HALO Clinical Study: A Single Arm, Prospective, Non-randomized, Multi Center Investigation of the SJM™ Masters HP™ 15mm Rotatable Mechanical Heart Valve
Phase: NA
Conditions: Mitral Valve Disease, Damaged Mitral Valve, Malfunctioning Mitral Heart Valve, Mitral Valve Replacement
Sponsor: Abbott Medical Devices

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 1 of 42 
Dec. 12, 2018 
 
 
 
 
 
 
 
Sponsored by: 
Abbott 
5050 Nathan Lane North 
Plymouth, MN 55442 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NCT Number: NCT02097420 
HALO Clinical Study 
A single arm, prospective, non-randomized, multi-center clinical investigation of the SJMTM 
Masters HPTM 15mm Rotatable Mechanical Heart Valve 
Study Document No: CL06404 
Version D 
Date: 12 December 2018 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 2 of 42 
Dec. 12, 2018 
 
 
 
TABLE OF CONTENTS 
1 
INTRODUCTION .................................................................................................................. 5 
1.1 
Background Information ............................................................................................... 5 
1.2 
Disease to be Treated ................................................................................................... 5 
1.3 
Current Treatment Options ........................................................................................... 5 
2 
INVESTIGATIONAL DEVICE .................................................................................................... 6 
2.1 
Device Name ............................................................................................................... 6 
2.2 
Device Description ....................................................................................................... 6 
2.3 
Intended Use............................................................................................................... 6 
3 
STUDY DESIGN ................................................................................................................... 6 
3.1 
Study Duration ............................................................................................................ 6 
4 
STUDY PURPOSE AND OBJECTIVE .......................................................................................... 6 
4.1 
Purpose ...................................................................................................................... 6 
4.2 
Objective .................................................................................................................... 7 
5 
ENDPOINTS........................................................................................................................ 7 
5.1 
Primary Safety Endpoint................................................................................................ 7 
5.2 
Primary Effectiveness Endpoints..................................................................................... 7 
5.3 
Secondary Effectiveness Endpoints ................................................................................. 8 
6 
STATISTICAL ANALYSIS ......................................................................................................... 8 
6.1 
Statistical Analysis and Reporting ................................................................................... 8 
7 
RISK/BENEFIT ANALYSIS ....................................................................................................... 8 
7.1 
Potential Benefits......................................................................................................... 8 
7.2 
Potential Risks ............................................................................................................. 8 
7.3 
Risk Minimization......................................................................................................... 9 
8 
ELIGIBILITY CRITERIA ........................................................................................................... 9 
8.1 
Eligibility Criteria for Pivotal IDE Subjects......................................................................... 9 
8.1.1 
Inclusion Criteria for Pivotal IDE Subjects............................................................... 9 
8.1.2 
Exclusion Criteria for Pivotal IDE Subjects .............................................................10 
8.2 
Eligibility Criteria for Adjunctive Subjects ........................................................................10 
8.2.1 
Inclusion Criteria for Adjunctive Prospective Subjects.............................................10 
8.2.2 
Exclusion Criteria for Adjunctive Prospective Subjects ............................................11 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 3 of 42 
Dec. 12, 2018 
 
8.2.3 
Eligibility Criteria for Adjunctive EU/CU Subjects....................................................11 
9 
STUDY PARTICIPATION .......................................................................................................11 
9.1 
Screening and Informed Consent...................................................................................11 
9.2 
Assessment Schedule ..................................................................................................12 
9.3 
Baseline.....................................................................................................................13 
9.4 
Procedure ..................................................................................................................13 
9.5 
Post-Procedure ...........................................................................................................13 
9.6 
Post-Procedure Anticoagulation Recommendation ..........................................................14 
9.7 
Additional Follow-up ...................................................................................................14 
10 
Discontinuation ..............................................................................................................15 
11 
ECHOCARDIOGRAPHY PROCEDURES..................................................................................15 
12 
BLOOD COLLECTION........................................................................................................16 
13 
DATA COLLECTION PROCEDURES ......................................................................................16 
13.1 
Data Entry and CRF Submission .....................................................................................16 
14 
INVESTIGATIONAL DEVICE HANDLING................................................................................16 
14.1 
Accountability ............................................................................................................17 
14.2 
Storage......................................................................................................................17 
14.3 
Returns .....................................................................................................................17 
15 
SAFETY..........................................................................................................................18 
15.1 
Adverse Event Definitions ............................................................................................18 
15.2 
Adverse Event Reporting ..............................................................................................19 
15.2.1 
Timeline for reporting Serious Adverse Events ......................................................19 
15.2.2 
Reporting Valve-Related Adverse Events ..............................................................19 
15.2.3 
Reporting Unanticipated Adverse Device Effects ...................................................20 
15.2.4 
Reporting Deaths ..............................................................................................20 
15.3 
Data Safety Monitoring Board (DSMB) ...........................................................................20 
16 
CONFIDENTIALITY ...........................................................................................................21 
17 
STUDY ADMINISTRATION.................................................................................................22 
17.1 
Study Sponsor ............................................................................................................22 
17.1.1 
Clinical Project Team .........................................................................................22 
17.1.2 
Amendments to the Investigational Plan ..............................................................22 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 4 of 42 
Dec. 12, 2018 
 
17.1.3 
Monitoring Procedures ......................................................................................22 
17.1.4 
Publication Policy..............................................................................................23 
17.1.5 
IRB Information ................................................................................................23 
17.2 
Study Investigators......................................................................................................23 
17.2.1 
Records ...........................................................................................................23 
17.2.2 
Compliance......................................................................................................23 
17.2.2.1 
Deviations to the Investigational Plan...............................................................24 
17.2.2.2 
Emergency Deviations from the Investigational Plan...........................................24 
17.2.2.3 
Informed Consent Compliance ........................................................................24 
17.2.3 
Institutional Audits............................................................................................25 
17.3 
Institutional Review Board (IRB) ....................................................................................25 
17.3.1 
Responsibilities ................................................................................................25 
17.3.2 
Composition ....................................................................................................25 
17.3.3 
Initial Approval .................................................................................................25 
17.3.4 
Annual Renewal................................................................................................25 
17.3.5 
Records ...........................................................................................................26 
Appendix 3: CDC Growth Charts ..................................................................................................29 
Appendix 11: Adverse Event Definitions .......................................................................................38 
 
 
 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 5 of 42 
Dec. 12, 2018 
 
1 
INTRODUCTION 
 
1.1 
Background Information 
 
The current commercially available mechanical mitral valves range in sizes from 16mm to 
37mm.  The mitral annulus in young pediatric patients can range from 12mm to 30mm with a 
mean of 18mm.1    A mitral valve annulus will typically require a sewing diameter of 
approximately 2mm larger than the valve size.  As a 16mm valve is currently the smallest 
diameter valve on the market there is a portion of the pediatric population that would benefit 
from the availability of a smaller diameter valve.    
 
Evidence exists to suggest that oversized valves are associated with increased mortality and 
morbidity rates particularly in the very young patient population.1-4   A small mitral annulus can 
rarely be enlarged to accept a prosthesis larger than its diameter.5   Intraoperative problems 
associated with implantation of a mitral prosthesis too large for the size of the annulus include 
damage to the conductive system, obstruction of the left ventricular outflow tract (LVOT), 
impairment of valve mobility, and damage to the left circumflex artery.2,6   The need for 
pacemaker insertion after mitral valve replacement due to interruption of the conduction 
system of the heart has been estimated at 5-16%.1,3-7  Mismatch of the  annulus size and the 
prosthesis can also lead to mitral stenosis necessitating a second valve replacement 
procedure.5,8,9 
 
1.2 
Disease to be Treated 
 
Mitral valve disease can be the result of congenital valve anomalies such as mitral stenosis, 
mitral insufficiency and complete or partial atrioventricular canal.  Other causes of mitral valve 
disease include endocarditis, rheumatic heart disease, and mitral insufficiency associated with 
Marfan syndrome .5,10   Approximately half of pediatric patients requiring mitral valve 
replacement have previously had valvuloplasty or valvulotomy to repair the diseased valve.4-
7,10,11 
 
