visit. 
• 
Number of subjects with recurrence of MR defined as changing of MR to moderate or 
severe according to ACC/AHA classification determined by TTE. 
Other 
• 
Number of subjects with re-operation or MV reintervention due MAR performance 
failure or malfunction 
• 
Quality of life scores as measured by the 15D© questionnaire. 
6.5 
Anticipated AEs to be Assessed 
In the clinical investigation 2010-040 a favorable safety and tolerability profile has been 
demonstrated for MAR. The most frequently reported AE was atrial fibrillation. The overall 
number of reported SAEs were 14, of these 6 SAEs were of cardiac disorders group.  
Based on the safety profile from the 2010-040 investigation, there were no ADEs, nor SADEs 
reported. AEs in the class of cardiac disorders may be expected 
For additional details on the safety and efficacy of MAR, please refer to the Investigator’s 
Brochure. 
6.6 
Clinical Investigation Materials and Equipment 
Medtentia International Ltd Oy will control the supply of the latest version of the Clinical 
Investigation Plan and all other materials required to conduct the clinical investigation. 
TTE, ECG and blood pressure measurements will be performed with hospital equipment and 
used within standard of care. Maintenance and calibration of the equipment is the responsibility 
of the investigation site and will be performed per hospital procedures. 
The clinical research associate (CRA) will verify that the site has applicable maintenance and 
calibration documents for these devices prior the subject enrolment. 
6.7 
Subject Enrollment 
The sample size will be determined by the number of qualifying subjects from the clinical 
investigation 2010-040 who can be located and who agree to participate in this follow-up 

 
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investigation. Subjects who underwent successful MAR implantation and completed 2010-040 
clinical investigation will be contacted and invited to participate in the follow-up study. 
Maximum of 11 subjects is anticipated to be enrolled in this follow-up clinical investigation. 
6.8 
Control 
This section is not applicable. 
6.9 
Duration of Participation 
The maximum duration of each subject’s participation in this observational investigation 
corresponds to the length on the study single visit, which expected to be approximately 3 hours. 
The point of enrollment is considered to be the time point at which the subject signs the 
Informed Consent Form (ICF). 
6.10 
Time Schedule 
The follow-up investigation visits for the 11 MAR patients will be occurring during May to June 
2019. The end of the clinical investigation is defined as the date of the last visit of the last 
subject in the investigation. 
7. 
INVESTIGATION POPULATION 
The aim is to enroll the subjects, who underwent MV repair operation with successful MAR 
implantation in clinical investigation 2010-040. 
7.1 
Inclusion and Exclusion Criteria 
The Investigator must ensure that the enrolled subjects who participated in the clinical 
investigation 2010-040 meet all the following inclusion criteria: 
1. 
Signed Informed Consent Form. 
2. 
Subject had a successful MAR implantation in clinical investigation 2010-040. 
3. 
Subject is willing to participate in the follow-up study and to comply with the 
requirements of the CIP. 
Exclusion criteria 
Subjects who participated in the clinical investigation 2010-040 but had the MAR replaced with 
another MV repair ring or system are not eligible for participation in this investigation 

 
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7.2 
Discontinuation or Withdrawal Criteria  
This clinical investigation consists of one visit only, therefore discontinuation or withdrawal of 
the subject by the Investigator is not expected. 
8. 
STUDY PROCEDURES 
8.1 
Informed Consent 
The subject may only be included in the follow-up study after providing written informed 
consent as described in Section 11.1 Informed Consent. Failure to obtain signed informed 
consent renders the patient ineligible for the study. 
8.2 
Subject Number 
The following series of numbers and letters will comprise the Subject Identification Code (SIC): 
CIP code (2010-040FU5) and 3-digit subject number (e.g., 001), which will be retained as was 
assigned in the clinical investigation 2010-040. 
8.3 
Visit Schedule and Assessments 
During the follow-up study each subject will visit the site only once.  
The Investigator will conduct the informed consent process (section 11.1), ensuring that the 
subject’s signature has been obtained on the ICF and that the subject has received a copy 
before any study specific procedures are conducted. Once the ICF is signed, the Investigator 
will perform the following assessments: 
- 
Collection of subject’s demographics 
- 
Recording any relevant medical history after the last follow-up visit (2 years after MAR 
implantation) of the clinical investigation 2010-040 
- 
Recording whether the subject had functional mitral regurgitation as defined by 
current ACC/AHA guidelines  
- 
Vital signs (pulse, blood pressure, and body temperature) and weight  
- 
New York Heart Association (NYHA) rating 
- 
ECG 
- 
Quality of Life Questionnaire (15D©) 
- 
TTE 

