On-X Heart Valve - 17mm Aortic and 23mm Mitral
Phase: NA
Conditions: Heart Valve Disease
Sponsor: On-X Life Technologies, Inc.

 
 
 
 
 
 
ON-X LIFE TECHNOLOGIES, INCORPORATED 
INVESTIGATIONAL PLAN 
 
 
 
 
ON-X® PROSTHETIC HEART VALVE 
17mm AORTIC 
23mm MITRAL 
 
 
 
 
CONFIDENTIAL 
 
SPONSOR 
 
ON-X LIFE TECHNOLOGIES, INC. 
1300 EAST ANDERSON LN, BLDG. B 
AUSTIN, TEXAS 78752 
September 29, 2017 
 
 
 
 
 
2010-01, REV H 

 
 
i
TABLE OF CONTENTS 
 
SECTION 
 
 
 
 
 
 
 
PAGE 
 
1.0 
Purpose 
 
 
 
 
 
 
   1 
2.0 
Protocol 
 
 
 
 
 
 
   1 
2.1 
Study Design  
 
 
 
 
 
   2 
2.2 
Patient Population and Selection Criteria 
 
 
   2 
2.2.1 Screen Failures 
 
 
 
 
 
   4 
2.3 
Institutional Review and Informed Consent  
 
   4 
2.3.1    Collaborating Parties  
 
 
 
 
   5 
2.4 
Investigational Procedures 
 
 
 
 
   5 
2.4.1 Preoperative Procedures 
 
 
 
 
   7 
2.4.2 Operative Procedures  
 
 
 
 
   8 
2.4.3 Early Postoperative/Discharge Procedures 
 
 
   8 
2.4.4 Late Follow-up Reporting 
 
 
 
 
   9 
2.4.5 Complication Reporting 
 
 
 
 
   9 
2.4.6 Echocardiography Procedures 
 
   
              16 
2.4.7 Blood Studies for Hemolysis  
 
 
  
  17 
2.4.8    Explants 
 
 
 
 
 
 
  17 
2.4.9    Monitoring Procedures 
 
 
 
 
  18 
2.4.10 Statistical Analysis 
 
 
 
 
 
  21 
2.5 
Case Report Forms 
 
 
 
 
 
  21 
3.0 
Device Description and Risk Analysis 
 
 
  21 
4.0 
Labeling 
 
 
 
 
 
 
  23 
5.0 
References 
 
 
 
 
 
 
  23 
 
Appendix A 
Complete Echocardiography Protocol 
Appendix B 
Case Report Forms 
Appendix C 
Example Informed Consent  
Appendix D 
Investigator’s Agreement 
Appendix E 
Labeling 
 
Appendix F 
Investigator List 

 
2010-01, REV H 
 
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1.0 
PURPOSE 
 
 
 
The purpose of the proposed study is to assess the safety and efficacy of the 17mm 
On-X Aortic Prosthetic Heart Valve when used to replace diseased aortic valves and  
the 23mm On-X Mitral Prosthetic Heart Valve when used to replace diseased mitral 
valves in human subjects. 
 
The On-X 17mm aortic valve will be implanted in approximately 20 and at least 15 
patients and will be followed for 1 year.  Enrollment of On-X 23mm mitral valve 
patients has been discontinued due to low enrollment potential.  Follow-up of enrolled 
patients will continue according to the protocol for 1 year. 
2.0 
PROTOCOL 
 
 
 
This study is prospective.  All centers will follow a common protocol in which 
eligible patients will be asked to participate in the 1-year follow-up of the On-X 
valve.  The objective of the trial is to establish the clinical safety and effectiveness of 
the size 17mm aortic valve.  It is expected that 20 centers from both within and 
outside the United States implanting between 1 to 2 valves will be involved.  The 
number enrolled at a single center will depend entirely on the study as a whole 
reaching the required 15 patients.  A copy of the investigator’s agreement for the trial 
is contained in Appendix D. 
Valve safety: 
• 
Although sample size will limit the value of event rate calculations, early (30-
day) and late time-related incidence and associated rate of all deaths and each 
valve related cardiovascular complication will be determined.  Adverse events 
are those defined by the STS/AATS definitions(1), as well as all other 
cardiovascular complications.  Rates of valve thrombosis, thromboembolism, 
hemorrhage (both all and major), endocarditis, hemolysis, hemolytic anemia, 
mortality, reoperation, valve explantation and prosthetic valve dysfunction 
(structural, non-structural and paravalvular leak (both all and major)) are 
primary safety endpoints to be evaluated using both linearized and actuarial 
statistical methods. 
• 
Hemolytic potential of the valve will be measured using a CBC, reticulocyte 
count, serum haptoglobin, serum lactate dehydrogenase and plasma free 
hemoglobin.   
 
Valve effectiveness: 
• 
Functional status changes will be assessed using classification nomenclature 
developed by the New York Heart Association (NYHA).  The assessment 

 
2010-01, REV H 
 
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shall include proportions within class and cross tabulation of changes over 
time. 
• 
Hemodynamic performance of the valve will be determined by 
echocardiography.  The following specific parameters will be evaluated using 
standard descriptive statistics: peak and mean pressure gradients, effective 
orifice area (EOA), cardiac output (CO), valvular regurgitation and indices of 
EOA and CO to body surface area (BSA), and performance index of EOA to 
geometric orifice area (GOA). 
Valve safety and effectiveness will be compared by valve position to corresponding 
historical controls contained in the clinical results presented in the original PMA for 
other size On-X valves (P000037 and P000037/S001).  The trial is designed 
specifically to meet the criteria established by ISO(2) and recognized by FDA for 
clinical trials of a single size of a prosthetic heart valve.  The data will be used to 
obtain and maintain appropriate regulatory approvals where needed. 
2.1 
STUDY DESIGN (SAMPLE SIZE) 
 
Patients meeting all the appropriate criteria will be recruited for clinical trial 
participation.  Enrollment is non-randomized, and continues until the sample size 
requirement is met, unless the sponsor terminates the clinical trial early for unforeseen 
reasons.  
 
Submission for premarket approval in the U.S. will occur after international standards 
criterion of at least 15 patients will be followed for one year.  This follow-up will 
include echocardiography, blood damage, NYHA status and any adverse events. 
 
 
2.2 
PATIENT POPULATION AND SELECTION CRITERIA 
 
The indications for replacement of a patient’s natural or prosthetic valve will be those 
which the principal investigator follows in his routine practice of cardiovascular 
surgery. 
 
The following are criteria for inclusion of patients in this study: 
1. Patients  of any age; unless waived by local IRB assent of the patient and in all cases consent 
of parent or legally authorized representative is required if a patient is under the age of 
majority and not legally emancipated. 
2. Patients who are sufficiently ill to warrant replacement of their diseased natural or prosthetic 
valve, based on standard cardiovascular diagnostic workups. 
3. Patients who are in sufficient satisfactory condition, based on the physical exam and 
investigator’s experience, to be an average or better operative risk,  (i.e., likely to survive one 
year postoperatively). 
4. Patients who require an isolated aortic valve replacement size 17 mm.  
5. Patients who are geographically stable and willing to return to the implanting center for 
follow-up visits. 

 
2010-01, REV H 
 
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6. Patients or legally authorized  representatives who are adequately informed of their 
participation in the clinical study and what will be required of them in order to comply with 
the protocol. 
7. Patients requiring concomitant cardiovascular surgery, such as coronary bypass may be 
included in the study. 
The following are criteria for exclusion of patients from this study: 
1. Patients who are pregnant, planning to become pregnant or are lactating. 
2. Patients who have a noncardiac progressive disease, which in the investigator’s experience 
produces an unacceptable increased risk to the patient. 
3. Patients who have a documented history of substance (drug or alcohol) abuser or are prison 
inmates. 
4. Patients with a previous prosthetic valve, where it is not being replaced by a study valve, or 
patients requiring multiple valve replacement. 
5. Patients with active endocarditis or active myocarditis. 
6. Patients who require mitral, tricuspid or pulmonic valve replacement. 
7. Patients who have not agreed to return for the required number of follow-up visits or who are 
geographically unavailable for follow-up. 
8. Patients who cannot be maintained on long-term anticoagulant therapy. 
9. Patients with non-cardiac illness resulting in a life expectancy of less than 1-year. 
10. Patients previously enrolled and implanted in this trial may not re-enter after withdrawal. 
11. Patients already enrolled in another investigational device or drug study (nor can enrolled 
patients be enrolled in other studies). 
12. Patients with acute preoperative neurological deficit, myocardial infarction, or cardiac event 
who have not returned to baseline for at least 30-days prior to enrollment. 
13. Patients with aortic aneurysm or other medical condition that creates a higher than usual risk 
of surgical complication. 
14.  Patients who are prisoners or mentally ill, and pediatric patients of assent age who are 
incapable of understanding their assent as judged by the principal investigator. 
Patients are free to withdraw from the study at any time for any reason without 
prejudicing their medical care.  Surviving patients who have their valve explanted for 
any reason will also be considered withdrawn.  There are no other anticipated reasons 
for withdrawal from the study. 
 
At each center, patient recruitment will occur in the following manner.  Determine 
whether or not the patient is eligible to receive the On-X valve by assessing if the 
patient meets the selection criteria.  If the patient is eligible, discuss all aspects of the 
On-X clinical trial requirements and invite the patient or patient’s legally authorized 
representative to participate.  If the patient or representative agrees to participate, 
obtain informed consent and enroll the patient in the clinical trial.  All patients who 
might receive a small valve should be consented even though a larger valve may be 
used based on findings during surgery.  This may create some screen failures but will 
avoid losing potential patients in what is expected to be a small patient group overall.  

 
2010-01, REV H 
 
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Recruitment will continue until the overall study has reached its patient enrollment 
requirements. 
 
2.2.1. Screen Failures  
 
The principal investigator will select patients to approach for enrollment based on his 
professional judgment using all available preoperative data.  It is not expected that 
large patients (body surface area (BSA) >1.8M2) or patients with echo finding of 
native valve diameters greater than 19mm aortic will be screened as candidates, but 
those with small body size <1.5M2 or smaller than the above valve diameters by echo 
will be screened.  All patients approached or evaluated for enrollment will be entered 
on the screening log contained in the case report forms in Appendix B.  If prior to 
surgery the patient is dropped from consideration or during surgery a different valve is 
implanted, then the screen failure will be noted in the log with sufficient explanation 
to allow assessment of the cause of the screen failure and determination of affect on 
the study. 
 
 
2.3 
INSTITUTIONAL REVIEW AND INFORMED CONSENT 
Institutional review through the appropriate standing committee of the clinical center 
(either Ethics Committee or Institutional Review Board) must be obtained as required 
by local rules, and a copy of the approval document must be supplied to the sponsor.  
A list is contained in Appendix F. 
Informed consent must be obtained for each patient prior to participation in the 
clinical trial in accordance with local rules.  As this study includes some pediatric 
patients, consent shall include assent of the patient as well as consent of his/her parent 
or legally authorized representative whenever such patient is recruited.  Assent may 
be waived by the local IRB if the patient is incapable due to age, maturity or 
psychological state.  Local IRB rules or individual case review can be used to 
determine if waiver is appropriate, which if not addressed in the IRB approval 
document must be obtained case-by-case.  It is the responsibility of the principal 
investigator to obtain such waiver prospectively as needed.  A copy of the informed 
consent should be provided to the patient or representative and they should be 
encouraged to review it. It is recommended that the informed consent be reviewed as 
part of the preoperative procedures with prospective enrollment.  An example 
informed consent document is in Appendix C. 
Each clinical center must have a staff echocardiologist responsible for conduction of 
the echocardiographic portions of this study.  Additionally, coagulation profiles are to 
be reported as the international normalized ratio (INR), and hemolysis study blood 
samples must be sent to a local laboratory and the laboratory normal ranges must be 
supplied to the sponsor. 
This study also requires that copies of all echocardiography electronic recordings be 
sent to the sponsor for review. 