1.3 
Current Treatment Options 
 
Surgical reconstruction to repair the mitral valve is the optimal treatment in the pediatric 
population.  Surgical repair can in some cases eliminate the need for future mitral valve 
replacement and in other cases postpone it.2,4,7,11  The pulmonary autograft technique 
described by Ross and Yacoub and modified by Kabbani has shown promise in those patients 
with mitral valves that have an effective orifice area of at least 3cm2.5,7 
 
When the mitral valve cannot be repaired surgically the only remaining treatment option is 
replacement with a prosthetic valve.7   A second and sometimes third valve replacement after 
initial mitral valve replacement is expected in the very young pediatric population.  The rate of 
mitral valve re-operation reported in the literature for patients younger than five years of age is 
approximately 40%.4,7,10,11    

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 6 of 42 
Dec. 12, 2018 
 
 
Mechanical valves are generally chosen over bioprosthesic valves when a very small size is 
required because they exhibit better hemodynamic characteristics than bioprostheses.5   Valve 
replacement with allografts and xenografts are reported to show poor durability in pediatric 
patients.5   In addition, the rate of premature calcification observed with bioprostheses appears 
to be high in this population.2,7,8,11 
 
2 
INVESTIGATIONAL DEVICE 
 
2.1 
Device Name 
 
SJMTM Masters HPTM 15mm Rotatable Mechanical Heart Valve (15mm MHV).    
 
2.2 
Device Description 
 
The investigational device is a 15mm, rotatable, bileaflet mechanical heart valve designed for 
implantation in the mitral position. This valve is part of the SJMTM Masters HPTM Series product 
line.  The Hemodynamic Plus (HP) model has been designed to maximize effective orifice area.  
This is made possible by removing the sewing cuff from the annulus.   
 
2.3 
Intended Use 
 
The 15mm MHV is intended for use as a replacement mitral valve in patients five years or less 
of age with a diseased, damaged, or malfunctioning mitral valve.  This device may also be used 
to replace a previously implanted prosthetic mitral heart valve.     
 
3 
STUDY DESIGN 
 
The study is a single arm, prospective, non-randomized, multi-center clinical investigation.   
 
3.1 
Study Duration 
 
Each enrolled subject will be assessed at baseline, procedure, post-procedure, 30 days, six 
months, 12 months, and annually thereafter for as long as the valve remains implanted.  Each 
enrolled subject will be followed for five years from the date of implant, until subject 
withdrawal, or until study closure, whichever occurs earliest. 
 
4 
STUDY PURPOSE AND OBJECTIVE 
 
4.1 
Purpose 
 
The purpose of the study is to provide evidence of safety and effectiveness to support a 
supplement to the St. Jude Medical Masters Series PMA (P810002) for approval of the 15mm 
MHV.    

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 7 of 42 
Dec. 12, 2018 
 
 
The rationale for this study is to offer a replacement mitral valve for patients with anatomy that 
is too small for the currently commercially available valves ranging in size from 16mm to 37mm. 
 
4.2 
Objective 
 
The objective of this study is to evaluate the safety and effectiveness of the 15mm MHV in subjects 
five years or less of age with a diseased, damaged, or malfunctioning mitral heart valve.  The 
objective will be evaluated by assessing valve-related adverse events, subject survival, subject 
growth, and echocardiogram assessment of hemodynamic function through the five year follow-
up visit as long as the valve remains implanted.   
  
5 
ENDPOINTS 
 
5.1 
Primary Safety Endpoint 
 
The primary safety endpoint for this study is the actuarial (Kaplan-Meier) rate of total valve-
related adverse events experienced through 365 days post implant or until the valve is 
removed/replaced due to anatomical growth of the subject, whichever occurs first.  Valve-
related adverse events to be evaluated are:  
• Death 
• Endocarditis  
• Hemorrhage (whether or not due to anticoagulant/antiplatelet medication) [all and 
serious] 
• Nonstructural dysfunction (including perivalvular leak [all and serious], hemolysis, and 
hemolytic anemia) 
• Reoperation (including valve explant, not due to anatomical growth of the subject) [all 
and valve-related] 
• Structural valve deterioration  
• Thromboembolism 
• Valvular thrombosis 
 
5.2 
Primary Effectiveness Endpoints 
 
The primary effectiveness endpoints in this study include the following: 
1. Survival at 12 months post implant or survival until the valve is removed/replaced due 
to anatomical growth of the subject, whichever occurs first.   
2. Peak gradient as assessed by echocardiography at 12 months post implant or when the 
valve is removed/replaced due to anatomical growth of the subject, whichever occurs 
first.   
3. Mean gradient as assessed by echocardiography at 12 months post implant or when the 
valve is removed/replaced due to anatomical growth of the subject, whichever occurs 
first.  

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 8 of 42 
Dec. 12, 2018 
 
4. Valvular regurgitation as assessed by echocardiography at 12 months post implant or 
when the valve is removed/replaced due to anatomical growth of the subject, 
whichever occurs first.   
 
5.3 
Secondary Effectiveness Endpoints 
 
The secondary effectiveness endpoints include the following: 
1. Increase in percentile ranking on the CDC growth chart for height at 12 months post 
implant or until the valve is removed/replaced due to anatomical growth of the subject, 
whichever occurs first, compared to baseline. 
2. Increase in percentile ranking on the CDC growth chart for weight at 12 months post 
implant or until the valve is removed/replaced due to anatomical growth of the subject, 
whichever occurs first, compared to baseline. 
 
CDC growth charts are provided in Appendix 3.  
 
6 
STATISTICAL ANALYSIS 
 
6.1 
Statistical Analysis and Reporting 
 
Kaplan-Meier adverse event rates with 95% confidence intervals and early rates will be 
calculated for all safety and survival endpoints.    
 
Hemodynamic function will also be evaluated at each visit for each of the following variables: 
• Mean pressure gradients across the mitral valve 
• Peak pressure gradients across the mitral valve 
• Cardiac output 
• Cardiac index 
• Valvular regurgitation (and the site, as appropriate) 
 
7 
RISK/BENEFIT ANALYSIS 
 
7.1 
Potential Benefits 
 
Replacement of a diseased mitral valve with the 15mm MHV may improve hemodynamic 
function of the valve thereby providing the opportunity for improved physical growth and 
development.  An additional potential benefit of receiving an appropriately sized mitral valve 
replacement is avoidance of complications associated with implantation of a mitral prosthesis 
too large for the size of the annulus which may include damage to the conductive system, 
obstruction of the left ventricular outflow tract (LVOT), impairment of valve mobility, and 
damage to the left circumflex artery. 
 
7.2 
Potential Risks 
 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 9 of 42 
Dec. 12, 2018 
 
Potential risks of receiving a mechanical mitral valve include: 
• The need for a second valve replacement due to either dehiscence, valve failure or 
malfunction, development of mitral stenosis, unacceptable hemodynamic status or 
eventual somatic outgrowth.  
• Heart failure requiring cardiac transplant.  
• Cardiac arrhythmia with or without the need of pacemaker implantation.  
• Hemolysis potentially resulting in anemia with or without splenomegaly and/or 
development of cholelithiasis. 
• Infection including but not limited to endocarditis, myocarditis, cellulitis and/or 
septicemia. 
• Thromboembolism or hemorrhage causing stroke, myocardial infarction or other 
significant impairment. 
• Obstruction or distortion of adjacent cardiac structures. 
 
All of the identified risks have the potential to result in death.  The mortality rate reported for 
mitral valve replacement in the pediatric population is highly variable and ranges between 
approximately 5 and 30%.3,7,12-15    
 
7.3 
Risk Minimization 
 
Risks will be minimized by selecting Investigators that: 
• 
Have experience implanting mechanical mitral valves in patients under the age of 
five. 
• 
Appreciate the need for closely monitoring and managing anti-coagulation regimens. 
• 
Are willing to partner with the subject’s personal cardiologist to ensure appropriate 
care and follow-up. 
 
8 
ELIGIBILITY CRITERIA 
 
8.1 
Eligibility Criteria for Pivotal IDE Subjects 
 
A subject is eligible to participate in the study if he/she meets all inclusion criteria and meets no 
exclusion criterion. 
 