 
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8.3.1.1 
Demographics 
Demographic data will be collected: date of birth, age, sex, race, and smoking habits. 
8.3.1.2 
Medical history  
At the visit the subject’s medical history will be documented including significant medical 
events, defined as events of cardiovascular origin and events fulfilling ADE and DD criteria, 
experienced since the last visit in the clinical investigation 2010-040. 
8.3.1.3 
Assessment for functional mitral regurgitation 
The symptoms will be collected from the subjects and TTE values in order to assess whether 
subject had functional mitral regurgitation as defined by current ACC/AHA guideline.  
8.3.1.4 
Vital signs 
Vital signs will be recorded using standard equipment available at the site. Parameters to be 
measured at the visit include pulse, systolic and diastolic blood pressure, body temperature 
and weight. Pulse and blood pressure will be measured after the subject has been in a resting 
position for at least five minutes and repeated three times. The average value will be entered 
in eCRF. Weight will be measured in indoor clothing, but without shoes. All measurements will 
be recorded directly in the eCRF. Investigator will be asked to comment on any clinically 
significant abnormalities. 
8.3.1.5 
Assessment of heart failure status  
The status of each subject will be assessed according to the NYHA scale. 
8.3.1.6 
Electrocardiography (ECG) 
A 12-lead ECG will be performed and the print-outs will be evaluated by the Investigator. Any 
clinically significant abnormality will be recorded in eCRF. 
8.3.1.7 
Transthoracic echocardiography (TTE) 
TTE will be performed using the same standardized method described in detail in a separate 
Echocardiography Imaging and Submission Guidelines, version 2.0, dated 11-Jun-2013, as 
used in the main study 2040-040. TTE results will be documented in the subjects’ charts and 
eCRF. 
Mitral regurgitation will be assessed during the TTE. 
The following parameters will be assessed: 
• MR class (classes I – IV), according to the ACC/AHA classification 
• Coaptation height (mm) 

 
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• Left ventricle remodeling (standard measurement points, mm) 
o 
LV end systolic diameter 
o 
LV end diastolic diameter 
o 
Left ventricle ejection fraction (LVEF) 
• Venae contracta (mm) 
• Mitral valve peak gradient (mmHg) 
• Regurgitant volume (ml) 
• Effective Regurgitant Orifice Area (cm2) 
8.4 
Adverse Events, Adverse Device Effects and Device Deficiencies 
This is an observational follow-up study, consisting only of one visit. Significant medical events 
will be considered as events of cardiovascular origin and other events fulfilling, ADE and DD 
criteria. These events will be collected from the subject retrospectively from the timepoint of 
the last visit in the clinical investigation 2010-040. 
It is of utmost importance that all staff involved in the investigation are familiar with the 
definitions and procedures and it is the responsibility of the Investigator to ensure this. 
 
Adverse Event (AE) 
Adverse Events are defined as any untoward medical occurrence, unintended disease or injury 
or any untoward clinical signs (including abnormal laboratory finding), in subjects, users or 
other persons whether or not considered related to the investigational medical device. 
Note 1: This definition includes events related to the investigational medical device. 
Note 2: This definition includes related to the procedures involved. 
Note 3: For users or other persons, this definition is restricted to events related to the 
investigational medical device 
 
Adverse Device Effect (ADE) 
Adverse event related to the use of the investigational medical device. 
Note 1: This includes any adverse event resulting from insufficiencies or inadequacies in the 
instruction for use, or any malfunction of the investigational medical device. 
Note 2: This includes any event that is a result of a use error or intentional abnormal use of the 
investigational medical device. 
 