 
2010-01, REV H 
 
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2.3.1  Collaborating Parties 
 
Core cardiology laboratory and cardiologist – Department of Echocardiography, 
Guy’s and St. Thomas’ Hospital Trust, London, England – Dr. John 
Chambers. 
 
Duties: Echo consulting, review and calculations. 
 
Core pathology laboratory and pathologist – Clinical Pathology Laboratories, Austin, 
Texas – Dr. Mark Silberman. 
Duties: Explant pathology analysis and report. 
 
Data Safety Monitoring Board –  
Surgeons: Dr. Sidney Levitsky, Harvard University, Dr. Richard Engelman, 
University of Massachusetts 
Cardiologist: Dr. Karen Hamilton, University of Florida 
Statistician: Dr. Jay Herson, Johns Hopkins University 
 
Duties: Review of study progress, adjudication of adverse events, 
recommendations about study continuation or termination.  Meetings to be 
held at least annually by conferencing methods or in person. 
 
 
 
2.4 INVESTIGATIONAL PROCEDURES   
 
The sponsor will provide case report forms (CRFs) to each principal investigator for 
the purpose of recording patient data. Assessments will be obtained for the 
preoperative, operative/discharge period and postoperatively at three to six months 
and one year from the date of implant (Table 2.4.1 summarizes the required 
information at each visit).  

 
2010-01, REV H 
 
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Table 2.4.1 - Patient Progress and Data Record 
 
 
 
Interval of 
Follow-up  
 
Preoperation Operation Early/discharge 3-6 
Month 
1 Year 
Form/Data 
 
 
 
 
 
 
 
 
 
 
 
Preoperative Form CRF 1 
X 
 
 
 
 
Echocardiography CRF 2 
X 
 
X 
X 
X 
Echo Recordings 
X 
 
X 
X 
X 
Blood Sample to Lab 
O 
 
 
X 
X 
Implantation Data Card 
 
X 
 
 
 
Operative Form CRF 3 
 
X 
 
 
 
Early Follow-up CRF 4 
 
 
X 
 
 
Late Follow-up CRF 4 
 
 
 
X 
X 
Complication CRF 5 
 
O 
O 
O 
O 
Reoperative CRF 6 
 
O 
O 
O 
O 
Death Summary/ Autopsy 
 
O 
O 
O 
O 
Explant Summary 
 
O 
O 
O 
O 
 
 
 
 
 
 
 
X 
Required Data 
 
 
 
O 
Required only if needed 
 
 
 
 
Not 
applicable 
 
 
 

 
2010-01, REV H 
 
7 
 
 
 
All appropriate sections of the CRFs must be filled out accurately and completely. 
Echocardiography recordings are to be forwarded to the sponsor for eventual 
assessment by a core cardiologist.  All case report forms must be reviewed, signed 
and dated by the investigator(s).  The CRFs should be sent expeditiously to the 
sponsor, when completed, and be kept in the patient record notebooks.  Blood 
samples for hemolysis assessment are to be properly forwarded to the laboratory, per 
its protocol. 
 
To protect patient confidentiality, the sponsor will use the information from the 
CRF’s for statistical and device tracking purposes only and will treat medical records 
as confidential. For this reason, the sponsor is not routinely collecting patient names, 
but using patient initials for patient identification; thus better protecting patient 
confidentiality.  A representative of the U.S. Food & Drug Administration or other 
appropriate regulatory authority may look at, and perhaps copy, some of the medical 
records; these organizations also have rules for protection of patient privacy that they 
must follow. 
 
2.4.1. 
Preoperative Procedures 
 
 
 
 
The investigator will determine and document on CRFs whether each patient meets 
the selection criteria previously outlined before enrollment into the study.  He will 
also obtain informed consent for study participation from each patient prior to 
enrollment.  A copy of the informed consent form will be kept by the investigator in 
the patient’s study notebook.  Patients not meeting the selection criteria or not 
receiving informed consent should not be enrolled in the study. 
 
The investigator will determine and record on CRF1 each patient’s demographics and 
relevant medical history, i.e., New York Heart Association (NYHA) functional class, 
cardiac rhythm, preoperative conditions, and diagnosis for valve replacement, etc.  A 
preoperative echo/Doppler evaluation of the valve(s) being replaced is required 
according to the procedures of this study; a cardiac catheterization is not requested.  
 
Blood studies on each patient will include:  white blood cell count, red blood cell 
count, hemoglobin, hematocrit, serum lactate dehydrogenase (with fractionation by 
isoenzymes if above normal), plasma free hemoglobin, reticulocyte count, and 
haptoglobin.  This will be recorded preoperatively, if possible, and at both follow-up 
intervals.  The laboratory report including normal ranges will suffice as a CRF for 
these tests. 
 
Specific Instructions for  Form CRF1  
 
These instructions are made to assist the study coordinator in filling out the form. 
Complete all items on the form. If information is unavailable to answer any item, 
make a note on the form. When asked to specify a particular answer, use a short 
description.  On all check off lists, the space to be checked is either in front of, or 
below the answer. Please check any and all items that apply to the patient. 

 
2010-01, REV H 
 
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For patient study ID use patient initials. NYHA functional class uses the generally 
familiar nomenclature of that association.  For the purposes of this study the 
commonly used classes of IIa and IIb are not used, either subgroup is considered class 
II.  For infants and toddlers the Ross Scale functional classification can be substituted 
for NYHA classification anytime this data element is requested. 
 
Previous cardiovascular surgery, and for pediatric patients pediatric comorbidities, 
should be noted with a one or two word name of surgery and the date performed (page 
2 of CRF1).  Room is given for three prior procedures. Attach a separate explanation 
if more prior surgery was done. For coronary artery bypass surgery, please note the 
number of grafts by the following notation:  CABG x 2 = double graft; CABG x 3 = 
triple graft; and so on. 
 
If the patient has been maintained on any permanent, preoperative anticoagulant 
therapy, the most recent available preoperative INR should be measured and recorded. 
 
2.4.2  Operative Procedures 
 
The surgical technique employed is that developed and perfected by the principal 
investigator in his normal practice of cardiac surgery.  Operative details such as 
cardioplegia are not specified in the protocol.  
 
An echo/Doppler assessment of the study valve(s) is required on each patient just 
prior to discharge (CRF2).  The echocardiography tapes will also be provided to the 
sponsor, each echo exam on each patient will be recorded on a separate tape.   
 
The investigator will record on CRF3 information regarding the particular valve(s) 
implanted and other details concerning the surgery such as suture technique and any 
concomitant procedures.  The implantation data card contained in the valve package 
will be provided to the distributor within 24 hours of the surgery. 
 
 
Specific Instructions  for Form CRF3 
 
Use the patient study ID assigned on the preoperative form (CRF1) to identify the 
patient. Check any and all of the items that apply to this patient.  Where explanations 
are needed, print a brief description of the required data. 
 
Carefully record the valve position, size and serial number.  For concomitant 
procedures, there are spaces for these additional procedures.  Write in the name of the 
procedure done.  For coronary artery bypass grafting, also note the number of grafts 
(i.e., CABG x 2 = double graft, CABG x 3 = triple graft, and so on). 
 
Where requested, attach additional CRFs or reports. Also any appropriate 
intraoperative hemodynamic evaluation form, or complication form is required. 
 
2.4.3   Early Postoperative/Discharge Procedures 
 
The investigator will record the date of the patient’s discharge from the hospital and 
the date of the early follow-up examination on CRF4.  The discharge follow-up exam 
records the patient’s status at the time of discharge or at 30 days, whichever comes 

 
2010-01, REV H 
 
9 
first.  The patient’s NYHA and cardiac rhythm status and any complications will be 
noted along with the patient’s antithromboembolic therapy.  It is important to record 
the international normalized ratio (INR) at the time of the exam.  Wherever possible 
this value should be within the therapeutic range described below before a patient is 
discharged from the hospital. 
 
Mechanical heart valve recipients should be maintained continuously on anticoagulant 
therapy, except where contraindicated.  Postoperatively, the continuous warfarin 
(tradename Coumadin®) therapy shall maintain the following therapeutic levels of 
INR:  2.0 to 3.0 for aortic valves.  These procedures generally follow guidelines 
published by various medical societies. 
 
Preoperative echocardiograms on the dysfunctional valve being replaced, 
predischarge, 3-6 month and one year postoperative Doppler echocardiograms on the 
study valve are required for each patient.  At each postoperative assessment, the 
investigator will need to determine the patient’s availability for future follow-up.  If 
any patient needs to be seen at other than a regularly scheduled follow-up visit, the 
same follow-up information as required at regular times will be documented by the 
investigator on the follow-up form, and that follow-up will be indicated as an interim 
visit. 
 
2.4.4   Late Follow-up Reporting 
 
Late follow-up is required in the 3-6 month postoperative interval, and at 1-year 
(between 11 and 14 months postoperatively).  Follow-up must be in person; telephone 
or questionnaire follow-up is unacceptable.  A late follow-up form (CRF4) is due at 
each follow-up on each patient whether or not follow-up has occurred. 
 
Late follow-up information includes in all cases the patient ID, cardiac rhythm (from 
electrocardiogram or echocardiogram), NYHA classification, and anticoagulant 
therapy information, including INR.  Blood samples shall be drawn and forwarded to 
the local laboratory at each regularly scheduled late follow-up.  These samples are the 
same as the preoperative tests and are handled in the same manner.  Echocardiography 
studies are required at the 3-6 month and 1-year follow-up.  Those data should be 
included at that time, but should also be added when done optionally at any other 
follow-up.  For any new complication, a complication report (CRF5) must be 
completed and attached. All complications that have occurred between follow-up 
examinations must be reported on the appropriate form. 
 
2.4.5   Complication Reporting 
 
All complications should be recorded by the investigator on the proper complication 
form, CRF5. Start and stop dates and etiology should be noted.  The investigator will 
attempt to evaluate the relationship of all deaths, reoperations, explants, or 
cardiovascular complications to the study valve as presented in the AATS/STS 
guidelines(1) and will provide pertinent details of the event on the CRF.  Copies of 
autopsy report and/or death summary must be included where applicable. Every effort 
should be made to return any explanted valve(s) (at autopsy or reoperation) to the 

 
2010-01, REV H 
 
10
sponsor, see section 2.4.8.  Please complete CRF6. Return kits for explanted valves 
can be provided by the sponsor. 
 
The investigator will report any serious or unexpected complication occurring during 
the investigation to the monitor within 24 hours, followed by a written report in ten 
working days, after the investigator first learns of the event.  A serious or unexpected 
complication would include those complications not generally expected in a heart 
valve patient. 
 