8.1.1 Inclusion Criteria for Pivotal IDE Subjects 
 
1. 
Subject requires mitral valve replacement.* 
2. 
Subject’s legally authorized representative gives written consent to participate in the 
clinical study. 
3. 
Subject is willing and able to return for data collection and follow-up for the 
duration of the clinical study. 
 
*Subjects undergoing concomitant procedures (e.g. valve repair) are eligible for this study 
other than those noted in the exclusion criteria. 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 10 of 42 
Dec. 12, 2018 
 
 
8.1.2 Exclusion Criteria for Pivotal IDE Subjects 
 
1. 
Subject is > 5 years of age. 
2. 
Subject has a contraindication to anticoagulant/antiplatelet medication. 
3. 
Subject has a prosthetic valve(s) at a site other than the mitral valve prior to the 
study procedure.* 
4. 
Subject requires concomitant replacement of the tricuspid, pulmonary, or aortic 
valve. 
5. 
Subject has active endocarditis.  
6. 
Subject has active myocarditis.   
7. 
Subject has had an acute preoperative neurological deficit that has not returned to 
baseline or stabilized ≥ 30 days prior to the study procedure. 
8. 
Subject has had an acute cardiac adverse event that has not returned to baseline or 
stabilized ≥48 hours prior to the study procedure.  
9. 
Subject has a non-cardiac illness resulting in a life expectancy of < 1 year.  
10. Subject has a known requirement for additional cardiac surgery within 12 months 
after the study procedure. 
11. Subject has been previously enrolled and implanted in this study.   
12. Subject is participating in another study for an investigational drug and/or device. 
13. Subject has any other medical condition that in the opinion of the Investigator will 
interfere with the study results.   
 
*Subjects who have undergone a previous Ross procedure of the pulmonary valve are 
eligible for this study.   
  
8.2 
Eligibility Criteria for Adjunctive Subjects 
 
In an effort to ensure data on all real-world use conditions are consistently collected and 
reported on, a subject is eligible to participate in protocol Revision C if he/she meets all of the 
following inclusion criteria and meets no exclusion criterion.  Separate criteria are presented 
below for the two arms of adjunctive subjects of Revision C (Adjunctive Prospective Subjects in 
Sections 8.2.1 and 8.2.2 and Adjunctive EU/CU Subjects in Section 8.2.3). 
8.2.1 Inclusion Criteria for Adjunctive Prospective Subjects 
 
1. 
Subject requires mitral valve replacement.* 
2. 
Subject’s legally authorized representative gives written consent to participate in the 
clinical study. 
3. 
Subject is willing and able to return for data collection and follow-up for the 
duration of the clinical study. 
 
*Subjects undergoing concomitant procedures (e.g. valve repair) are eligible for this 
study. 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 11 of 42 
Dec. 12, 2018 
 
 
8.2.2 Exclusion Criteria for Adjunctive Prospective Subjects 
 
1. 
Subject is > 5 years of age. 
2. 
Subject has a contraindication to anticoagulant/antiplatelet medication. 
 
8.2.3 Eligibility Criteria for Adjunctive EU/CU Subjects 
 
In order for Adjunctive EU/CU Subjects with a previous implant attempt to be eligible for 
study participation, the following criteria must be met: 
 
1. The subject must have been ≤ 5 years of age at the time of mitral valve 
replacement with the 15mm MHV. 
2. An implant was attempted with the 15mm MHV, where implant attempt is 
defined as the device physically contacting the subject’s cardiac anatomy.  
3. The legally authorized representative signs the study informed consent for 
this protocol allowing access to all relevant historical medical information 
and prospective follow-up (if applicable). 
4. Either 
(a) the legally authorized representative and site agree to follow the 
subject per the assessment schedule and complete all required 
assessments per this protocol from the time of consent going forward.   
OR 
(b) the subject’s status is deceased or explanted, but an implant with 
15mm MHV was attempted.  
 
9 
STUDY PARTICIPATION 
 
9.1 
Screening and Informed Consent 
 
This study will be performed in accordance with applicable confidentiality, privacy and security, 
and data protection laws. The subject’s legally authorized representative must provide written 
informed consent prior to performing any protocol-required baseline testing that is not 
standard of care for valve procedures.   

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 12 of 42 
Dec. 12, 2018 
 
9.2 
Assessment Schedule  
All enrolled subjects will be assessed according to the following schedule for as long as the valve is implanted.   
 
Table 1: Assessment Schedule 
ASSESSMENTS 
Baseline 
Procedure 
Post-
Procedure1 
(+ 24 hours) 
30 Days1  
(± 14 days) 
6 Months1 
(± 30 days) 
12 Months1 
(± 60 days) 
Annual Visits 
through 60 
Months1 
(± 60 days) 
Explant (Prior 
to procedure) 
Medical History 
X 
 
 
 
 
 
 
 
Physical Exam (PE) 
X 
 
X 
X 
X 
X 
X 
X 
Transthoracic Echocardiogram (TTE)2 
X 
 
X 
X 
X 
X 
X 
X 
Blood Collection3 
X 
 
X 
X 
X 
X 
X 
X 
Anticoagulant/Antiplatelet 
Medication Collection 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Collection4 
 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Follow-up5 
 
 
X 
X 
X 
X 
X 
X 
1. 
Visits are to occur as long as the valve remains implanted.  
2. 
The study specifies TTE rather than transesophageal echocardiography (TEE) to minimize subject risk.  Echocardiographic data collected from TEE warranted for any 
other medical purpose is allowed.   
3. 
Plasma free hemoglobin for hemolysis evaluation.  Spot urine urobilinogen is an acceptable alternative if a non-hemolyzed blood sample cannot be obtained.   
4. 
Refer to section 15.2 for a list of adverse events that are required to be collected and reported.  
5. 
Required only for subjects who have an unresolved adverse event.    

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 13 of 42 
Dec. 12, 2018 
 
9.3 
Baseline 
 
Obtain written informed consent from the subject’s legally authorized representative prior to 
conducting any study-related testing that is not considered standard of care for valve 
procedures.  All baseline tests must occur prior to the procedure. It is preferable if the testing is 
completed no more than one month prior to the procedure date.    
 
The following baseline assessments are required: 
• Medical history   
• Physical exam 
• Transthoracic echocardiogram 
• Blood collection (Plasma free hemoglobin for Hemolysis evaluation). Spot urine 
urobilinogen is an acceptable alternative if a non-hemolyzed blood sample cannot 
be obtained.   
• Anticoagulant/antiplatelet medication collection 
 
For Adjunctive EU/CU Subjects, baseline assessments should be collected from subject’s 
medical records, when available, for visits conducted prior to enrollment. 
 
9.4 
Procedure 
 
The 15mm MHV is implanted surgically pursuant to the Instructions for Use.   
 
The following assessments are required at the time of the procedure: 
• Anticoagulant/antiplatelet medication collection 
• Adverse event collection 
 
For Adjunctive EU/CU Subjects, procedure assessments should be collected from subject’s 
medical records, when available, for procedures conducted prior to enrollment. 
 
9.5 
Post-Procedure 
 
If the subject does not have the 15mm MHV implanted the subject should be discontinued from 
the study and followed per the physician’s standard of care. 
 
As there are insufficient data to indicate otherwise, the sponsor recommends that subjects 
implanted with the 15mm MHV be routinely maintained on anticoagulants unless, for other 
reasons, it is not medically indicated.   
 
The following assessments are required after the enrolled subject leaves the surgical suite with 
the valve implanted. These assessments must be completed at least 24 hours after the 
procedure:  
• Physical exam 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 14 of 42 
Dec. 12, 2018 
 
• Transthoracic echocardiogram 
• Blood collection (Plasma free hemoglobin for Hemolysis evaluation). Spot urine 
urobilinogen is an acceptable alternative if a non-hemolyzed blood sample cannot 
be obtained.   
• Anticoagulant/antiplatelet medication collection 
• Adverse event collection 
• Adverse event follow up  
 
For Adjunctive EU/CU Subjects, post-procedure assessments should be collected from subject’s 
medical records, when available, for visits conducted prior to enrollment. 
 
9.6 
Post-Procedure Anticoagulation Recommendation 
 
As there are insufficient data to indicate otherwise, the sponsor recommends that patients 
implanted with the 15mm MHV be routinely maintained on anticoagulants to avoid the risk of 
thrombus formation and thromboembolic complications, unless it is not medically indicated. 
 