 

 
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Serious Adverse Event (SAE) 
Adverse Event that: 
1. 
Leads to a death, injury or permanent impairment to a body structure or body function 
2. 
Leads to a serious deterioration in the health of the subject, that either resulted in: 
a. 
a life-threatening illness or injury or  
b. 
a permanent impairment of a body structure or a body function, or 
c. 
in-patient hospitalization or prolonged hospitalization,  
d. 
in medical or surgical intervention to prevent life-threatening illness  
3. 
Leads to fetal distress, fetal death or a congenital abnormality or birth defect 
 
Serious Adverse Device Effect (SADE) 
Adverse device effect that has resulted in any of the consequences characteristic of a serious 
adverse event. 
 
Unanticipated Serious Adverse Device Effect (USADE) 
Serious adverse device effect which by its nature, incidence, severity or outcome has not been 
identified in the current version of the risk analysis report. 
Note: Anticipated serious adverse device effect (ASADE) is an effect which by nature, 
incidence, severity or outcome has been identified in the risk analysis report. 
 
Device Deficiency (DD) 
Inadequacy of a medical device related to its identity, quality, durability, reliability, safety or 
performance, such as malfunction, misuse or use error and inadequate labeling. 
8.4.1 
Significant Medical Events 
Due to the nature and regulatory strategy of this investigation, the scope of adverse event 
reporting in this investigation has been limited to collection and reporting of the following 
significant medical events: 
- 
Significant medical events according to the Table 1. 
- 
Any Device Deficiency (DD) that might have led to a SAE if (a) suitable action had not 
been taken or b) intervention had not been made or c) if circumstances had been less 
fortunate. DD relates to inadequacy of an investigational medical device related to its identity, 

 
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quality, durability, reliability, safety or performance. This may include malfunctions, use error, 
or inadequacy in the information supplied by the manufacturer. 
Regulatory authorities and EC will be informed about the retrospective events in the final report 
to be written in the end of this investigation. 
The Investigator must record any of the events listed in the Table 1, regardless of relationship 
to the investigational medical device, and any DD that might have led to a SAE in the eCRF. 
Each unique event or diagnosis must be documented separately. Clearly related signs, 
symptoms and abnormal diagnostic procedure results should be grouped together and 
reported as a single diagnosis or syndrome whenever possible. 
Table 1. Significant medical events required to be collected and reported by the Investigator (the 
list is based on standardized event reporting and data collection recommendations, Hicks et al. 2014 
and 2017) 
Event 
Description 
Death 
- Cardiovascular 
- Non-cardiovascular  
- Undetermined cause of death 
Heart failure  
Presentation of the patient for an urgent, unscheduled 
clinic/office/emergency department visit or hospital 
admission, with a primary diagnosis of heart failure 
Myocardial infarction 
 
Hospitalization  
For cardiovascular causes 
Stroke or another 
cerebrovascular event 
Should be assessed by a neurologist and CT/CMR imaging 
Severity should be documented: 
- Disabling  
- Nondisabling 
Percutaneous coronary 
intervention 
It is defined as the placement of an angioplasty guidewire, 
balloon, or other device into a native coronary artery or 
CABG for the purpose of mechanical coronary 
revascularization 
The assessment of coronary lesion severity by intravascular 
ultrasonography, coronary flow reserve, or fractional flow 

 
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reserve is not considered a percutaneous coronary 
intervention procedure 
Peripheral vascular 
intervention 
It is defined as a catheter-based or open surgical procedure 
designed to improve arterial or venous blood flow or 
otherwise modify or revise vascular conduits 
Arrhythmias and conduction 
system disturbances 
 
Unplanned cardiac surgery 
for any cause 
When a surgery is performed after implantation of a device, a 
new or worsened disease state that prompted the surgery is 
coded as the event, not the surgery itself.   
Specific device-related 
technical failure issues and 
complications 
 
 
Classification of Causal Relationship 
For each reported event, the causal relationship between the event and the investigational 
device will be classified as related, not related or unknown. At this long-term assessment of 
the MAR the causal relationship with implant procedure is considered not applicable. 
The event should be considered as not device related if it could be expected to occur even 
when the device performs at 100% of expectations. 
 