Adverse events are defined by the United States FDA as complications, meaning: 
 
“Operative mortality, morbid events, and consequences of morbid events. 
Complications may or may not be device related.” 
 
According to the European EN 540, an adverse event is defined as: 
 
“Any undesirable clinical occurrence in a subject whether it is considered to be device 
related or not.” 
 
This study uses the term “complication” to mean any adverse event or adverse device 
effect (a device-related adverse event), which may be mild, moderate, or severe.  If as 
a result of a complication during a clinical investigation a subject has to be 
hospitalized, if hospitalization is unduly prolonged because of potential disability, if 
hospitalization is unduly prolonged because of potential danger to life, if a reoperative 
intervention has been necessary, or if the event is terminal, the complication is 
regarded as severe. 
 
The definitions which appear in the following sections will be used to report 
complications associated with the use of the On-X prosthesis. Complications will be 
recorded and dated when they are observed or estimated to have occurred and 
treatment(s) documented. An event will be recorded once unless there are multiple 
occurrences of that event. For example, a cerebrovascular accident (CVA) reported 
once with sequelae still present at subsequent follow-visits will not be reported again. 
If another CVA occurs that is unrelated to the initial episode, then it is reported as a 
separate incident. 
When determining whether a complication is valve related this study will use the definitions 
of the AATS/STS guidelines(1).  More specific guidance on these determinations is contained 
in the following discussions of the various types of complications. In any case, adequate 
documentation must be supplied to support the contention that a complication generally 
regarded as valve-related is not valve related. Information that pertains to reoperation, 
explant, and death must be recorded on the appropriate sections of CRF5 and/or 6. For death, 
the cause of death must be established, and an autopsy performed when possible.  An explant 
analysis must be conducted in all cases when a valve is explanted whether by reoperation or 
autopsy. Attach supporting hospital reports when appropriate. Following completion of the 
information, the investigator must review, date, and sign the CRF.  

 
2010-01, REV H 
 
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Specific Instructions for Completing CRF5. 
 
The complication form (CRF5) allows the identification of event type, and how each 
event was diagnosed and treated; what the outcome of the complication was; and 
what the patient’s status at the time of the event was.  Death from unrelated causes is 
also reported on CRF5. Details of any reoperation are given on a separate form 
(CRF6), which also asks for a description of any explant (from reoperation or 
autopsy).  A separate CRF5 should be completed for each independent complication. 
 
Study valve related reoperation is defined as any operation that repairs, alters or 
replaces a previously implanted study prosthesis, also included are operations that 
treat other valve related complications but do not involve surgery on this valve, i.e., 
surgery to resolve a hemorrhagic complication.  This category also includes incidental 
replacement of the prosthesis, e.g., the patient undergoes surgery for a different 
cardiovascular procedure and the surgeon decides to remove the study valve. 
Cardiovascular surgical procedures other than repair or replacement of the study valve 
will also be recorded on the CRF5.  
 
Death will be recorded as cardiac or not, and valve related or not.  Valve related 
deaths include deaths from the following causes: 
•  
thrombosis or thromboembolism; 
•  
endocarditis; 
•  
prosthetic valve dysfunction; 
•  
anticoagulant related hemorrhage; 
•  
hemolysis; and 
• 
congestive heart failure, where documentation of a cause other than the 
valve cannot be given; and sudden unexplained death without autopsy 
which can definitely assign other causes than the valve.  
 
Deaths caused by heart failure in patients with advanced myocardial disease and 
satisfactorily functioning prosthetic valves are not considered valve related. Any death 
that occurs within 30 days of reoperation for a valve related complication is 
considered valve related. 
 
Classification of each complication is described in the sections that follow. 
 
 
Thromboembolism                   
Thromboembolism is defined as any valve thromboembolus exclusive of infection. 
This includes any new focal or global neurological deficit (transient or permanent), 
myocardial infarction, prosthetic thrombosis, or peripheral arterial embolus. 

 
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A thromboembolic cerebrovascular accident (CVA) is an infarction of the central 
nervous system determined or suspected to be due to thromboembolism as diagnosed 
by imaging study with or without clinical symptoms. 
A transient neurological event is defined as an abrupt onset of a focal neurological 
dysfunction caused by brain, spinal cord or retinal ischemia without acute infarction 
lasting at least one minute and no longer than 72 hours. 
Intraoperative myocardial infarctions are not counted.  Postoperative myocardial 
infarction is also not counted unless the infarction is caused by coronary embolus 
detected by operation, autopsy or clinical imaging.  Emboli caused by non-thrombotic 
material (atherosclerosis, myxoma) are not counted. 
Thrombi that are secondary to another primary complication; i.e., endocarditis, are 
recorded but also noted to be a secondary event by stating so in their etiology. 
Excluded from the thromboembolism category are: 
• Events which occur intraoperatively or within 24 hours of surgery due to 
myocardial infarction or stroke. 
• Any peripheral arterial emboli proven to have originated from another 
cause, e.g., atrial myxoma. 
• Failure to awaken from the surgical procedure. 
• Pulmonary emboli. 
• Events due to proven ischemic disease of the extremities. 
However, if any of these complications occur, document the events anyway in the 
Complications Form. 
For any thromboembolic event it is important to determine the INR of the patient at 
the time of the event, if possible.  Every attempt should be made to do so. 
 
Thrombosis 
Thrombosis is any premortem thrombus adhering to or near the study valve that 
occludes part of the blood flow path or that affects valve function.  This is listed as  
its own category and should be confirmed by reoperation (explant) or autopsy. 
Thrombolytic therapy, other than that used to stabilize a patient prior to surgery, is not 
recommended as a treatment for thrombosed valves. In this study suspected 
thrombosed valves are to be replaced through reoperation, wherever possible.  
Clinical judgment can be used to diagnose the presence of thrombosis (lack of normal 
prosthetic valve sound, prolonged lowered blood pressure, loss of consciousness, 
cardiovascular shock) if the clinical diagnosis is accompanied by a confirming 
medical test (echocardiography, cineradiography or angiography). 
 
Bleeding Event       

 
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Bleeding Event is defined as any episode of internal or external bleeding in patients. 
Episodes immediately related to this surgery will be recorded as perioperative.  This 
also includes any episode of hemorrhagic tamponade. The INR at the time of 
hemorrhage should be determined, if possible. These events will be classified as 
major or minor, and are defined as follows. 
• Major:  An episode of internal or external bleeding that causes death, 
permanent injury, operation, hospitalization, or requires transfusion or 
pericardiocentesis. Examples include nosebleeds that require outpatient 
transfusion, cerebral bleeding that results in neurological damage and/or 
death, and gastrointestinal bleeding that requires hospitalization. 
• Minor:  All other episodes of internal or external loss of  blood. 
Examples include nosebleeds that do not require transfusion, hematomas 
due to trauma or surgery that do not require transfusion, and ocular 
hemorrhage. Bleeding or bruising from traumatic wounds are excluded, 
unless the bleeding goes uncontrolled enough to require intervention that 
would place the event in the major category. 
 
Prosthetic Valve Endocarditis       
Prosthetic valve endocarditis is defined as documented evidence of infection of the 
prosthesis based on histopathological evidence in a surgical or autopsy specimen 
and/or customary clinical criteria, including an appropriate combination of clinical 
signs (fever,  new/altered cardiac murmurs, splenomegaly, systemic emboli, 
immunopathological lesions) and possibly positive blood cultures as available. The 
organism(s) involved should be identified whenever possible. 
 
Prosthetic Valve Dysfunction        
Prosthetic valve dysfunction is defined as any change in valve performance which 
results from intrinsic or extrinsic abnormalities that cause stenosis or regurgitation. 
Prosthetic valve dysfunction can be classified as structural deterioration, nonstructural 
dysfunction, or paravalvular leak. 
a. 
Structural Valve Deterioration 
Structural valve deterioration is any change in function of the prosthesis which results 
from an intrinsic abnormality that causes stenosis or regurgitation. The diagnosis can 
be based on an examination of the explanted or damaged valve or clinical 
investigation. Examples include excessive wear, leaflet escape, leaflet fracture, 
housing crack, leaflet pitting, or sewing ring deterioration. Excluded from this 
category is structural deterioration which results from endocarditis, paravalvular leak, 
and thrombosis. 
b. 
Nonstructural Valve Dysfunction 
Nonstructural dysfunction of the valve is any change in function of the prosthesis that 
results in stenosis or regurgitation which is not intrinsic to the valve. Examples 

 
2010-01, REV H 
 
14
include patient-prosthesis mismatch, inappropriate positioning or sizing, leaflet 
entrapment by suture or pannus, paravalvular leak and hemolysis. The diagnosis 
should be based on examination of the damaged or explanted valve, or clinical 
investigation. Events to be excluded are those associated with endocarditis and 
thrombosis. 
c. 
Paravalvular Leak 
Any evidence of leakage of blood around the prosthesis between the sewing ring and 
native annulus. Diagnosis of paravalvular leak may be obtained from 
echocardiography; however, definitive diagnosis will be obtained at reoperation, 
explant, or autopsy. Indicate severity of the leak. 
Indicate if the event is secondary to another valve-related complication, e.g., 
endocarditis, hemolysis, thromboembolism, thrombosis. Such events will be 
classified as major (required surgical or percutaneous intervention) or minor (does not 
require surgical or percutaneous intervention). 
 
Hemolytic Anemia        
Hemolytic anemia will be recorded as a complication in all cases of hemolytic anemia 
that are attributable to the valve, based on usual clinical criteria, such as easy 
fatigability, dyspnea, faintness, pallor, rapid pulse, low blood pressure or other 
common signs of anemia, and which require intervention:  such as long-term iron 
supplement, transfusion, prosthesis replacement, etc.  Indicate if hemolytic anemia is 
primary or secondary to another valve related adverse event (e.g., paravalvular leak). 
Events that are not considered valve-related are those due to liver disease, myocardial 
infarction, or systemic infection, where these causes are confirmed by other clinical 
evidence. 
Hemolytic anemia that requires intervention will be considered to be clinically 
significant hemolytic anemia.  Hemolytic anemia that does not require intervention 
will be considered to be clinically insignificant hemolytic anemia and will be 
reported.  Hemolytic anemia should be distinguished from compensated hemolysis or 
compensated hemolytic state, where the hematocrit is stable and there is no anemia 
because increased red blood cell production is able to keep up with accelerated red 
blood cell destruction from hemolysis. 
For purposes of this clinical trial, hemolysis is defined from blood studies alone by 
the following inclusive criteria, but is not reported as a complication until associated 
with anemia that is treated medically or surgically (i.e. clinically significant hemolytic 
anemia).  Thus, hemolysis and clinically significant hemolytic anemia are analyzed 
separately. 
Ongoing hemolysis: 
• Serum lactate dehydrogenase greater than 200% of the upper normal limit; 
• Reticulocyte count of at least 4.0%; 

 
2010-01, REV H 
 
15
• Plasma free hemoglobin above upper limit of laboratory normal; 
• Reduction of 20% in haptoglobin below normal range; and 
• Untreated clinical sequelae (once treated this becomes hemolytic anemia). 
Hemolytic anemia by laboratory test additionally requires: 
• Hematocrit below laboratory normal range; 
• Hemoglobin below the laboratory normal range; 
 
Unanticipated Valve-Related Event       
It is unknown what kind of event would qualify, but in case any unknown valve-
related complication should arise that does not meet any other defined criterion, 
pleased record on the Complications Form.  Should this happen this event must be 
reported to the monitor immediately, since it is likely to create immediate regulatory 
reporting requirements.  An occurrence of an unknown negative effect is very serious 
and must not be left unreported for any length of time. 
 