The recommended anticoagulation therapy for patients implanted with the 15mm MHV are 
based on the 2013 AHA Guidelines for the Prevention and Treatment of Thrombosis in Pediatric 
Patients24 in combination with experience from subjects previously enrolled in this study. 
 
Acceptable forms of anticoagulants include intravenous unfractionated heparin or oral 
warfarin.  When using warfarin the recommended target INR is 2.5 to 3.5 for valves implanted 
in the mitral position in the absence of risk factors for thrombus formation.  In the presence of 
risk factors consider using a higher target INR or adding aspirin to therapeutic warfarin.  Risk 
factors include first 3 months post-implant, younger age (< 6 months), small size (<6 kg), low 
flow state, unreliable oral intake, previous thromboembolism, and hypercoagulable condition.  
Home INR monitoring may be associated with a reduced rate of complications.  Use of low 
molecular weight heparin may be associated with an increased rate of complications based on 
input from HALO IDE investigators. 
 
In patients receiving warfarin, the INR should be monitored daily until therapeutic levels are 
achieved, and then may be decreased in frequency when stable with a minimum of monthly 
testing.  The INR should be tested whenever there is illness or with any changes in medication 
or diet. 
 
The final choice for anticoagulation therapy is left to the clinical judgement of the investigator. 
 
9.7 
Additional Follow-up 
 
Protocol required follow-up visits should be completed by the Investigator.  To aid in subject 
follow-up compliance, subjects can return to their primary cardiologist for follow up visits but 
data must be obtained by the Investigator for review and submission to the Sponsor.  

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 15 of 42 
Dec. 12, 2018 
 
Investigators should inform cardiologists of all required follow-up tests prior to the visit and 
every effort should be made to obtain complete tests results with all required data points after 
the visit occurs.  Protocol deviations will be required for all missed testing (refer to section 
17.2.5 Protocol Compliance).  
 
The following assessments are required at follow-up visits at the intervals noted on the 
assessment schedule in section 9.3 for all enrolled subjects that have the valve implanted:  
• Physical exam 
• Transthoracic echocardiogram 
• Blood collection (Plasma free hemoglobin for Hemolysis evaluation). Spot urine 
urobilinogen is an acceptable alternative if a non-hemolyzed blood sample cannot 
be obtained.   
• Anticoagulant/antiplatelet medication collection 
• Adverse event collection 
• Adverse event follow-up 
 
 
For Adjunctive EU/CU Subjects, additional assessments should be collected from subject’s 
medical records, when available, for visits conducted prior to enrollment. 
 
10 
Discontinuation 
 
Subjects must be informed about their right to withdraw from the study at any time and for any 
reason without sanction, penalty, or loss of benefits to which the subject is otherwise entitled.  
Withdrawal from the study will not jeopardize the subject’s future medical care or relationship 
with an Investigator.  All reasonable efforts should be made to retain the subject in the clinical 
study until study completion.  Subjects will be asked what the reason for 
termination/withdrawal is but have the right not to answer.   
 
The Principal Investigator may also withdraw a subject from the study at any time if he/she 
believes it is in the subject’s best interest.   
 
 
11 
ECHOCARDIOGRAPHY PROCEDURES 
 
Hemodynamic function will be evaluated by calculating the number of observations, mean, 
standard deviation, minimum and maximum values for each of the following variables: 
• Mean pressure gradients across the mitral valve 
• Peak pressure gradients across the mitral valve 
• Cardiac output 
• Cardiac index 
• Valvular regurgitation 
 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 16 of 42 
Dec. 12, 2018 
 
Transthoracic echocardiogram (TTE) examinations are required for each subject at baseline, 
post-procedure, 30 days, 6 months, 12 months, and annually thereafter for as long as the valve 
remains implanted.  
 
The study specifies TTE rather than transesophageal echocardiography (TEE) to minimize 
subject risk.  Echocardiographic data collected from TEE warranted for any other medical 
purpose is allowed.    
 
For Adjunctive EU/CU Subjects, echocardiograms should be collected from subject’s medical 
records, when available, for visits conducted prior to enrollment.  Additionally, 
echocardiograms should be collected even if any echocardiographic assessments occurred 
outside of a specified visit window as they may be used as supporting source documentation on 
the subject. 
 
CDs of the echocardiography exams from each required visit will be forwarded to the 
echocardiography core laboratory (core lab) for interpretation.  The primary responsibility of 
the core lab is to provide consistent interpretation of TTE data across all study sites by 
completing the TTE Case Report Form (CRF).   
 
The sponsor will use only the measurements from the core lab for analysis.  If the core lab 
determines the echocardiogram is unreadable, the subject may be asked to return for another 
echocardiogram.   
 
12 
BLOOD COLLECTION 
 
Plasma free hemoglobin will be collected and analyzed for hemolysis at baseline, post-
procedure, 30 days, six months, 12 months, and annually thereafter for five years as long as the 
valve remains implanted.  Spot urine urobilinogen is an acceptable alternative if a non-
hemolyzed blood sample cannot be obtained.  
 
13 
DATA COLLECTION PROCEDURES 
 
13.1 Data Entry and CRF Submission 
 
All required data will be recorded on standardized specific Case Report Forms (CRFs).     
 
14 
INVESTIGATIONAL DEVICE HANDLING 
 
The sponsor will control the availability of the study valve by shipping valves only to qualified 
study Investigators who have IRB and sponsor approval.  The sponsor will keep records that 
indicate the destination and date of shipment.  Study valves are not transferable between 
Investigators unless prior written approval is obtained from the sponsor. 
 
 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 17 of 42 
Dec. 12, 2018 
 
14.1 Accountability 
 
Upon receipt of the 15mm MHV, Investigators will maintain the following accurate, complete, 
and current records relating to device accountability (21 CFR 812.140 (2)): 
 
Records of receipt, use or disposition of study valves including: 
• Type and quantity 
• Date of receipt 
• Location 
• Expiration date 
• Serial number 
• Names of all persons who received, used or disposed of each unit, and 
• Why and how many units of the study valve have been used, returned to the 
Sponsor, repaired, or otherwise disposed of. 
 
All study valves must be accounted for on the Device Disposition Report even if they are not 
used.  
 
14.2 Storage 
 
The sponsor requires that all study valves be stored according to the labeling, in a secure area 
to prevent unauthorized access or use.  The study site will prevent use of the investigational 
product for non-investigational procedures.   
 
14.3 Returns 
 
Valves which are expiring, not successfully implanted or are explanted should be returned to 
the sponsor.  All unused 15mm MHV product must be returned to the sponsor at the 
completion of the study.   
 
Prior to returning study valves, contact the sponsor clinical study team to obtain a return 
number.  Communicate the serial numbers for all valves being returned.  After the return 
number is received, update the applicable Device Disposition Report(s) with the new 
disposition of the valve, reason for return, and return number.  Send a copy of the updated 
report to the clinical study team by email.  Keep the original for your records.   
 
Ensure all opened product is clearly identified.  If possible, return the valve in its original 
packaging and include all components (e.g. valve holder).  Include a copy of the Device 
Disposition Report(s) with the items being returned.  Write the return number on the outside of 
the package and ship to the address provided with the return number.  
 
 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 18 of 42 
Dec. 12, 2018 
 
15 SAFETY 
 
Safety will be evaluated through the analysis of adverse events related to the 15mm MHV.  All 
valve-related adverse events will be collected and adjudicated by the Data Safety Monitoring 
Board (DSMB) in accordance with Akins et al.25  
 
15.1 Adverse Event Definitions 
 
Adverse Event: 
 
An adverse event (AE) is any undesirable clinical occurrence that is a negative change from 
baseline.   
 
Unanticipated Adverse Device Effect (UADE): 
 
Any serious adverse effect on health or safety or any life-threatening problem or death caused 
by, or associated with a device, if that effect, problem, or death was not previously identified in 
nature, severity, or degree of incidence in the Investigational Plan including a supplementary 
plan or application); or any other unanticipated serious problem associated with the device that 
relates to the rights, safety, or welfare of subjects (21 CFR 812.3(s)). 
 