Classification of Severity 
Severity of each reported event will be assessed using the following definitions: 
Mild:  aware of sign or symptom, but easily tolerated. 
Moderate: discomfort enough to cause interference with usual activity. 
Severe: incapacitating with inability to work or do usual activity. 
8.4.2 
Medical Care 
After participation in a clinical investigation the subject will be advised or referred by the 
Investigator for a medical care according to national guidelines. 

 
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9. 
STATISTICS 
9.1 
General Statistical Considerations 
Descriptive statistics will be used to present and summarize the data collected in the clinical 
investigation. Continuous data will be presented with the number of observations, mean 
value, standard deviation, minimum, median and maximum value. Categorical data will be 
presented as counts and percentages. 
Any deviations from this section and/or the Statistical Analysis Plan (SAP) will be described 
and justified in the Final Clinical Study Report, as appropriate. 
9.2 
Statistical Methods 
A statistical analysis plan detailing the statistical analyses will be written and finalized prior to 
final data analyses. 
9.2.1 
Primary Endpoints 
9.2.1.1 
Safety 
The occurrence, nature and frequency of significant medical events since the last visit of 
clinical investigation 2010-040 as defined in section 8.4 will be listed and tabulated. 
9.2.1.2 
Performance 
The percentage of subjects with stable MR condition or any improvement in MR class as 
described in the ACC/AHA Guidelines 5 years after MAR implantation will be calculated with 
its two-sided 95% CI (if applicable). 
9.2.2 
Secondary Endpoints 
9.2.2.1 
Safety 
All-cause mortality collected retrospectively since the last visit of clinical investigation 2010-
040 will be summarized in a frequency table. 
The occurrence, nature and frequency of adverse device effects (ADEs) and/or device 
deficiencies (DDs) since the last visit of clinical investigation 2010-040 will be summarized. 
Number of cardiovascular admissions occurred since the last visit of clinical investigation 
2010-040 will be summarized. 

 
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Descriptive statistics with two-sided 95% CIs, when appropriate, will be presented for all safety 
data for the MAR population. 
9.2.2.2 Other Safety 
The number of subjects with clinically significant abnormal findings in TTE, ECG, or vital signs 
and type of abnormal findings will be listed and tabulated. 
9.2.2.3 
Performance 
The MR parameters left ventricle reverse remodeling (standard measurement points) and 
coaptation height will be tabulated using descriptive statistics. For the same parameters, a 
comparison with the clinical investigation 2010-040 2-year follow-up visit will be presented by 
absolute change and %-change. The changes in MR parameter values may also be analyzed 
graphically. 
The Changes in NYHA classification when compared to the clinical investigation 2010-040 2-
year follow-up visit will be summarized. 
The number of subjects with recurrence of MR defined as changing of MR to moderate or 
severe according to ACC/AHA classification determined by TTE will be tabulated. 
The percentage of subjects with recurrence of MR from 2-year follow-up visit will be calculated 
with their two-sided 95% CI. 
9.2.2.4 
Other 
Number of subjects with re-operation or MV reintervention due MAR performance failure or 
malfunction will be summarized. 
Quality of life scores as measured by the 15D©questionnaire will be summarized. 
9.3 
Reporting of Deviations 
Any deviations will be collected to a deviation log by the study monitor and listed by subject in 
the final report. 
9.4 
Missing, Unused and Spurious Data 
The handling of missing data will be detailed in the Statistical Analysis Plan. 
 