Congestive Heart Failure        
Congestive heart failure will be considered valve related if the event is new and is not 
continued from a preoperative heart failure condition, and is caused by one of the 
following prosthesis-related events:  Anticoagulant-related hemorrhage, endocarditis, 
hemolysis, nonstructural dysfunction, paravalvular leak, structural deterioration, 
thromboembolism, thrombosis, or reoperation. 
The most common causes of non-valve related congestive heart failure are coronary 
artery disease, hypertension, valvular heart disease (due to a valve other than the study 
valve), cardiomyopathy, cor pulmonale, congenital heart disease, or unknown causes.  
When an event is considered not valve related the reasons for that decision must be 
recorded. 
 
Other Cardiovascular and Pulmonary Complications         
Other cardiovascular and pulmonary complications are defined as a complication or 
any new diagnosis that is not related to the prosthesis, but is important to subsequent 
morbidity and mortality of the patient, e.g., cardiomyopathy, aortic aneurysm, chronic 
obstructive pulmonary disease, pulmonary embolism. These events may be 
characterized by the following factors:  necessity for intervention, new or unduly 
prolonged hospitalization, or death.  Minor events of no importance to the patient’s 
valve related morbidity or mortality, such as acute upper respiratory infections, should 
not be reported. 
 
Other Non-Cardiovascular Complications          
Neurological, gastrointestinal, hepatic, renal, and other complications are defined as a 
complication or any new diagnosis that is not related to the prosthesis but is important 
to subsequent  morbidity and mortality of the patient, e.g., cerebrovascular accident, 

 
2010-01, REV H 
 
16
transient ischemic attack, ulcer bleeding, hepatic disease, coagulopathy, kidney 
failure, infection. These events may be characterized by the following factors:  
necessity for intervention, new or unduly prolonged hospitalization, or death.  Minor 
events of no importance to the patient’s valve related morbidity or mortality, such as 
acute intestinal virus infections, should not be reported. 
2.4.6  Echocardiography Procedures 
In addition to preoperative echoes, echocardiographic evaluation of the study 
prosthesis is required when the patient is stable during the early postoperative 
follow-up (prior to discharge or 30 days, whichever occurs first); at 3-6 months and at 
the 1-year follow-up (between 11 and 14 months). Regurgitation and stenosis 
information is required for all remaining heart valves as these results may impact the 
study valve.  
Preoperative echocardiography of the valves being replaced is required in this study.  
For preoperative echocardiographic data, the best available examination information 
will be used.  
Record only one patient echocardiography examination per recording. Attach the 
following information to each recording: 
• Patient study ID 
• Name of the institution and investigator 
• Date of the echocardiography examination 
The echocardiography protocol used will generally follow that developed by FDA 
guidelines or ISO standards (Appendix A contains summary of the protocol), 
however, to provide a uniform method whereby data collection will be common to all 
echocardiography centers only one method will be used to derive the echo study 
output data.  The derived data will conform to ISO standards.  Additionally, only 
directly measured data will be provided by the center, and all calculated data will be 
derived centrally by the core lab.  Regurgitation will be assessed by the investigator’s 
echocardiographer and reassessed by the study cardiologist to provide for consistency 
across the centers.   
Transthoracic echocardiographic examinations will follow a step-by-step progression 
of the following interrogation regions:  left parasternal, apical and periapical, right 
parasternal, subcostal, and suprasternal.  For each interrogation include 2D and M-
mode recording for structure, function and timing data, and color Doppler for flow 
pattern to guide the pulsed (PW) and continuous (CW) Doppler measurements.  It is 
understood that the right parasternal view is difficult to get in the immediate post-
operative period.  If needed, this view can be dropped from the early post-operative 
exam. 
 
Specific Instructions for Completing CRF2 

 
2010-01, REV H 
 
17
Provide the patient study ID and other basic information listed at the beginning of the 
form.  
Using the echocardiography report from your center, provide the anatomical data 
collected from 2D or M-mode studies.  Valve hemodynamics are to be gathered from 
the position giving the best signal.  If the position used is different from those listed in 
the progressions noted in the previous section, then note the position used for either 
pressure or regurgitation measurement. 
Provide the hemodynamic data requested on the form from the view that provides the 
best signal. Summarize the results of the echocardiography exam and forward the 
recording of the session to the monitor. 
For the purposes of this study regurgitation will be graded as none, trivial, 1+ = mild, 
2+ = moderate, 3+ = moderately severe, or 4+ = severe. 
 
Subaortic diameter measurement should be made from the trailing edge of the left 
septal echo to the leading edge of the anterior mitral leaflet echo.  If severe left 
ventricular hypertrophy or bowing of the anterior mitral leaflet exist, this measure 
should not be made and the space should be left blank on the CRF.  If in pediatric 
patients this dimension cannot be reliably measured as judged by the core 
echocardiographer, the nominal valve tissue annulus diameter (i.e. 17mm for the 
aortic valve) will be used for aortic orifice area calculations and the orifice area 
calculation by continuity equation will be skipped for the mitral valve. 
 
Diastolic filling period in this study is arbitrarily defined as the time from the onset of 
flow to when flow falls below 10 cm/sec.  This allows calculation of transmitral flow. 
 
2.4.7   Blood Studies for Hemolysis 
Preoperatively and at each scheduled late follow-up the study protocol calls for blood 
studies to determine the level of hemolysis in the patient.  The specific tests required 
are red cell count, white cell count, hemoglobin, hematocrit, plasma free hemoglobin, 
serum lactate dehydrogenase (SLDH), reticulocyte count, and serum haptoglobin. 
When SLDH is elevated above the upper end of normal, it is to be fractioned and 
quantified by its five isoenzymes. 
Blood tests must be processed according to local requirements.  Local laboratory 
normal ranges for all tests must be provided. 
2.4.8  Explants 
Whenever a valve reoperation occurs whether or not as a result of one of the 
complications described in Section 2.4.5 above complete and return CRF 6. 
Explants are requested at autopsy whenever practical.  Reoperative explants may also 
occur.  Return of explanted valves within the study is required. 
 

 
2010-01, REV H 
 
18
Specific explant analysis requirements are included in this plan. An explanted 
mechanical valve prosthesis refers to a study valve that has been removed from the 
patient at reoperation or autopsy. The recommended procedures have been developed 
to ensure accuracy, consistency and completeness of the analysis of explanted valves. 
This section outlines in detail the procedures for explanting, recording data and 
returning the explanted valves. 
 
 
Explanting the Valve 
 
 
When explanting a valve at reoperation or autopsy: 
1. Inspect the mechanical valve prosthesis prior to removal including the 
condition of the annulus for evidence of dysfunction such as thrombi, 
paravalvular leak, vegetations, pannus overgrowth. Culture of pertinent areas 
of the valve when appropriate is mandatory. 
2. Examine the lining of the chambers of the heart, both proximal and distal to 
the valve for possible jet lesions or endocardial fibrosis. 
3. Special attention should be paid to the possibility of extrinsic interference with 
the valve function, particularly by retained mitral valve leaflet tissue or 
sutures. 
4. If possible, photograph the mechanical valve prosthesis in situ. For valves 
obtained at autopsy, photograph both the inflow and outflow aspects. 
5. DO NOT rinse the valve. 
6. Request an explant kit from the sponsor and place the valve in the jar provided 
in the explant kit. 
7. If no explant kit is available, place the valve in either 1% glutaraldehyde 
solution or 10% buffered formalin until a kit is obtained.  
8. Record observations on CRF6 in the appropriate locations. 
 
 
Data and Shipping Requirements 
To send the data and return the valve to study sponsor: 
1) 
Attach a copy of the reoperative or autopsy report to the appropriate CRF6. 
2) 
Attach any in situ photographs to CRF6. 
3) 
Ship the valve as instructed in the explant kit, clearly marked as an explant, 
and inform the monitor by telephone or telefax of its shipment. 
4) 
Notify your clinical research monitor if the valve cannot be returned. 
5) 
If the valve is examined by a pathologist at the hospital where it was 
explanted, send that report to the monitor as well. 
Each returned heart valve received by the sponsor (or monitor) will be tracked and 
analysis information compiled and stored. Each explant will be analyzed by the 
independent study pathologist and his/her report will be provided to the investigator 
and monitor.  
  
2.4.9  Monitoring Procedures 
 
The monitor of the study shall be a professional staff member of the Clinical Studies 
Department of the sponsor or a consulting Clinical Research Organization.  
Monitoring of the clinical trial will be a continuous process to ensure that high quality 
data are obtained through compliance with the investigational plan. Case report forms 

 
2010-01, REV H 
 
19
or electronic data will be reviewed for accuracy, completeness, and conformity with 
requirements. Particular attention will be paid to blood damage studies, 
echocardiography and complication reporting. Frequent communication will be 
maintained with each clinical center to keep both the center and the sponsor informed 
and aware of the clinical trial progress. 
On-site monitoring of all study centers will occur at least annually to ensure continued 
acceptability of the center by assessing compliance to the investigational plan, 
adherence to data collection procedures, verification of the accuracy of submitted 
clinical data to the patient’s source documents, maintenance of clinical trial records, 
verification of informed consent, and verification of control of test articles. Reports of 
each center’s visits will be provided to the investigator and sponsor, and if necessary, 
appropriate corrective action will be taken to ensure compliance to the investigation 
plan. 
 
 
Preinvestigation Visit: 
Preinvestigation visits will be conducted by the sponsor or sponsor representative to 
review the investigational plan and discuss the report of previous investigations with 
the investigator and staff to assure that they: 
• Understand the investigation of the device and the requirements for its 
accountability. 
• Understand the nature of the investigational plan including record, reports and 
recruitment of patients. 
• Understand the requirement for an adequate, well controlled clinical trial. 
• Understand and accept the obligation to conduct the clinical investigation in 
accordance with applicable national regulations. 
• Understand and accept the obligation to obtain Ethics Committee or Institutional 
Review Board (IRB) review and approval before the clinical trial may be initiated, 
ensure continuing review of the trail by the Ethics Committee or IRB and keep the 
sponsor informed of any actions by the Ethics Committee or IRB that concern the 
clinical trial. 
• Have access to an adequate number of suitable patients to conduct the 
investigation. 
• Have adequate facilities and staffing to conduct the investigation. 
• Have sufficient time from other obligations to fulfill the responsibilities of the 
investigation. 
• Particular attention will be given complication reporting. 
 