Serious Adverse Event: 
 
Serious adverse events will be defined as those adverse events resulting in the following; death, 
life-threatening adverse event, inpatient hospitalization or prolongation of existing hospital 
stay, persistent or significant disability/incapacity or medically significant event. 
   
Non-serious Adverse Event: 
 
Non-serious adverse events will be defined as those events requiring health care professional 
directed medical intervention but that are not life threatening, and are not likely to have long-
term (> 6 months) sequelae, and do not require long term (> 6 months) therapy.  
  
Anticipated Adverse Events: 
 
Complications associated with replacement mechanical heart valves include, but are not limited 
to: 
• hemolysis;  
• infections;  
• thrombus;  
• thromboembolism;  
• valve dehiscence;  
• unacceptable hemodynamic performance;  

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 19 of 42 
Dec. 12, 2018 
 
• hemorrhagic complications secondary to anticoagulant medication;  
• prosthetic failure;  
• heart failure;  
• damage to other cardiac structures including the cardiac conduction system;  
• obstruction or distorting of adjacent cardiac structures; or  
• death.   
 
Any of these complications may require reoperation or explantation of the study valve. 
 
15.2 Adverse Event Reporting 
 
15.2.1 
Timeline for reporting Serious Adverse Events  
The investigator should report all SAEs to the Sponsor as soon as possible but no later than 
outlined below. 
Clinical Site 
Reporting timelines 
All Sites 
SAEs must be reported to the Sponsor no later than 3 calendar days from 
the day the site personnel became aware of the event or as per the 
investigative site’s local requirements, if the requirement is more stringent 
than those outlined. 
 
The date the site staff became aware the event met the criteria of an SAE must be recorded in 
the source document.  The Investigator will further report the SAE to the local IRB according to 
the institution’s IRB reporting requirements. 
15.2.2 
Reporting Valve-Related Adverse Events 
 
Safety surveillance within this trial (and the safety reporting performed by the investigator) 
starts: 
• as soon as the subject is enrolled for Pivotal IDE subjects enrolled under protocol 
revision A or B. 
• as soon as the subject is enrolled for Adjunctive Prospective Subjects. 
• from the time of attempted initial implant (defined as the device physically 
contacting the subject’s cardiac anatomy) for enrolled Adjunctive EU/CU Subjects.   
 
Safety surveillance and safety reporting will continue until the last study visit has been 
performed, or the subject is deceased, or the subject concludes participation in the trial. 
Investigators are responsible for promptly reporting, as soon as they become aware, all serious 
and non-serious valve-related adverse events as specified in Akins et al.25 to the sponsor by 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 20 of 42 
Dec. 12, 2018 
 
completing the Adverse Event CRF. Serious adverse events should be reported as specified in 
Section 15.2.1.  Reportable events include: 
• Death 
• Endocarditis 
• 
Hemorrhage (whether or not due to anticoagulant/antiplatelet medication)  
• Nonstructural dysfunction (including perivalvular leak, hemolysis, and hemolytic 
anemia) 
• Reoperation (including valve explant, not due to anatomical growth of the subject) 
• Structural valve deterioration 
• Thromboembolism (valve-related) 
• Valvular thrombosis 
• Unanticipated Adverse Device Effects (UADEs) 
 
Refer to Appendix 11 for definitions of all reportable valve-related adverse events.  All 
unresolved adverse events should be followed by the Investigator until resolution.  Updates to 
adverse events should be provided to the sponsor by completing the AE Follow-Up CRF.     
 
The sponsor may request that additional information such as operative notes, clinic notes, 
discharge summaries, histopathology reports, or a physician’s summary of the event be 
provided to the sponsor as supporting documentation for all reported events.    
 
15.2.3 
Reporting Unanticipated Adverse Device Effects 
 
An Investigator shall submit to the sponsor and the reviewing IRB a report of any unanticipated 
adverse device effect occurring during an investigation as soon as possible, but in no event later 
than ten (10) working days after the Investigator first learns of the effect (21 CFR 812.150 (a) 
(1)). 
 
15.2.4 
Reporting Deaths 
 
An Investigator shall submit to the sponsor a report of any death occurring during the study as 
soon as possible without undue delay.  All deaths will be reported by the sponsor to the FDA 
within ten (10) working days of becoming aware of the death. 
 
 
Send all source documents to the sponsor clinical study team via email.   
 
15.3 Data Safety Monitoring Board (DSMB) 
 
An independent DSMB will be formed to regularly review study progress with regard to safety.  
At a minimum, the DSMB will meet semi-annually.  Members of the DSMB will have no 
affiliation with the HALO Clinical Study.   

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 21 of 42 
Dec. 12, 2018 
 
 
A DSMB Manual of Operations will be developed and agreed upon by the sponsor and DSMB 
members prior to initiation of the trial.  The manual will describe the specific functions of the 
DSMB.  The primary responsibilities of the DSMB are to: 
• Establish adverse event definitions (and refine definitions as necessary during the 
conduct of the clinical study) 
• The DSMB will act as a Clinical Events Committee (CEC) to adjudicate whether or not 
adverse events are valve-related and determine the severity of the events  
• Review and validate the subject sample (i.e., review inclusion/exclusion deviations 
and other protocol deviations) 
• Provide oversight for issues affecting general subject welfare 
• Establish study termination guideline criteria 
• Recommend premature study termination 
 
At any time during the course of the study, the DSMB may offer opinions or make formal 
recommendations concerning aspects of the study that impact subject safety (e.g., safety-
related protocol changes or input regarding adverse event rates associated with the 
investigational study).  Additionally, the DSMB may act as an advisory panel for questions 
regarding informed consent, subject enrollment, protocol implementation, study endpoints, 
data discrepancies, and other issues that may present during the course of the study.  
 
The DSMB will review all adverse events reported by the site and determine the following: 
adverse event type, relatedness to the procedure or device (if known), and whether the event 
is anticipated or unanticipated.  Following each DSMB meeting a report will be sent to 
Investigators indicating the final adjudication of all adverse events reviewed during the 
meeting.  
 
In all reports to the FDA adverse events will be pulled from the DSMB adjudication unless the 
adverse event has not been adjudicated, as noted in the report. 
 
16 
CONFIDENTIALITY 
 
All subject information collected during the course of this study will be kept confidential 
according to applicable state and federal laws and regulations.  
 
The FDA or other US government agencies (including regulatory agencies) and regulatory 
authorities in other countries may inspect and copy subject records or other information about 
subjects related to this study.   
 
Any information about subjects that leaves the institution conducting the study will be modified 
to remove certain information that could identify the subject (e.g., subject’s name, age on the 
day of enrollment, address, and hospital number) and only be identifiable by a subject ID code.  

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 22 of 42 
Dec. 12, 2018 
 
Study data provided to the sponsor that is published in medical journals and/or presented at 
scientific conferences will not allow the identification of study subjects.  
 
Study results from this study may also be published in scientific journals or presented at 
conferences as an oral or poster presentation; however, the identity of a study subject will not 
be disclosed. 
 
17 
STUDY ADMINISTRATION 
 
17.1 Study Sponsor 
 
17.1.1 
Clinical Project Team 
 
A sponsor clinical project team will be developed and trained to select qualified 
Investigators, train investigative sites, monitor the clinical study, ensure IRB approval 
and renewal are obtained, and inform the IRB and FDA of any significant new 
information about the clinical study.  The team will adhere to Abbott/ St. Jude Medical 
Corporation internal procedures, CFR parts 11, 54, 56, 812 and all other applicable 
regulations.  The Sponsor will avoid improper influence on, or inducement of, the 
subject, monitor, any Investigators, or other parties participating in or contributing to 
the clinical study.   
 
17.1.2 
Amendments to the Investigational Plan 
 
Investigational Plan amendments may occur during the course of the study and will be 
reviewed prior to implementation to determine if the changes affect the:  validity of the 
data; risk-to-benefit ratio; scientific soundness of the Investigational Plan; or the rights, 
safety, or welfare of the human subjects involved in the clinical study.  
 
Investigational Plan amendments that affect any of the above criteria will require FDA 
and IRB/EC approval prior to implementation.  Amendments that do not meet the 
criteria above will be reported to the FDA according to 21 CFR 812.35. 
 