 

 
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9.5 
Datasets to Be Analyzed 
The Medtentia Annuloplasty Ring population (MAR population) consists of subjects, who 
underwent MV repair operation with successful MAR implantation in clinical investigation 2010-
040. All analysis will be performed on the MAR population. 
9.6 
Demographic and Baseline Characteristics 
Subject disposition, demographic and other baseline data will be presented using 
summary statistics and data from subjects in the MAR population. 
9.7 
Number of Subjects 
11 subjects with MAR implanted will participate in this follow-up study. 
10. 
DATA AND QUALITY MANAGEMENT 
10.1 
Site Monitoring 
The study will be monitored in compliance with the Declaration of Helsinki, ISO 14155:2011, 
the CIP, all applicable national and local regulations and according to xxxxx xxx standard 
operating procedures (SOPs). All monitoring activities will be conducted by a trained and 
qualified monitor who will document each monitoring visit. In general, during monitoring visits, 
the monitor will make sure the informed consent procedure has been appropriately carried out 
and will compare the eCRF entries to original source data at the investigation site. All data 
must be accurately recorded in the eCRF. 
Authorized representatives of the Sponsor and/or regulatory authorities may visit the site to 
perform audits/inspections, including source data verification. 
10.2 
Data Collection 
The origin of source data will be specified and agreed in the Origin of Source Data form (REC5-
121) with the Investigator. The following data may be recorded directly in the eCRF that will 
then be considered as source data:  
• 
Date of birth and sex 
• 
Vital signs, temperature, weight 
It is the responsibility of the Investigator to record essential information in the medical records 
in accordance with national regulations and requirements: 

 
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• 
Investigation code 
• 
Subject number 
• 
That informed consent for participating in the study was obtained 
• 
Diagnosis 
• 
Investigation visit 
• 
All AEs/ADEs/DDs 
Relevant datapoints of TTE measurements will be entered in eCRF. TTE data will be collected 
and stored in DVDs. 
The Investigator is responsible for ensuring the accuracy, completeness, legibility and 
timeliness of the data recorded in the eCRFs. The eCRFs will be completed, verified, 
monitored, and in the end of the study they will be signed by the Principal Investigator when 
all data are clean and without queries. 
10.3 
Access to Source Data and Documentation 
The Investigator should guarantee access to source documents for the monitor and auditors 
as well as for inspection by appropriate regulatory authorities, and the Ethics Committee (EC), 
if required.  
10.4 
Database Management and Quality Control 
Data management and handling will be conducted according to the investigation specific Data 
Management Plan in accordance with applicable guidelines and xxxxx xxx SOPs (xxxx 
xxxxxxxxxx xxxx xxx xxxxxx xxxxxxxx). 
The Investigator is responsible for maintaining accurate, complete, and up-to-date records for 
each subject. This includes maintaining any source documentation related to the investigation, 
including ECHO readings. The site will maintain a list of the subjects´ names and the Subject 
ID assigned to each individual participant Documents that identify the subject beyond the 
Subject ID will not be submitted to the sponsor (e.g. the signed informed consent document) 
and must be maintained in strict confidence by the Investigator, except to the extent necessary 
to allow inspections by the regulatory authorities and audits by the study monitor or sponsor 
representatives. 
All data will be collected in the Electronic Data Capture (EDC) system by IBM Clinical 
Development.  The specifics of the database design, testing, access and processes for data 
management and handling will be further defined in the investigation specific DMP and 
conducted in accordance with applicable guidelines and xxxxx xxx SOPxxxxx.  