 
Annual Center Monitoring Visit: 

 
2010-01, REV H 
 
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Following the preinvestigation visit, on-site monitoring visits will be conducted at 
least annually. 
On-site monitoring visits will assess the progress of the clinical trial and identify any 
concerns that result from device performance and review of the investigator’s clinical 
trial records, study management documents and patient consent forms. This review 
includes adherence to the investigational plan, Ethics Committee or IRB review of the 
clinical trial and its progress and maintenance of records and reports. 
To assure the integrity of the clinical trial data, individual patient records and other 
source documents are compared to reports from the investigator to determine that: 
• The information recorded in the case report forms and/or reports is accurate, 
complete and legible. 
• There are no omissions in the case report forms  of specific data (e.g., 
development of an intercurrent illness) 
• Missing follow-up visits are documented in the reports. 
• Patients failing to complete the clinical trial and the reason for failure are noted in 
the reports. 
• Informed consent has been documented. 
A record of the monitor’s findings will be maintained by the sponsor and investigator 
and will contain the following information: 
• The date(s) of the visit. 
• The name(s) of the monitor(s) who conducted the visit. 
• The name(s) and address of the investigator(s) and other center staff who were 
visited. 
• A statement of the findings, conclusions and any actions taken to correct 
deficiencies observed during the visit. 
Resolution of concerns and completion of assigned tasks will be documented by the 
monitor. 

 
2010-01, REV H 
 
21
2.4.10 Statistical Analyses 
Descriptive statistics will be calculated for all hemodynamic or hemolytic measures 
taken in the trial.  These will be compared by t-test or chi square test as appropriate to 
PMA results at equivalent time periods.  Demographic data will also be summarized 
using descriptive statistics and compared to PMA data where practical.  Limited 
sample size may limit the power of these comparisons.  Adverse event data will be 
evaluated both early and late in accordance with the AATS/STS guidelines on 
reporting valve studies.  Again, limited sample size may make comparisons to PMA 
data inappropriate and may make rate calculations unreliable.  However, calculations 
will be done and comparisons will be made to the PMA data; and an assessment of 
the power of these comparisons will be made. 
Screen failures will also be examined for potential biasing effects on the trial.  
Analysis will be dictated by the information available, if any. 
 
2.5 
CASE REPORT FORMS 
 
Example Case Report Forms are provided in Appendix B. A forms notebook for each 
patient will be provided by the sponsor. The notebook is designed to make keeping 
the records for the study more organized and to reduce the potential for mixing up 
data. Extra forms will be provided on request, or as needed. 
 
 
3.0  
DEVICE DESCRIPTION AND RISK ANALYSIS (17mm aortic and 23mm 
mitral) 
 
The On-X prosthesis is a bileaflet mechanical heart valve prosthesis.  The housing 
consists of On-X® pyrolytic carbon coating on a graphite substrate.  In other sizes the 
On-X valve has been in clinical use since 1996 and has been approved for commercial 
distribution in the US since 2001 (aortic valves) and 2002 (mitral valves). 
 
Two radiopaque leaflets are constrained by pivots in the housing walls.  The leaflets 
are On-X® pyrolytic carbon deposited on a graphite substrate which is mixed with 10 
weight % tungsten to allow for radiographic visualization.  In the closed position, the 
occluders rest at 40° within the valve orifice.  The valve design permits maximum 
leaflet opening angles of 90° from the plane of the housing, a position that follows 
flow.   The pivot design includes features that enhance and ensure closure response to 
reverse flow and opening response to forward flow. 
 
The rotatable sewing ring is made from polytetrafluoroethylene (PTFE) fabric 
attached to the valve housing by means of titanium retaining rings and 5-0 suture 
material.  The retaining rings positively attach the sewing ring to the valve housing by 
straddling a flange on the housing OD.  They also provide the means for radiographic 
visualization and identification.  There are no coatings or treatments on the fabric, 
although black orientation marks are included on the ring fabric.  The sewing rings 
are supra-annular and allow the tissue annulus to abut the pyrolytic carbon housing 

 
2010-01, REV H 
 
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directly, except in sizes larger than 25 mm, where the sewing rings become intra-
annular to allow the 25 mm housing (largest size made) to fit properly into larger 
tissue annuli. 
 
Valves are packaged on a valve holder /rotator with a separately packaged, removable 
handle to facilitate insertion and in situ orientation, and to provide protection during 
shipment and handling.  The package is designed for shipment protection as well as 
handling ease.  Valves are surgically clean and have been sterilized.  The instructions 
for use packaged with the valve describe the handling of the valve during surgery in 
detail.  Adhere to all instructions, warnings and precautions in the labeling.  Reusable 
valve sizers, rotators, handles and leaflet motion probes are provided non-sterile in a 
separate accessory kit.  These devices are designed to aid the proper selection and 
implantation of the On-X® valve, and should be cleaned and sterilized in accordance 
with their instructions prior to each use. 
 
The subjects for whom this device is intended are those seriously or critically ill 
patients whose prognosis without surgery for replacement or repair of the diseased 
natural or prosthetic valve is unacceptably poor in terms of survival, quality of  life, or 
both in the opinion of the attending physicians, based upon the patient’s disease 
history and physical and laboratory findings from standard cardiovascular diagnostic 
workups and who require a smaller than currently available valve size.  For this 
special subset of patients there are a number of widely accepted prosthetic heart 
valves in common use.  All prosthetic heart valve implants carry risks of serious 
complications, and/or death, related to thrombogenicity, hemodynamics and 
durability, among other causes.  Valvular reconstruction is also an option for this 
patient population, but not for all cases or conditions. 
 
The purpose of this investigation is to establish the hemodynamics, hemolytic 
potential and valve-related complication rates of a smaller On-X® prosthetic heart 
valve. The use of the valve is not expected, based on existing clinical and preclinical 
study results, to carry any increased risk over those of other mechanical heart valves.  
All diagnostic procedures included in the investigation are standard to the 
postoperative care of heart valve patients.  The normal diagnostic procedures used 
include blood tests from standard venipuncture draws, and physical examination, 
which are either non-invasive or minimally invasive with little or no risk to the 
patient.  Hazardous invasive techniques, such as cardiac catheterization, are not 
generally used, and are not expected to occur.  Reoperations will be conducted only 
when a complication creates a need for such action, and these events cause the same 
intervention for presently available prostheses. 
 
The use of modern cardiopulmonary bypass techniques; including cold cardioplegia, 
are expected to minimize operative risk consistent with the standards of practice for 
open heart surgery.  The use of properly balanced anticoagulant therapy along with 
explicit instructions to patients regarding the importance of their drug therapy, are 
expected to bring about an optimal balance between thrombotic and hemorrhagic 

 
2010-01, REV H 
 
23
complications.  Additional instructions to patients and their referring physicians are 
useful in minimizing complications, such as prosthetic endocarditis. 
 
Because the On-X® valve in a small size has demonstrated performance meeting or 
exceeding standards requirements in preclinical studies and in its clinical history in 
larger sizes has established reasonable safety and effectiveness, it is reasonable to 
continue to investigate this device to expand the size range available for human 
subjects under the controlled conditions described in the protocol, and within the 
patient population also described. 
4.0  
LABELING 
A copy of the device label is contained in Appendix E.  The labeling consists of the 
standard box label for the On-X valve used in production units with the 
investigational device label added.  The IFU in the box is also the standard production 
IFU with an insert sheet for the 17mm aortic valve and the investigational label 
added.  This size valve has been used internationally for over 15 years, but is not 
available in the US due to lack of hemodynamic or blood damage data. 
5.0 
REFERENCES 
 
1. Akins CW, Miller DC, Turina MI, et al.  Guidelines for reporting mortality and 
morbidity after cardiac valve interventions.  J Thorac Cardiovasc Surg 2008; 
135:732-8. 
2. ISO 5840, Standard for Cardiovascular Implants - Cardiac Valve Prostheses; 
2005. 

 
APPENDIX A 
 
COMPLETE ECHOCARDIOGRAPHY PROTOCOL 

 
2010-01, REV H 
 
2 
ON-X LIFE TECHNOLOGIES   
On-X® 17mm AORTIC/23mm MITRAL STUDY 
ECHOCARDIOGRAPHIC PROCEDURES 
 
1. 
General – interobserver and intraobserver variability 
1.1 
At each center, no more than two operators should perform studies. 
 
1.2 
At each center, one or at most two machines will be used for the study.  Velocity data 
will be calibrated using a string phantom or equivalent device. 
 
2. 
Exclusions 
2.1 
Poor echocardiographic window 
 
3. 
Recording studies 
3.1 
Unless impossible, every study will include the following standard imaging views: 
parasternal long-axis, parasternal short-axis, apical 4-chamber, apical 2-chamber, 
apical long-axis and subcostal.  Off-axis views as appropriate will also be necessary 
particularly to look for paraprosthetic regurgitation. 
 
3.2 
Doppler recordings will be made with a stand-alone continuous wave probe from 
apical views and for valves in the aortic position from additional right intercostals or 
suprasternal views.  Both orthograde waveforms and, if present, regurgitant jets will 
be recorded. 
 
3.3 
Subaortic pulsed recordings will be made in the apical 5-chamber view with the 
sample placed just below the level at which significant flow acceleration occurs. 
 
3.4 
Recordings should be made with the scale set to maximize signal size and with 
the maximum available sweep speed. 
 
3.5 
All images and waveforms used for calculating information will be recorded on 
electronic media. 
 
4. 
Data collected 
 
4.1 
Heart rate (BPM), height (cm) and weight (kg) are collected by the most convenient 
measure at the time of the echo exam.  Body surface area (BSA) is determined from 
the standard nomogram or standard equation below.  Geometric orifice area (GOA) is 
given by valve size in Table 8 of the On-X valve instructions for use.  BSA (m2) = 
(Wt(kg)0.425 X Ht(cm)0.725) X 0.007184. 
 

 
2010-01, REV H 
 
3 
4.2 
Diameter of the left ventricular outflow tract measured on three parasternal long-axis 
frames frozen in systole.  Diameters will be measured from the trailing edge of the left 
septal echo to the leading edge of the anterior mitral leaflet echo.  The maximum 
dimension will be taken.  If there is reverberation artifact from calcium, the 
leading edge to leading edge convention will be used; if this artifact is excessive, 
the measurement will not be made.  The best measurement (usually at the 
preoperative examination) will be assumed to remain constant throughout the 
study.  If measurement is not practical for pediatric patients the aortic tissue 
annulus diameter of the valve will be used, and the measurement will not be 
made for the mitral valve. 
 
4.3 
From the subaortic waveform (for prostheses in mitral or aortic positions):  peak 
velocity (v1), mean pressure (ΔP1) calculated by echo machine software, velocity 
integral (VTI1). 
 
4.4 
From the transaortic waveform (prostheses in the aortic position only):  peak velocity 
(v2), mean pressure (ΔP2) calculated by echo machine software, velocity integral 
(VTI2). 
 
4.5 
From the mitral waveform (prostheses in the mitral position only):  Pressure half-
time (PHT), mean pressure drop (ΔPm), peak instantaneous early velocity (vm), 
diastolic velocity integral (DVI). 
 
4.6 
Doppler measurements will be made over 3 cycles in sinus rhythm or over 5 to 
10 cycles in atrial fibrillation (depending on clinical judgment).  These will then 
be averaged. 
 