17.1.3 
Monitoring Procedures 
 
Monitoring is necessary to ensure adequate protection of the rights and safety of 
human subjects and the quality and integrity of the data obtained during the study.  It is 
the responsibility of the sponsor of the study to ensure proper monitoring of the 
investigation and to see that all the clinical requirements are met.  Monitoring activities 
will be conducted according to the Investigational Plan, Clinical Trial Agreement, ICH 
GCP guidelines, 21 CFR 812, and FDA guidance relevant to this clinical study.   
 
A  monitor will visit the investigator or designee periodically during the study to monitor 
progress, to assist in gathering the required data and to answer any questions.  During 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 23 of 42 
Dec. 12, 2018 
 
these visits, the clinical monitor will review the patient’s records to verify that all 
records and files are up to date and assure compliance with all requirements of the 
protocol and FDA regulations.  
 
The investigator will make patient and study records available to the clinical monitor for 
periodic inspection.   
 
17.1.4 
Publication Policy 
 
No study results obtained under this Investigational Plan, nor any information provided 
to the Investigator for the purposes of performing the study, will be published or passed 
on to any third party without the consent of the sponsor.  Investigators are obligated to 
follow the sponsor publication policy, which is outlined in the Clinical Trial Agreement. 
 
17.1.5 
IRB Information 
 
The sponsor requests waiver of the requirements under 21 CFR part 812.35(b) for 
submitting certification of IRB approval to the FDA prior to the beginning the study at a 
particular center.  In lieu of this requirement the sponsor will submit an IRB/Investigator 
list update in six month intervals. 
 
17.2 Study Investigators 
 
The Principal Investigator at each site is responsible for ensuring that the HALO Clinical Study is 
conducted according to the Clinical Trial Agreement and all amendments thereto, the 
Investigational Plan, any conditions of approval imposed by applicable regulatory authorities 
and/or the reviewing IRBs, and all applicable laws and regulations.  All Investigators shall avoid 
improper influence on or inducement of subjects, the Sponsor, and other Investigators 
participating in or contributing to the clinical study.   
 
Investigators are responsible for obtaining informed consent prior to enrolling any subject in 
the clinical study.  If new information becomes available during the study that can significantly 
affect a subject’s future health and medical care, or willingness to continue in the study, that 
information will also be provided to the subjects in written form.   
 
17.2.1 
Records 
 
Records and reports pertaining to this study to ensure that they no longer need to be 
retained on-site. 
 
17.2.2 
Compliance 
 
The sponsor will review and monitor Investigator compliance and determine if there is a 
need to secure compliance based on the severity and/or trends in non-compliance to 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 24 of 42 
Dec. 12, 2018 
 
the signed Clinical Trial Agreement with Abbott (formerly St. Jude Medical), the 
Investigational Plan, the applicable regulations or any conditions of approval imposed by 
the reviewing IRB or FDA (21 CFR 812.46 (a)).  Depending on the severity and/or trend in 
non-compliance, the Investigator may receive a formal warning or re-training through a 
site visit or conference call.   
 
17.2.2.1 
Deviations to the Investigational Plan 
 
A deviation is used to describe a situation in which the Investigational Plan was not 
followed.  Deviations may be identified at the site or by in-house sponsor personnel, 
and will be recorded on the Deviation CRF.  The site is responsible for notifying their 
IRB and providing IRB notification to the sponsor, if applicable. 
 
17.2.2.2 
Emergency Deviations from the Investigational Plan 
 
If a deviation from the Investigational Plan is necessary to protect the life or physical 
well-being of a subject in an emergency, the Investigator must notify the sponsor and 
the appropriate IRB within five (5) working days.  For all other changes in, or 
deviations from the Investigational Plan, prior written approval from the sponsor and 
the IRB is required. 
 
The FDA and IRB will be notified if the deviation affects the scientific soundness of the 
Investigational Plan. 
 
17.2.2.3 
Informed Consent Compliance 
 
If the 15mm MHV is used without obtaining informed consent, the Investigator will 
report such use to the sponsor and the appropriate IRB within five (5) working days 
with an explanation of the circumstances of such use per 21 CFR 812.150(a)(5).  
 
Informed consent deviations may include, but are not limited to: 
• 
Failure to obtain consent from the subject’s legally authorized representative 
• 
Failure to obtain the signature of the subject’s legally authorized representative 
• 
Failure to obtain date (and time, if required) of signature  of the subject’s legally 
authorized representative 
• 
Failure to obtain legally authorized representative initials on each page, if 
applicable 
• 
Failure to obtain signature of person conducting the informed consent process 
• 
Failure to obtain witness signature, if applicable 
• 
Use of unapproved informed consent form 
• 
Failure to obtain HIPAA Authorization, if applicable 
 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 25 of 42 
Dec. 12, 2018 
 
17.2.3 
Institutional Audits 
 
The Investigator will permit study-related auditing and inspections of all study-related 
documents by the IRB, government regulatory agencies, and the sponsor.  The 
Investigator will allocate time for these activities, allow access to all study-related 
documents and facilities, and provide adequate space to conduct these visits. 
 
 
17.3 Institutional Review Board (IRB)  
 
17.3.1 
Responsibilities 
 
All IRBs must comply with applicable IRB regulations (21 CFR part 50) and IDE 
regulations (21 CFR part 812) in reviewing and approving device investigations.  An IRB 
shall safeguard the rights, safety, and well-being of all study subjects. 
 
17.3.2 
Composition 
 
The IRB shall be composed of members meeting the minimum requirements set forth in 
21 CFR 56.107. 
 
17.3.3 
Initial Approval 
 
Prior to shipment of study valves, the sponsor will require documentation of IRB 
approval of the Investigational Plan and the ICF.  The initial IRB approval and approved 
ICF will be filed in the site Regulatory Binder. 
 
17.3.4 
Annual Renewal 
 
An IRB shall conduct continuing review of the clinical study at intervals appropriate to 
the degree of risk posed by the device, but not less than once per year (21 CFR 56.109).  
A copy of the IRB renewal will be sent to the sponsor and filed in the site Regulatory 
Binder. 
 
Continuation of research after expiration of IRB approval is a violation of the 
regulations.   
 
The following must be completed if the IRB fails to renew the study: 
• Research activities must stop if the IRB has not renewed the continuation of the 
study.   
• Study valves must be returned to the sponsor. 
• No new subjects may be enrolled into the study, and enrolled subjects cannot be 
seen for follow-up according to the protocol, except under the following 
circumstance:  

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 26 of 42 
Dec. 12, 2018 
 
 The IRB may provide a written directive that subjects should still be 
seen for safety follow-up pending re-approval.  Under this IRB 
directive, subjects should be seen for safety follow-up only, in order 
to assure subject safety and welfare is being overseen. 
• If the Investigator is actively pursuing approval, the IRB may be flexible in 
permitting currently enrolled subjects to continue to be seen. 
 The sponsor will require documentation from the IRB of this decision. 
 Subjects will need to be informed that the IRB approval has lapsed, 
and adverse events will be reported to the IRB and the sponsor. 
 