 
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The Investigator must promptly review the completed eCRFs for each subject. As the person 
ultimately responsible for the accuracy of all eCRF data, the Principal Investigator must confirm 
the entries with his signature in each subject’s eCRF. 
After data review by the monitor, queries for any missing, out of range or questionable data 
will be generated for Investigator to answer and complete. The Investigator will answer the 
query as documented on the side of the eCRF. All queries must be answered. 
10.5 
Data Retention and Retention Period 
10.5.1 
Investigator Records Retention 
All study documents must be retained by the Investigator for a period of at least 15 years after 
completion of the study. The Investigator must maintain adequate records of the clinical study, 
including: 
• Completed eCRFs 
• Medical records 
• Signed informed consent forms 
• ECG charts 
• ECHO reports 
• All correspondence between the Investigator and the EC, regulatory authorities, the 
sponsor, the CRO 
• Any other pertinent data relevant to the study 
The Investigator must not destroy any study specific documentation before receiving written 
permission for this from the sponsor.  
10.5.2 
Sponsor Records Retention 
The sponsor will maintain the following records for at least 25 years after the last device has 
been manufactured or until the company ceases to exist: 
• All correspondence pertaining to the investigation 
• Signed and dated Investigator Agreements and signed and dated Investigator 
curriculum vitae that were current at the time of the study 
• Copies of all EC approval letters, the EC review and approval procedures, and relevant 
EC correspondence 
• Name and address of the institution where the clinical investigation was conducted, as 
well as records of approval from site administration 

 
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• Correspondence with authority as required by national legislation 
• Insurance certificates 
• Names/contact address of the monitor 
• Statistical analyses and underlying supporting data 
• Final report of the clinical investigation 
• Study training records for site personnel and sponsor/CRO personnel. 
10.6 
Quality Assurance 
To assure accurate, complete and reliable data, the sponsor or its representatives will do the 
following: 
• Provide instructional material to the investigational sites as appropriate 
• Organize a meeting to instruct the Investigator and the study coordinator. This session 
will give instruction on the CIP, the IB, the completion of the eCRF and study 
procedures 
• Perform monitoring visits at the investigational site 
• Be available for consultation and stay in contact with study site personnel by email or 
phone 
• Review and evaluate eCRF data 
In addition, the sponsor or its representatives may check a sample of subject data recorded 
against source documents at the study site. 
To ensure the safety of study participants, and to ensure accurate, complete, and reliable data, 
the Investigator will keep records of clinical notes and subject medical records in the subject 
files as original source documents for the study. If requested, the Investigator will provide the 
sponsor, the applicable regulatory authority, and the applicable EC with direct access to 
original source documents. 
The study may be audited by the sponsor or its representatives at any time. Such an audit will 
be conducted according to a specific audit plan. Investigators will be given notice before an 
audit occurs. 
The regulatory authorities may inspect the study site. The Investigator is responsible for 
notifying the sponsor of such an inspection immediately upon gaining knowledge of it. During 
the audit or inspection, the Investigator/institution will permit the auditor, EC reviewer, and 
regulatory inspector(s) direct access to all relevant medical records and other source data, 
study-related files and eCRFs. 

 
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11. 
ADMINSTRATIVE PROCEDURES AND RESPONSIBILITIES 
11.1 
Informed Consent 
Prior to enrollment to the clinical investigation, ICF will be given to each prospective subject, 
including an explanation of the investigation, duration, explanation of medical record access 
and patient anonymity, and specifies that data will be recorded, collected, processed and may 
be transferred (to either EEA countries and/or non-EEA countries). The ICF may be utilized if 
approved by the responsible EC. Adequate time will be allowed for the subject to consider 
participation in the clinical investigation. Any coercion or undue influence of potential subjects 
to participate must be avoided, and the subject’s legal rights should not be waived. The subject 
will also be informed of his/her right to withdraw from the study at any time without giving a 
reason. If the subject is willing to participate in the investigation, both the subject and the 
Investigator or designated sub-Investigator who conducted the informed consent process must 
sign and date the ICF in accordance with local national requirements. The original signed ICF 
will be filed in the Investigator Site Files (ISF). The subject then will be given a copy of the 
signed ICF.  
The ICF must be fully signed and dated prior to data collection or any other investigation-
related activities required by the CIP. Failure to obtain signed informed consent renders the 
patient ineligible for the investigation  
The ICF complies with the ISO 14155:2011 standard and is considered appropriate for this 
study will be submitted to the EC. The ICF will be in Finnish and will contain language that is 
non-technical and understandable to the subject. Any changes to the ICF suggested by the 
Investigator must be agreed by Medtentia International Ltd Oy before submission to the EC 
and a copy of the EC approved version must be provided to the CRA after EC approval. 
11.2 
Statement of Compliance 
This clinical investigation was designed and shall be implemented and reported in accordance 
with the international standard of ISO 14155:2011 Clinical investigation of medical devices for 
human subjects - Good clinical practice, and with the ethical principles laid down in the 
Declaration of Helsinki (WMA Declaration of Helsinki - Ethical Principles for Medical Research 
Involving Human Subjects). 
This clinical investigation will be conducted in compliance with regional or national regulations, 
as appropriate. 