5. 
Calculations 
The data collected will be entered on a database and the following calculations will be 
performed at the central laboratory: 
 
5.1 
Effective area by the continuity equation (EOA) in the aortic position: 
EOA = CSA x VTI1 / VTI2 
 
 
 
[1] 
 
where CSA is left ventricular outflow cross-sectional area in cm2 calculated from the 
diameter assuming circular cross-section; VTI1 is subaortic velocity integral in cm 
and VTI2 is aortic velocity integral in cm. 
 
5.2 
Effective area by the continuity equation (MOA) in the mitral position: 
MOA =  CSA x VTI1 / DVI  
[2] 
 
where DVI is diastolic velocity integral in cm 
 

 
2010-01, REV H 
 
4 
5.3 
Effective area by the pressure half-time method (MOA1/2) in the mitral 
 
position: 
 
MOA1/2 = 220/PHT  
[3] 
 
5.4 
Peak pressure drop across the aortic valve: 
Peak ∆P = 4 (v2
2 – v1
2) 
 
 
 
[4] 
 
5.5 
Mean pressure difference across the aortic valve (per ISO requirement): 
Mean ∆P = ΔP2 – ΔP1 [5] (Per ISO 5840 – mean ΔP = aortic ΔP – subaortic ΔP) 
 
5.6 
Peak pressure drop across the mitral valve: 
 
Peak ΔP = 4vm
2  
[6] 
 
5.7 
Cardiac Output: 
 
CO = CSA x VTI1 x BPM  [7] 
 
5.8 
Indexed effective orifice areas (EOAI), and cardiac index (CI): 
 
EOAI = EOA/BSA  [8]; CI = CO/BSA  [9] 
 
5.9 
Performance Index (PI): 
 
PI = EOA/GOA  [10] 
 
 
 
 
 
6. 
Other analyses 
6.1 
For valves in the aortic position, mean and standard deviation values will be 
calculated for the following parameters:  peak transaortic velocity, mean transaortic 
velocity, mean pressure difference, peak pressure difference, effective orifice area, 
cardiac output and all indices. 
 
6.2 
For valves in the mitral position, mean and standard deviation values will be 
calculated for the following parameters:  peak transmitral velocity, peak transmitral 
pressure difference, mean transmitral pressure difference, effective orifice area by 
continuity equation, pressure half-time and effective orifice area by pressure half-
time, cardiac output and all indices. 
 
6.3 
The site and severity of aortic regurgitation and mitral regurgitation will be assessed. 
   
6.4 
The presence, site and size of any thrombus will be assessed. 
 

 
APPENDIX B 
 
CASE REPORT FORMS 

 
 
 
 
Institution: 
 
Investigator: 
 
ON-X LIFE TECHNOLOGIES 
On-X® 17mm Aortic/23mm Mitral Study 
Screening Log 
 
Page ___ of ___ 
 
2010-01, Rev H 
 
Patient 
Initials 
Screen Date 
Consent Date 
Drop-out 
Date 
Explanation of Timing and 
Cause 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
Institution: 
 
Investigator: 
 
ON-X LIFE TECHNOLOGIES 
On-X® 17mm Aortic/23mm Mitral Study 
CRF 1  
Preoperative Data 
 
Patient Initials  __________ 
 
2010-01, Rev H 
 
 
Visit Date (m/d/y):  ______/______/_______   
 
Date of Birth (m/d/y):  ______/_______/______                Sex:          Male          Female  
 
1.  Patient has met Inclusion/Exclusion criteria.      Yes        No   (If No, attach explanation) 
 
2.  Informed Consent has been given.                      Yes        No   (If No, follow notification procedure.) 
 
 
Date (m/d/y):  ______/______/______  (Keep signed Informed Consent in patient study file.) 
 
3.  NYHA Functional Class:              I                 II                   III                 IV              Unknown  
 
4.  Cardiac Rhythm: 
Sinus            Atrial Fibrillation 
                                           Paced           Other, specify: _________________________________________ 
 
5.  Disease Etiology:         Rheumatic 
   Calcific                           Pros. Valve Dysfunction 
 
 
 
             Congenital 
   Endocarditis                   Degenerative/Myxomatous 
 
 
 
             Other, specify:  ______________________________________________________ 
 
6.  Valvular Lesions: 
 
 
 
Mitral 
 
  Aortic 
 
 
Stenosis 
 
 
Regurgitation 
 
 
Mixed 
 
 
Other, specify:  ______________________ 
 
7.  Previous cardiac surgery:        Yes           No          ____________________________________________        
      or pediatric comorbidity:   (If yes, specify) 
                                                                                     ____________________________________________ 
 
                                                                                     ____________________________________________ 
                                                                                       
        
8.  Pre-operative Anticoagulation         Yes        No 
 
      Heparin         Warfarin/Coumadin           Clopidogrel              Aspirin            Indandione derivatives 
 
INR:  ____________  INR Target Range:______________  Date (m/d/y): ___________________ 
 
 
Investigator Signature:  _______________________________________  Date (m/d/y):_____/_____/_____ 

 
 
 
 
Institution: 
 
Investigator: 
 
ON-X LIFE TECHNOLOGIES 
On-X® 17mm Aortic/23mm Mitral Study 
CRF 2 (p1 of 2) 
Echocardiographic Data 
 
Patient Initials  __________ 
 
2010-01, Rev H 
 
 
 
1. 
ECHO DATE (m/d/y):  __________/__________/__________ 
 
2. 
VALVE  Position _____________,  Size _______ 
    Serial Number _____________ 
 
 
3. 
PHYSICAL ASSESSMENT: 
________________________________________ bpm  heart rate 
 
_______________________________________ cm  height 
 
________________________________________ kg  weight 
 
________________________________________ m2  BSA 
 
 
4. 
CARDIAC RHYTHM:                 Normal sinus 
 
                                                      Atrial fibrillation 
 
 
                                                      Atrial flutter 
 
 
                                                      Heart block:  degree  __________________________________________________ 
 
                                                      Paced 
 
 
                                                      Other:  _____________________________________________________________ 
 
5. 
IMAGING:      ________________________________________ cm     LVOT diameter systole 
 
 
 
6. 
SUBAORTIC WAVEFORM: 
________________________________________ m/s  Peak velocity 
 
________________________________________ mmHg  Mean gradient 
 
________________________________________ cm  Velocity time integral 
 
 
7. 
TRANSAORTIC  WAVEFORM (FOR AVR):    _________________________________ m/s          Peak velocity 
 
 
 
                                                                                  _________________________________ mmHg    Mean gradient 
 
 
        _________________________________ cm          Velocity time integral 
 
 
     
 
 
(continues to next page) 
 
 

 
 
 
 
 
Institution: 
 
Investigator: 
 
ON-X LIFE TECHNOLOGIES 
On-X® 17mm Aortic/23mm Mitral Study 
CRF 2 (p2 of 2) 
Echocardiographic Data 
 
Patient Initials  __________ 
 
2010-01, Rev H 
 
 
Date of Echo (m/d/y) __________________________ 
 
8. 
TRANSMITRAL WAVEFORM (FOR MVR):    _________________________________ m/s          Peak velocity 
 
 
 
       _________________________________ mmHg    Mean gradient 
 
 
       _________________________________ cm          Velocity time integral 
 
 
       _________________________________ ms          Pressure half-time 
 
9.         REGURGITATION:                No                          Yes, please complete amount and location below:   
 
 
 
  
Location:               Through  
         Paravalvular               Uncertain 
 
      
                                                     Amount:           
 
None                           
 
 
 
 
 
                                                                                    +1 Mild/Trivial 
 
 
 
 
 
                                                                                    +2 Moderate  
 
 
 
                                                                                    +3 Moderately severe 
 
 
                                                                                  
            +4 Severe 
 
 
 
 
10.           LEFT VENTRICULAR FUNCTION:               Normal (EF>50%) 
 
                   Mild impairment (EF40-50%) 
 
                            
                   Moderate impairment (EF30-<40%) 
 
                   Severe impairment (EF<30%) 
 
 
11. 
VALVE THROMBUS: ________ No _________ Yes.  If yes, specify location and amount: ____________________________ 
 
     
12. 
OTHER ABNORMALITIES:  Describe:  ____________________________________________________________________ 
 
 
 
 
Investigator’s Signature:  _______________________________________      Date (m/d/y):____/_____/_____ 
 

 
 
 
 
Institution: 
 
Investigator: 
 
ON-X LIFE TECHNOLOGIES 
On-X® 17mm Aortic/23mm Mitral Study 
CRF 3 
Operative Data 
 
Patient Initials  __________ 
 
2010-01, Rev H 
 
 
 
Surgery Date (m/d/y):  _____/_____/_____   Surgeon:_________________________Emergency:    Yes    No 
 
Valve Information:    Type ____________    Size:  ______    Serial #:   _____________________ 
 
Concomitant          CAB                                                                   Aneurysm         Aortic                Abdominal 
Cardiovascular                                                                                                           Ventricular       Arch 
Procedures:            Valve         A        M        T        P 
                                                                                                           Other, specify:________________________ 
                                ASD                                                                    ____________________________________ 
 
                                VSD                                                                     None 
 
Suture                            Interrupted                Pledgeted                Everting Mattress               Noneverting 
Technique: 
                                      Continuous               Other, specify: ___________________________________________________  
 
Crossclamp time:  _______________Minutes 
 
Cardioplegia: 
  
      Cold              Warm                Both                  
 
      Antegrade               Retrograde           Both 
 
Intraoperative Drugs: 
 
 
Heparin       Yes        No 
 
 
 
Intraoperative Adverse Events:        Yes           No     (If Yes, complete below.) 
Prolonged Hypotension           Yes        No                         Difficulty Restarting Rhythm             Yes        No 
Excessive Bleeding                  Yes        No                        Difficulty Weaning from Bypass        Yes        No 
Cardiac Tamponade                 Yes        No                        Study Valve Explanted                        Yes        No 
Cardiac Arrest                          Yes        No                        Death                                                  Yes        No 
Other                                        Yes         No      
Other, if Yes, explain:___________________________________________ 
Valve Orientation:  Check the most accurate valve orientation description below based upon the direction of the valve axis. 
Aortic:     LC/RC Commissure      RC/NC Commissure      NC/LC Commissure       Other, describe:__________ 
Mitral:     Anatomical       Anti-anatomical          Other, describe: __________________________________ 
 
Investigator Signature:  _____________________________________  Date (m/d/y): _____/_____/______  

 
 
 
 
Institution: 
 
Investigator: 
 
ON-X LIFE TECHNOLOGIES 
On-X® 17mm Aortic/23mm Mitral Study 
CRF 4 
Follow Up 
 
Patient Initials  _________ 
 
2010-01, Rev H 
 
 
Visit Date (m/d/y)  ______/______/______  
          PostOperative/Discharge 
 
 
 
 
 
 
 
          Early (3 to 6 months) 
 
 
 
 
 
 
 
          1-Year (11 to 14 months) 
 
 
 
 
 
 
 
          Off Schedule 
 
 
Patient Status                          Missed Follow Up Visit.  Reason, ________________________________________ 
(If follow up                            Lost to Follow Up: 
Off Schedule)                               Efforts to Contact and Results:_______________________________________ 
                                                 Adverse Event    (Complete Complications Form CRF 5) 
 
 
Type of Examination:       Office/Outpatient        Hospital        Telephone         Other ________________________ 
 
 
 
NYHA Class:                 I                II                   III                  IV                 Unknown 
      
 
Cardiac Rhythm:                          Sinus                                  Regular  
                                                     Paced                                  Irregular  
                                                     Atrial Fibrillation               Other, specify:______________________________ 
 
 
Anticoagulant                               None                                  Warfarin/Coumadin 
Therapy: 
                                                     Clopidogrel                        Heparin 
 
                                                     Aspirin                                Other ______________________________________ 
 
INR  _________________    Blood Collection Date (m/d/y): ______/______/______ (closest to date of visit) 
 
 
New Complications:  (Since last follow up)              Yes              No       (Complete complication form, CRF 5) 
   
 
Echo Completed (m/d/y)_______________ Attach CRF 2 and send echo, applicable at discharge, 3-6 months 
and 1 yr follow-up. 
 