17.3.5 
Records 
 
Each reviewing IRB must maintain the following records (21 CFR 56.115): 
• 
All pertinent correspondence relating to the study 
• 
All records of membership and affiliations 
• 
Meeting minutes 
 
 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 27 of 42 
Dec. 12, 2018 
 
Bibliography of Summarized References   
 
1. Shanmugam, G., MacArthur, K., Pollock, J. Pediatric mitral valve replacement: Incremental 
risk factors impacting survival and reintervention (2005) Journal of Heart Valve Disease, 14 
(2), pp. 158-165. 
2. Alsoufi, B., Manlhiot, C., Al-Ahmadi, M., McCrindle, B.W., Kalloghlian, A., Siblini, G., Bulbul, 
Z., Al-Halees, Z. Outcomes and associated risk factors for mitral valve replacement in 
children (2011) European Journal of Cardio-thoracic Surgery, 40 (3), pp. 543-551. 
3. Alsoufi, B., Manlhiot, C., McCrindle, B.W., Al-Halees, Z., Sallehuddin, A., Al-Oufi, S., Saad, E., 
Fadel, B., Canver, C.C. Results after mitral valve replacement with mechanical prostheses in 
young children (2010) Journal of Thoracic and Cardiovascular Surgery, 139 (5), pp. 1189-
1196.e2. Cited 8 times. 
4. Selamet Tierney, E.S., Pigula, F.A., Berul, C.I., Lock, J.E., del Nido, P.J., McElhinney, D.B. 
Mitral valve replacement in infants and children 5 years of age or younger: Evolution in 
practice and outcome over three decades with a focus on supra-annular prosthesis 
implantation (2008) Journal of Thoracic and Cardiovascular Surgery, 136 (4), pp. 954-961.e3. 
Cited 15 times. 
5. Brown, J.W., Fiore, A.C., Ruzmetov, M., Eltayeb, O., Rodefeld, M.D., Turrentine, M.W. 
Evolution of mitral valve replacement in children: A 40-year experience (2012) Annals of 
Thoracic Surgery, 93 (2), pp. 626-633.  
6. Sim, H.-T., Lee, S.-C., Shin, H.J., Park, J.-J., Yun, T.-J., Jhang, W.-K., Seo, D.M. Mitral Valve 
Replacement Using Mechanical Prostheses in Children: Early and Long-Term Outcomes 
(2012) Pediatric Cardiology, pp. 1-7. Article in Press. 
7. Henaine, R., Nloga, J., Wautot, F., Yoshimura, N., Rabilloud, M., Obadia, J.-F., Di-Filippo, S., 
Ninet, J. Long-term outcome after annular mechanical mitral valve replacement in children 
aged less than five years (2010) Annals of Thoracic Surgery, 90 (5), pp. 1570-1576. 
8. Beierlein, W., Becker, V., Yates, R., Tsang, V., Elliott, M., de Leval, M., van Doorn, C. Long-
term follow-up after mitral valve replacement in childhood: poor event-free survival in the 
young child. (2007) European journal of cardio-thoracic surgery : official journal of the 
European Association for Cardio-thoracic Surgery, 31 (5), pp. 860-865. 
9. Raghuveer, G., Caldarone, C.A., Hills, C.B., Atkins, D.L., Belmont, J.M., Moller, J.H. Predictors 
of prosthesis survival, growth, and functional status following mechanical mitral valve 
replacement in children aged <5 years, a multi-institutional study (2003) Circulation, 108 (10 
SUPPL.), pp. II174-II179. 
10. Rafii, D.Y., Davies, R.R., Carroll, S.J., Quaegebeur, J.M., Chen, J.M. Age less than two years is 
not a risk factor for mortality after mitral valve replacement in children (2011) Annals of 
Thoracic Surgery, 91 (4), pp. 1228-1234. Cited 3 times. 
11. Kanter, K.R., Kogon, B.E., Kirshbom, P.M. Supra-annular mitral valve replacement in children 
(2011) Annals of Thoracic Surgery, 92 (6), pp. 2221-2229. 
12. Tunaoǧlu, F.S., Halid, V., Olguntürk, R., Özbarlas, N., Kula, S., Sinci, V. An infant with severe 
mitral insufficiency and collapse of the left lung due to hammock mitral valve: Emergency 
mitral valve replacement (2006) Anadolu Kardiyoloji Dergisi, 6 (3), pp. 283-285. 
13. Kanter, K.R., Forbess, J.M., Kirshbom, P.M. Redo mitral valve replacement in children (2005) 
Annals of Thoracic Surgery, 80 (2), pp. 642-646. 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 28 of 42 
Dec. 12, 2018 
 
14. Çetin, G., Özkara, A., Mert, A.M., Hatemi, A.C., Öztunç, F., Güven, Ö. Supraannular mitral 
valve replacement in a child with congenital mitral stenosis (2004) Anadolu Kardiyoloji 
Dergisi, 4 (2), pp. 175-177. Cited 1 time. 
15. Ando, M., Takahashi, Y., Kikuchi, T. Mitral Valve Replacement for Children with a Small 
Annulus Using ATS Open Pivot Prosthesis (2003) Japanese Journal of Thoracic and 
Cardiovascular Surgery, 51 (9), pp. 403-406. Cited 1 time. 
16. Wada, N., Takahashi, Y., Ando, M., Park, I.-S., Kikuchi, T. Mitral valve replacement in 
children under 3 years of age (2005) Japanese Journal of Thoracic and Cardiovascular 
Surgery, 53 (10), pp. 545-550. 
17. Eble, B.K., Fiser, W.P., Simpson, P., Dugan, J., Drummond-Webb, J.J., Yetman, A.T. Mitral 
valve replacement in children: Predictors of long-term outcome (2003) Annals of Thoracic 
Surgery, 76 (3), pp. 853-859. 
18. Sachweh, J.S., Tiete, A.R., Mühler, E.G., Groetzner, J., Gulbins, H., Messmer, B.J., Daebritz, 
S.H. Mechanical aortic and mitral valve replacement in infants and children (2007) Thoracic 
and Cardiovascular Surgeon, 55 (3), pp. 156-162. 
19. Kojori, F., Chen, R., Caldarone, C.A., Merklinger, S.L., Azakie, A., Williams, W.G., Van Arsdell, 
G.S., Coles, J., McCrindle, B.W. Outcomes of mitral valve replacement in children: A 
competing-risks analysis (2004) Journal of Thoracic and Cardiovascular Surgery, 128 (5), pp. 
703-709. 
20. Masuda, M., Kado, H., Tatewaki, H., Shiokawa, Y., Yasui, H. Late results after mitral valve 
replacement with bileaflet mechanical prosthesis in children: Evaluation of prosthesis-
patient mismatch (2004) Annals of Thoracic Surgery, 77 (3), pp. 913-917. 
21. Saito, A., Sekiguchi, A., Chikada, M., Tonari, K. Mitral valve replacement in a 15-month-old 
infant with infective endocarditis (2003) Interactive Cardiovascular and Thoracic Surgery, 2 
(2), pp. 143-145. 
22. Higashita, R., Ichikawa, S., Niinami, H., Ban, T., Suda, Y., Takeuchi, Y. Long-term results after 
Starr-Edwards mitral valve replacement in children aged 5 years or younger (2003) Annals 
of Thoracic Surgery, 75 (3), pp. 826-829. 
23. Erez, E., Kanter, K.R., Isom, E., Williams, W.H., Tam, V.K.H. Mitral valve replacement in 
children (2003) Journal of Heart Valve Disease, 12 (1), pp. 25-30. Cited 25 times. 
 
Additional References   
 
24. Giglia, Therese M., M. Patricia Massicotte, James S. Tweddell, Robyn J. Barst, Mary Bauman, 
Christopher C. Erickson, Timothy F. Feltes et al. "Prevention and Treatment of Thrombosis in 
Pediatric and Congenital Heart Disease." Circulation 128, no. 24 (2013): 2622-2703. 
25. Akins C.W., Miller, D.C., Turina, M.I., Kouchoukos, N.T, Blackstone, E.H., Grunkemeier, G.L, 
Takkenberg, J.J.M., David, T.E., Butchart, E.G., Adams, D.H., Shahian, D.M., Hagl, S., Mayer, 
J.E., Lytle, B.W. Guidelines for reporting mortality and morbidity after cardiac valve 
interventions (2008) Annals of Thoracic Surgery, 85, pp. 1490-1495.  
26. Li, J.S., Sexton, D.J., Mick, N., Nettles, R., Fowler Jr., V.G., Ryan, T., Bashore, T., Corey, R. 
Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis 
(2000) Clinical Infectious Diseases, 30, pp. 633-638.   
 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 29 of 42 
Dec. 12, 2018 
 
Appendix 3: CDC Growth Charts 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 30 of 42 
Dec. 12, 2018 
 
 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 31 of 42 
Dec. 12, 2018 
 
 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 32 of 42 
Dec. 12, 2018 
 
 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 33 of 42 
Dec. 12, 2018 
 
 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 34 of 42 
Dec. 12, 2018 
 
 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 35 of 42 
Dec. 12, 2018 
 
 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 36 of 42 
Dec. 12, 2018 
 
 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 37 of 42 
Dec. 12, 2018 
 
  

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 38 of 42 
Dec. 12, 2018 
 
Appendix 11: Adverse Event Definitions 
 
Listed below are guidelines for uniform reporting of adverse events related to the study valve.  
The definitions and categorization of event types are consistent with those recommended by 
Akins et al.25  The DSMB will review and adjudicate adverse events according to these reporting 
guidelines.   
 