 
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11.3 
Approval from Ethics Committee or Regulatory Authority 
The clinical investigation will not begin until the approval from both EC and regulatory authority 
has been obtained, as appropriate. 
The CIP and the final version of the ICF must be approved or given a favorable opinion in 
writing by a properly constituted EC before investigation start. A signed and dated statement 
from the EC that the CIP and ICF have been approved must be forwarded to Medtentia 
International Ltd Oy before study initiation. 
The study must be reviewed and approved by the responsible regulatory authority before study 
initiation, according to local and national regulations. Any additional requirements imposed by 
the EC or regulatory authority will be followed. 
If any alterations, other than changes of an administrative nature only, are made to the study 
CIP, a formal CIP amendment will be issued and submitted to the relevant EC for approval. 
The amendment will not be implemented until EC approval.  
Since this is short clinical investigation, no amendments are expected. 
11.4 
Subject Data Protection 
The ICF explains that the data will be stored in a database, maintaining confidentiality in 
accordance with national data legislation, and that only authorized representatives of the 
Sponsor, regulatory authority or an EC may require direct access. The computerized data will 
be identified by subject number only. The Investigator will file the medical records relevant to 
the investigation, including medical history, for verification of data. 
Identification list, which includes enough information to link records, i.e. eCRF and clinical 
records will be preserved for possible future inspections/audits and will be available only for 
monitoring and auditing purposes. 
Information collected during the study will be stored in Investigator Site Files (ISF) at the site. 
Clinical Investigation Master Files (CIMF) will be kept at xxxxx xxxxx office until the end of the 
study, after which the CIMF will be shipped to the sponsor. 
11.5 
Investigator Responsibilities for EC and Regulatory Authority 
Prior to study start, the Investigator is required to sign a Clinical Investigation Plan signature 
page confirming his agreement to conduct the study in accordance with all of the instructions 
and procedures found in this CIP and associated documents and to give access to all relevant 
data and records to Medtentia International Ltd Oy, monitors, auditors, Quality Assurance 

 
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representatives, designees, EC and regulatory authorities as required. If an inspection of the 
investigational site is requested by a regulatory authority, the Investigator must immediately 
inform Medtentia International Ltd Oy that this request has been made. 
11.6 
Imposed Additional Requirements 
This section is not applicable. 
11.7 
Reporting Responsibilities 
11.7.1 
Investigator Reporting Responsibilities 
The Investigator or designee is responsible for completing (including review and signature) 
eCRFs, as well as for submitting reports to the sponsor of deviations from the CIP. If any action 
is taken by the EC with respect to the investigation, the Investigator will forward the information 
to the sponsor as soon as possible.  
11.7.2 
Sponsor Reporting Responsibilities 
The sponsor is responsible for preparation and reporting the final clinical investigation report 
according to the guideline presented in Annex C of ISO 14155-1:2011. This report, or parts of 
it, must be submitted to the relevant authorities, if applicable. 
11.8 
Insurance 
The sponsor maintains appropriate clinical trial liability insurance coverage as required under 
applicable laws and regulations and will comply with applicable local law and custom 
concerning specific insurance coverage. If required, proof of the clinical trial insurance policy 
will be provided to the EC. If required by national regulations, indemnification will be provided. 
11.9 
Amendments to the Clinical Investigation Plan  
Since this is short clinical investigation, no amendments are expected. 
 