 
Investigator Signature:  _____________________________________ Date (m/d/y):  ______/______/_______ 
 

 
 
 
Institution: 
 
Investigator: 
 
ON-X LIFE TECHNOLOGIES 
On-X® 17mm Aortic/23mm Mitral Study 
CRF 5 
Complications 1 of 2 
 
Patient Initials  _________ 
 
2010-01, Rev H 
 
 
 
Start Date (m/d/y):  ______/______/________        Stop Date (m/d/y):  ______/______/______ or         Ongoing 
 
Duration:  _____________            Weeks              Days              Hours            Minutes 
 
Etiology: 
____________________________________________________________________________________  
 
 
 
Complication Type (complete 1 form for each event)  
 
Complication number:  ________ 
 
1.           Thromboembolism         Neurologic:      TIA            Peripheral:       Major        Cardiac: MI          
 
                                                                              CVA                                   Minor 
 
                                                                              Fatal 
 
2 
Valve Thrombosis 
 
3. 
Bleeding Event  
 
            Major            Minor 
                     Cerebral            Cardiac         Ocular              GI              Nosebleed          Hematoma           Other 
 
       Anticoagulant related  
Antiplatelet related 
         Not drug related 
 
4. 
Prosthetic Endocarditis (Organism:  _______________________) 
 
Risk Factor:             Dental Work               IV Drug Use               Recent Infection                Other 
 
5.           Prosthetic Valve Dysfunction 
 
                         Nonstructural                        (Type: _________________________________) 
                         Structural                              (Type: _________________________________) 
                         Paravalvular Leak                (       Minor                   Major) 
 
6.           Hemolytic Anemia (conduct blood tests)        Primary        Secondary to: _______________________ 
 
Clinically significant 
Insignificant 
 
7.           Congestive Heart Failure                            Valve Related                     Not Valve Related 
 
8.           Reoperation                                                 Repair                     Explant 
 
9.           Other Valve Related                                    Explain: ________________________________________ 
 
10.         Death  -  Primary Cause:           Valve related           Other cardiac             Other             Unknown 
(continues next page……………..) 
 

 
 
 
Institution: 
 
Investigator: 
 
ON-X LIFE TECHNOLOGIES 
On-X® 17mm Aortic/23mm Mitral Study 
CRF 5 
Complications 2 of 2 
 
Patient Initials __________ 
 
2010-01, Rev H 
 
 
Complication number: _____________ 
 
Treatment:           None            Medication           Hospitalization               Surgery (Complete CRF6) 
 
Patient Condition at Time of Event 
 
       Cardiac Rhythm                Sinus                        Paced                   Atrial Fibrillation 
 
                                                 Other 
 
NYHA Class              I                     II                  III                  IV                 Unknown 
 
Anticoagulant Therapy             Warfarin              Clopidogrel                  Heparin 
 
       INR:  ___________            Aspirin                 None                           Other ____________________________ 
 
 
Outcome: 
 
                     Event Fully Resolved 
 
                     Permanent Impairment (Specify: __________________________________________) 
 
                     Event Ongoing 
 
                     Death Date (d/m/y):  ______/______/______ 
 
                              Autopsy                     Yes               No 
 
                              Explant                      Yes               No        (If yes, complete CRF-6) 
 
 
Relationship to Device: 
 
               Valve Related:                  Yes                       No 
 
 
 
Investigator Signature:  ____________________________________ Date (m/d/y):  ______/______/________ 

 
 
 
 
Institution: 
 
Investigator: 
 
ON-X LIFE TECHNOLOGIES 
On-X® 17mm Aortic/23mm Mitral Study 
CRF 6 
Reoperative Data 
 
Patient Initials  __________ 
 
2010-01, Rev H 
 
 
Reoperative Procedure:      Procedure Date (m/d/y):  ______/______/______ 
 
 
                                                                                        Replacement Valve Mfg: ________________________ 
      Study Valve Replacement                          Aortic     Size: ___________mm  Type: ____________________ 
           (complete Explant data below)             Mitral      Size: ___________mm  Type: ____________________ 
 
 
                                                            
     Study Valve Repair  Specify: ____________________________________________ 
 
 
     CABG 
 
     Pacer Implantation 
 
     Aneurysm Repair 
                                     
                                                Replacement             Procedure: _______________________________________ 
     Non Study Valve 
                                                Repair                       Replacement Valve Mfg: ___________________________ 
 
                                                                                 Size: ___________mm  Type:________________________ 
 
 
Explant Condition:              Reop             Autopsy              Explant Date (m/d/y):  ______/______/______ 
(check all that apply) 
 
     Pannus Overgrowth 
     PVL 
     Thrombus 
     Vegetation            Organism:   ______________________________________________________________ 
     Other                     Specify:  ________________________________________________________________ 
 
 
Valves Returned:                Yes      Date Returned (m/d/y):  ______/______/______ 
 
                                             No      If No, Explain, ________________________________________________ 
 
 
Investigator Signature: ____________________________________  Date (m/d/y):  ______/______/________ 

 
 
 
 
APPENDIX C 
 
Example Informed Consent 

 
 
On-X® Prosthetic Heart Valve Size 17mm Aortic Clinical Investigation 
Patient Informed Consent/Assent Form 
 
Statement of Research 
 
You are being invited to participate in a clinical trial (research study) as described below. 
 
Please Read the following explanation before agreeing to participate in this study which will 
involve the On- X Prosthetic Heart Valve size 17mm aortic. 
 
Information about the Research 
 
The On-X® mechanical heart valve consists of an On-X® pyrolytic carbon housing and two 
leaflets with a titanium alloy ring around the housing. There is a sewing ring made of knitted 
plastic cloth (polytetrafluoroethylene) attached to the housing with two titanium rings and 
suture material. I understand these materials have a long history of use in cardiac valves.  The 
larger sizes of this valve have also been available for patients for more than 15 years. 
 
The On-X® heart valve, (the Prosthesis), is intended for treatment of patients who have been 
diagnosed with disease of a heart valve, and require replacement of their natural aortic valve, 
or previously implanted mechanical or tissue aortic valve. 
 
The purpose of this study is to show that the smaller size Prosthesis is safe and effective, and 
will perform in a manner comparable to the larger size On-X heart valves.  Your surgeon has 
determined that you will likely require the 17mm aortic valve if your aortic valve is being 
replaced.  If in surgery your surgeon finds you do not need this size valve, a different valve 
will be used and you will be told after surgery. 
 
The smaller size of the On-X Prosthesis is an investigational device, meaning that 
government regulatory authorities require clinical studies to establish the safety and 
effectiveness of this size heart valve, and that the device safety and effectiveness has not been 
established to allow commercial marketing for these sizes. This clinical study will involve 
approximately 15 patients from up to 40 selected sites from both within and outside the 
United States. All patients will follow the same procedures and follow-up schedule. When 
the information has been collected, it will be submitted to the appropriate regulatory 
authorities for possible approval to sell this size of the valve without further study. 
 
Patients who have valvular heart disease, are of the proper body size and require replacement 
of their heart valve are being invited to participate in this study. Your treatment will be 
similar to that provided to patients who have their heart valves replaced with the larger size 
On-X prosthetic heart valves. 
 
Before surgery, you will have routine diagnostic tests to assess the status of your heart valves. 
You will then have surgery with implantation of the Prosthesis. Your progress will be closely 

 
 
monitored and recorded at the following times: discharge (or within 30 days following 
surgery), three to six months after surgery, and 11 to 14 months following surgery.  Total 
duration of the study is expected to be 3 years.   
 
Laboratory blood samples will be drawn and other procedures and diagnostic tests (history 
and physical examination and echocardiography – a diagnostic machine that creates images 
of your heart with sound waves) will be done according to the requirements of the protocol 
during the appropriate follow-up visits. The Prosthesis tests will allow your doctor to assess 
the status and function of your heart and the Prosthesis. In addition, you will need life-long 
anticoagulant medication therapy which will require frequent laboratory blood tests.  Long-
term baby aspirin therapy (unless you have a medical condition that does not allow it) is also 
recommended.  The understanding of the use of these medications is important to your 
overall care. If the Prosthesis is explanted for some reason, it must be returned to the study 
sponsor, as a requirement of the study protocol.  Also, autopsies are requested should death 
occur during the study period to retrieve the prosthesis for evaluation. 
 
Risks and Discomforts 
 
Certain risks are associated with any surgical procedure. General surgical risks include 
anesthesia complications, drug reactions, and infection.  General risks of heart surgery 
include disturbances of the heart beat, chest pain, heart attack, and potential damage to heart 
structures that are not directly part of the surgery, that is, other valves and blood vessels.   
The primary risk associated with the Prosthesis is similar to that of all commercially available 
heart valves, that is, failure to restore function.  Specifically, this might involve breakage of 
the valve, blood leak around the valve, clotting on or around the valve which can move from 
the valve as well and cause injury – including stroke – from blockage of blood vessels, tissue 
growth on the valve could interfere with its function, blood damage which may lead to 
anemia or infection of the valve.  Use of blood thinners as necessary with mechanical valves 
carries the risk of excessive bleeding. As a heart valve patient you are also subject to the 
continuous risk of heart failure.  As with any other prosthetic valve, the complications that 
may occur with the Prosthesis can result in minor to severe consequences, including 
permanent disability, reoperation, explants of the valve or death.  
 
Foreseeable risks and discomforts will be minimized by thorough preoperative evaluation and 
close intraoperative and postoperative monitoring of your condition.   There may be risks or 
discomforts that are not yet known. 
 

 
 
Benefits 
 
Expected benefits from use of the Prosthesis are similar to those associated with 
commercially available heart valves with two moving flaps (bileaflet valves). The primary 
benefit is restoration of heart function by replacement of the diseased heart valve.  Another 
benefit will be that your progress and health status will be carefully monitored.  Any 
complication that might arise may be detected and treated (if necessary) at an early stage, 
decreasing the potential for more serious problems.  Also, knowledge that is gained by your 
participation may be of potential benefit to other patients. 
 
Alternative Methods of Treatment 
 
Alternatives to heart valve replacement with the Prosthesis include replacement of your aortic 
valve with a different mechanical or tissue heart valve; or repair of your native heart valve. 
Another alternative is that you may decide not to undergo any surgical treatment, and remain 
cared for with medications. 
 
Confidentiality 
 
Confidentiality of your medical records will be maintained at all times by those associated 
with this research study. Regulatory authorities (those responsible for the well-being of 
patients involved in research studies) and the sponsor (On-X Life Technologies, Inc.) and 
monitor of the study may inspect and perhaps copy the medical research records, if necessary, 
to ensure the validity of the information. Knowledge that is gained from the study may be 
published in scientific journals; however, no patient will be identified. 
 
A description of this clinical trial will be available on www.clinicaltrials.gov as required by 
U.S. Law. This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results. You can search this Web site at any time.  
 
Research Related Injuries 
 
If physical injury occurs due to involvement in the research, medical treatment will be 
available, but you (or your insurance company) should be responsible for payment for the 
cost of treatment. Compensation for lost wages and/or direct or indirect losses will not be 
available. Further information about research-related injuries is available from the hospital 
(telephone: ________-_________-__________). 
 
Your participation in this study does not waive any legal rights or release the hospital or its 
agents from liability for negligence. 
 

 
 
Questions about the Research 
 
Nothing in this document is intended to limit the authority of the doctor to provide 
emergency medical care to the extent that the doctor is permitted to do so under applicable 
local laws. 
 
If you have questions about the research or develop a study-related problem, you should 
contact Dr. _____________________________________________________ at the 
following telephone number: __________- ___________ - ______________. During non-
business hours, you should contact the on-call doctor at _________________ - 
____________ - _____________. 
 
If you have any questions about your rights as a research subject, you should contact the 
Ethics Committee Chairperson (Name): ____________________________________  at 
_________ - __________ - __________. 
 
Voluntary Participation 
 
Your participation in this research study is voluntary. Your refusal to participate will not 
jeopardize your future treatment or benefits at (Name of Hospital or Institution). _______ 
________________________________________________________________. 
 
You are free to discontinue participation for any reason in this study at any time without fear 
of penalty or loss of medical care.   Your doctor may withdraw you from the study for just 
cause without your permission. 
 
Progress of the Study 
 
As the study progresses and information is collected, your doctor will inform you of any new 
and significant findings related to the Prosthesis or the procedures associated with its use 
which may affect your willingness to continue in the study. 
 
Costs 
 
There will be no additional cost to you beyond the usual customary costs associated with 
heart valve replacement. However, neither On-X Life Technologies, Inc. nor (Name of 
Hospital or Institution) is responsible for compensation in the event of any physical injury 
that might occur as a result of your participation in this study. Information (tests, physical 
examination, x-rays, etc.) that is gathered purely for the purposes of this research study (that 
is, not part of the usual medical intervention for heart valve replacement) will be provided to 
you free of charge.  
 
 
 

 
 
Signatures 
 
You are making a decision whether or not to participate in this study.  Your signature 
indicates that you have read the information provided, have discussed this study with your 
doctor and his or her staff, and have decided to take part. Again, you may withdraw from the 
study at any time, or choose not to participate without any prejudice to you. You will receive 
a copy of this form for your personal records. 
 
Assent 
 
____________ 
 
 
 
____________________________________ 
Date 
 
 
 
 
 
Signature of minor patient, if applicable 
 
Assent waived 
 
____________ 
 
 
 
____________________________________ 
Date 
 
 
 
 
 
Investigator Signature 
 
Consent 
 
____________                                                 ___________________________________ 
Date                                                                  Patient or Legal Representative Signature 
 
Reason, if patient or legal representative did not sign: 
___________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________ 
 
 
______________                                                ___________________________________ 
Date                                                                                       Witness Signature 
 
I have fully explained this research study to the participant, and in my opinion, and his/hers, 
there was sufficient information regarding the risks and benefits to make an informed 
decision. I will inform the participant in a timely manner of any changes in the procedure or 
the risks and benefits if any occur. 
 
 
_________________                          __________________________________________ 
Date                                                                             Investigator Signature 

 
 
APPENDIX D 
 
Investigators Agreement 
 

 
 
INVESTIGATOR AGREEMENT FOR ON-X® PROSTHETIC HEART VALVE SIZE 
17MM AORTIC AND 23MM MITRAL CLINICAL INVESTIGATION 
 
I wish to participate in the supplemental clinical investigation of the On-X ® Prosthetic Heart 
Valve, Aortic and Mitral Models. I understand that this is a new prosthesis which is 
manufactured by ON-X LIFE TECHNOLOGIES and is planned for testing in a clinical trial. 
 
I am familiar with the intent of the investigation of this product, including the objective of the 
proposed clinical trial and the proposed trial procedures. I believe that, because of my 
training and experience and available patient population, I am qualified to investigate the 
product performance under the proposed Clinical Investigation Plan. I agree to conduct the 
clinical investigation under the purview of an appropriate Institutional Review Board (IRB) 
or Ethics Committee. 
 
I specifically, and further, agree that: 
 
1. I will conduct the clinical investigation and explant procedure in accordance with 
the Investigator Agreement, the Clinical Investigation Plan, any applicable 
regulations and any condition of approval imposed by any hospital or other 
reviewing authority. I will obtain all preoperative and operative data and complete 
follow-up data for each valve implant, as defined in the Clinical Investigation 
Plan. 
2. All use of the product involving human subjects will be under my direct 
supervision. I will not release the prosthesis or its components to anyone other 
than another physician responsible to me without written consent from ON-X 
LIFE TECHNOLOGIES. 
3. Information concerning the product and the study must be provided to each patient 
participating in this clinical investigation. Written informed consent must be 
obtained from each patient who participates in this clinical investigation. 
4. All information which I hereafter obtain from ON-X LIFE TECHNOLOGIES or 
any other person acting on behalf of ON-X LIFE TECHNOLOGIES about or 
relating to the prosthesis, including its components, which is the subject of this 
study and all information which I have or will obtain under or concerning this 
study is considered by ON-X LIFE TECHNOLOGIES to be proprietary and 
confidential to ON-X LIFE TECHNOLOGIES. I will maintain all such 
information in confidence and will not use such confidential information, or 
release, reveal or disclose such confidential information to anyone without the 
written consent of ON-X LIFE TECHNOLOGIES or prior public disclosure by 
ON-X LIFE TECHNOLOGIES.  I will also assure that any and all co-
investigators listed here and reporting to me will maintain confidentiality as 
described above. 
5. I will notify ON-X LIFE TECHNOLOGIES, in writing, when approval for this 
investigational study is obtained from the Institutional Review Board (IRB) or 
Ethics Committee. 

 
 
6. I have never participated in an investigational study which has been terminated for 
reasons of noncompliance. 
7. Additional investigators (including echocardiologist) participating in this study 
and reporting to me are: 
 
_______________________           ______________________________________ 
Name (Surgeon)                                                                     Address 
 
_______________________           ______________________________________ 
Name (Surgeon)                                                                    Address                                                            
 
_______________________           ______________________________________ 
Name (Surgeon)                                                                     Address 
 
_______________________           ______________________________________ 
Name (Surgeon)                                                                     Address 
 
_______________________          ______________________________________ 
Name (Surgeon)                                                                     Address 
 
_______________________           ______________________________________ 
Name (Surgeon)                                                                     Address 
 
_______________________           ______________________________________ 
Name (Surgeon)                                                                     Address 
 
8. The study coordinator currently participating in the study under my direct 
supervision is: 
 
       ______________________        _______________________________________ 
       Name                                                                                   Address 
 
________________________________________ ___________________________     
Signature of Investigator 
 
 
 
 
Type or Print Name 
________________________________________ ___________________________ 
Institution 
 
 
 
 
 
 
Address 
________________________________________ ___________________________ 
City/State/Country 
 
 
 
 
Telephone 
________________________________________ ___________________________ 
FAX  
 
 
 
 
 
Date 

 
 
APPENDIX E 
 
LABELING 
 

 
 
APPENDIX F 
 
INVESTIGATOR LIST 
 
The following principal investigators have agreed to participate in this clinical investigation 
and the respective committees have reviewed and approved this investigational plan before 
commencement. 
 
Active Sites 
STUDY 
ID* 
CENTER 
INVESTIGATOR and ADDRESS 
005 
Mayaguez Medical 
Center 
Raul Garcia-Rinaldi 
Western Cardiovascular Surgery 
Mayaguez Medical Center 
P.O. Box 6684 Marina Station 
Mayaguez, PR  00681-6684 
006 
Maine Medical Center 
Reed Quinn 
Maine Medical Center 
Department of Surgery 
22 Bramhall Street 
Portland, ME  04102-3175 
007 
UT Southwestern 
Medical Center 
Timothy Pirolli 
UT Southwestern Medical Center 
Children’s Medical Center 
1935 Medical District Drive – MC B3.10 
Dallas, TX  75235 
008 
University of Oklahoma 
Harold Burkhart 
University of Oklahoma Children’s Hospital 
Section of Thoracic & Cardiovascular Surgery 
920 Stanton L. Young Blvd., WP-2230 
Oklahoma City, OK  73104 
009 
Children’s Heart Center 
of Nevada 
Michael Ciccolo 
Children’s Heart Center of Nevada 
3006 S. Maryland Pkwy., Suite 690 
Las Vegas, NV 89109 
010 
Cincinnati Children’s 
Hospital 
David Luís Simón Morales 
Chief of Pediatric Cardiovascular Surgery 
The Heart Institute 
Cincinnati Children’s Hospital Medical Center 
The University of Cincinnati College of Medicine 
3333 Burnet Avenue – MLC 2013 
Cincinnati, OH  45229 

 
 
012 
MultiCare Health System 
Dennis Nichols 
MultiCare CT Surgical Associates 
314 Martin Luther King, Jr. Way, Ste. 202 
Tacoma, WA  98405 
013 
University of Virginia 
James Gangemi 
University of Virginia 
P.O. Box 800679 
Room 4054, University Expansion 
Charlottesville, VA  22908 
014 
University of Michigan 
 
Ming-Sing Si 
Michigan Congenital Heart Center 
11-735 C.S. Mott Children's Hospital 
1540 E. Hospital Dr. SPC 4204 
Ann Arbor MI  48109 
015 
El Camino Hospital 
Vincent Gaudiani, MD 
Taft Center for Clinical Research 
El Camino Hospital 
2500 Grant Road 
Mountain View, Ca 94040 
 
Palo Alto Medical Foundation 
2490 Hospital Drive 
Suite 109 
Mountain View, California 94040 
016 
Nationwide Children’s 
Hospital 
Patrick McConnell, MD 
Cardiothoracic Surgery 
Nationwide Children’s Hospital 
700 Children’s Drive 
Columbus, OH  43205-2664 
*Study IDs are not sequential.   
 
Closed Sites 
STUDY 
ID 
CENTER 
INVESTIGATOR and ADDRESS 
001 
Hospital Clinico 
Provincial 
Jose Luis Pomar 
Chief – Dept. of Cardiovascular Surgery 
Hospital Clinico Provincial 
Carrer de Villaroel, 170 
University of Barcelona 
08036 Barcelona, Spain 
002 
University Hospital 
Salamanca 
Jose Gonzalez Santos 
Chief – Dept. of Cardiac Surgery 
Hospital Universitario de Salamanca 
Paseo de San Vincente 58-182 
37007 Salamanca, Spain 

 
 
 
 
This list will be updated as needed and whenever a change occurs.  CVs of principal 
investigators are kept in a separate file.