11.10 
Deviations from the Clinical Investigation Plan 
The Investigator is not allowed to deviate from the CIP, except when necessary to protect the 
subject’s life, physical well-being or right in an emergency or when caused by unforeseen 
circumstances that are beyond the Investigator’s control (e.g. subject did not attend scheduled 
visit). Prior approval by the sponsor is required for changes in or deviations from the CIP, 

 
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except in an emergency. If the changes or deviations may affect the rights, safety, or welfare 
of participants, EC approval is required. Such approval will be documented in writing and 
maintained in the ISF and Trial Master File (TMF). 
The site will report all deviations, regardless of whether medically justifiable or taken to protect 
the subject in an emergency, to the sponsor in a timely manner on a protocol deviation form. 
In addition, the Investigator is required to adhere to the EC procedures for reporting deviations. 
Deviations include, but are not limited to the following list: 
• 
Failure to obtain informed consent prior to conducting study specific activities 
• 
Incorrect version of the ICF used 
• 
CIP-required testing and/or measurements were not done or were done incorrectly 
• 
Source data permanently lost. 
A sponsor representative or monitor will review site compliance with regard to deviations at the 
monitoring visit. The monitor will discuss any deviations that occurred at the investigational site 
directly with the Investigator and will summarize the findings in a follow-up letter to the site. In 
addition, all deviations from the CIP will be documented in the final study report. 
11.11 
Corrective 
and 
Preventive 
Action 
and 
Principal 
Investigator 
Disqualification Criteria 
See section 11.10 Deviations from the CIP. After analyzing and taking corrective actions, site 
personnel will be retrained by the sponsor or its representatives on the relevant study 
procedures. All necessary measurements will be taken to prevent reoccurrence of the CIP 
deviation.  
11.12 
Suspension or Premature Termination  
This section is not applicable. 
11.13 
Investigator and Site Selection  
Investigator and Site are pre-selected by Medtentia International Ltd Oy. The Principal 
Investigator will be cardiologist xxxxx xxxxx and the site xxxxxxxxxx xxxxxxxx xx xxxxxxxx. 
 
 

 
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12. 
PUBLICATION POLICY 
All information supplied by the sponsor in connection with this investigation will remain the sole 
property of the sponsor and is to be considered confidential information. No confidential 
information will be disclosed to others without obtaining prior written consent from the sponsor 
and will not be used except in the performance of this investigation. 
The publication of study results will be agreed between the sponsor and the Investigator. The 
sponsor intends to publish the results of the study. However, the sponsor retains the right to 
review and approve in writing any publication, poster, presentation or manuscript before they 
are made public in order to prevent publication of any confidential information. 
 

 
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14. 
APPENDICES 
14.1 
New York Heart Association Functional Classification 
Functional Capacity 
Objective 
Assessment 
Class I. Patients with cardiac disease but without resulting 
limitation of physical activity. Ordinary physical activity does 
not cause undue fatigue, palpitation, dyspnea, or anginal pain. 
A. No objective evidence 
of 
cardiovascular 
disease. 
Class II. Patients with cardiac disease resulting in slight 
limitation of physical activity. They are comfortable at rest. 
Ordinary physical activity results in fatigue, palpitation, 
dyspnea, or anginal pain. 
B. Objective evidence of 
minimal 
cardiovascular 
disease. 
Class III. Patients with cardiac disease resulting in marked 
limitation of physical activity. They are comfortable at rest. 
Less than ordinary activity causes fatigue, palpitation, 
dyspnea, or anginal pain. 
C. Objective evidence of 
moderately 
severe 
cardiovascular disease. 
Class IV. Patients with cardiac disease resulting in inability to 
carry on any physical activity without discomfort. Symptoms of 
heart failure or the anginal syndrome may be present even at 
rest. If any physical activity is undertaken, discomfort is 
increased. 
D. Objective evidence of 
severe 
cardiovascular 
disease. 
 
Source: (New York Heart Association Functional Classification, 2013) American Heart Association 
https://manual.jointcommission.org/releases/TJC2018A/DataElem0439.html  
Accessed 28 Mar 2019.