Death 
 
All deaths will be reported and categorized as either ‘valve related’, ‘other cardiac related’, or 
‘other cause’ as defined below.   
 
Valve-Related: 
 
Death due to any of the following events involving the study valve: structural valvular 
deterioration, nonstructural dysfunction, valve thrombosis, embolism, bleeding event, 
endocarditis, or reintervention.  Sudden, unexplained deaths of which the cause or 
relationship has not been determined by clinical investigation or autopsy findings are 
considered valve related.   
 
Other Cardiac: 
 
Death resulting from cardiac causes, excluding valve-related death.  Examples include 
congestive heart failure, acute myocardial infarction, and documented fatal arrhythmias. 
 
Other Cause: 
 
Death due to any cause, excluding valve-related mortality or other cardiac death. 
 
Endocarditis 
 
Any infection involving the study valve that is diagnosed according to Modified Duke Criteria26 
for endocarditis will be reported.  Modified Duke Criteria are defined as follows:   
 
1. Definite Infective Endocarditis 
 
Definite infective endocarditis is defined by pathologic criteria or clinical criteria as 
defined below.  The presence of both pathologic and clinical criteria is not necessary to 
meet the definition of definite infective endocarditis.   
 
a. Pathologic Criteria 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 39 of 42 
Dec. 12, 2018 
 
i. Microorganisms demonstrated by culture or histologic examination of a 
vegetation, a vegetation that has embolized, or an intracardiac abscess 
specimen; or 
ii. Pathologic lesions; vegetation or intracardiac abscess confirmed by 
histologic examination showing active endocarditis 
 
b. Clinical Criteria 
i. 2 major* criteria; or 
ii. 1 major* criterion and 3 minor** criteria; or 
iii. 5 minor** criteria 
 
2. Possible Infective Endocarditis 
a. 1 major* criterion and 1 minor** criterion; or 
b. 3 minor** criteria 
 
3. Rejected 
a. Firm alternate diagnosis explaining evidence of infective endocarditis; or 
b. Resolution of infective endocarditis syndrome with antibiotic therapy for ≤ 4 
days; or 
c. No pathologic evidence of infective endocarditis at surgery or autopsy, with 
antibiotic therapy for ≤ 4 days; or 
d. Does not meet criteria for possible endocarditis, as above  
 
 
*Duke Major Criteria: 
 
1. Blood culture positive for infective endocarditis 
a. Typical microorganisms consistent with IE from 2 separate cultures: 
i. Viridans streptococci, Streptococcus bovis, HACEK group, 
Staphylococcus aureus; or 
ii. Community-acquired enterococci, in the absence of a primary 
focus, or 
b. Microorganisms consistent with infective endocarditis from persistently 
positive blood cultures, defined as follows: 
i. At least 2 positive cultures of blood samples drawn > 12 hours 
apart; or 
ii. All of 3 or a majority of ≥ 4 separate cultures of blood (with first 
and last sample drawn at least 1 hour apart) 
c. Single positive blood culture for Coxiella burnetii or antiphase I IgG 
antibody titer > 1:800 
 
2. Evidence of endocardial involvement 
 
3. Echocardiogram positive for infective endocarditis (TEE recommended), defined 
as follows: 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 40 of 42 
Dec. 12, 2018 
 
a. Oscillating intracardiac mass on valve or supporting structures, in the 
path of regurgitant jets, or on implanted material in the absence of an 
alternative anatomic explanation; or 
b. Abscess; or 
c. New partial dehiscense of prosthetic valve 
 
4. New valvular regurgitation (worsening or changing of pre-existing murmur not 
sufficient) 
 
 
**Duke Minor Criteria: 
 
1. Predisposition, predisposing heart condition or injection drug use 
 
2. Fever, temperature > 38◦C 
 
3. Vascular phenomena, major arterial emboli, septic pulmonary infarcts, mycotic 
aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway’s 
lesions 
 
4. Immunologic phenomena: glomerulonephritis, Osler’s nodes, Roth’s spots, and 
rheumatoid factor 
 
5. Microbiological evidence: positive blood culture but does not meet a major 
criterion as noted above (excludes single positive cultures for coagulase-negative 
staphylococci and organisms that do not cause endocarditis) or serological 
evidence of active infection with organism consistent with infective endocarditis 
   
Endocarditis meeting the Duke definitions for ‘definite’ or ‘possible’ will be reported. 
 
Positive blood cultures are not required for the diagnosis of study valve endocarditis.  
Morbidities associated with active infection, such as valve thrombosis, thrombotic embolus, 
bleeding event, or paravalvular leak, are included under this category, and not counted in other 
categories of morbidity. 
 
Hemorrhage 
 
Any episode of major internal or external bleeding that causes death, hospitalization, 
pericardiocentesis, permanent injury (e.g., vision loss), or requires transfusion will be reported.  
 
Note: A bleeding event is reportable whether or not the subject is taking anticoagulant or 
antiplatelet medication. 
 
Note: Embolic stroke complicated by bleeding is classified as a neurological event under 
“embolism” and is not included as a separate bleeding event. 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 41 of 42 
Dec. 12, 2018 
 
 
Nonstructural Dysfunction 
 
Any abnormality not intrinsic to the valve itself that results in stenosis or regurgitation of the 
study valve or hemolysis will be reported.  Nonstructural dysfunction refers to problems 
(exclusive of thrombosis and infection) that do not directly involve valve components yet result 
in dysfunction of a study valve, as diagnosed by reoperation, autopsy, or clinical investigation. 
 
Examples of nonstructural dysfunction include:  entrapment by pannus, tissue, or suture; 
paravalvular leak; inappropriate sizing or positioning; residual leak or obstruction after valve 
implantation or repair; and clinically significant intravascular hemolytic anemia.  More than 
mild recurrent or residual mitral regurgitation after surgical or percutaneous interventional 
valve procedures (coronary sinus interventions, direct reparative methods, or other methods 
aimed at achieving ventricular remodeling) is nonstructural dysfunction, unless there is 
disruption of the valve components themselves, which would then be structural deterioration.   
 
Sudden or progressive dysfunction or deterioration of the study valve may be structural, 
nonstructural, or both as determined by reoperation, autopsy, or clinical investigation. 
 
Reoperation 
 
Reoperation is any operation that repairs, alters or replaces the study valve.  The reasons for 
reoperation are to be reported and may include reasons other than valve-related morbidity, 
such as recall, excessive noise, or incidental or prophylactic removal. 
 
Thrombolytic or catheter-aided therapy of valve-related morbidity is not considered 
reoperation; however, the morbid event that prompted the intervention should be reported. 
 
Structural Valve Deterioration 
 
Dysfunction or deterioration involving the study valve (exclusive of infection or thrombosis), as 
determined by reoperation, autopsy, or clinical investigation will be reported.  Structural valve 
deterioration refers to changes intrinsic to the valve, such as wear, fracture, poppet escape, 
calcification, leaflet tear, stent creep, and suture line disruption of components (e.g., leaflets) of 
the study valve. 
 
Thromboembolism 
 
Any thromboembolic event that occurs in the absence of infection after the immediate 
perioperative period (when anesthesia-induced unconsciousness is completely reversed) will be 
reported as valve-related.  Thromboembolic events occurring during the procedure will be 
reviewed and adjudicated by the DSMB to determine if the event is valve or procedure related.  
Subsets of thromboembolic events are: 
 

 
HALO Clinical Study 
 
CL06404 Revision D 
Investigational Plan 
Page 42 of 42 
Dec. 12, 2018 
 
Neurologic:  
 
A neurologic thromboembolism is one that results in a central, new neurological deficit, 
whether temporary or permanent and whether focal or global, that occurs after the subject 
emerges from anesthesia.  Types of neurologic events are: 
 
• Stroke:  A prolonged (>72 hours) or permanent neurologic deficit that is usually 
associated with abnormal results of magnetic resonance imaging or computed 
tomographic scans.  Subjects with minimal, atypical, or protean symptoms that 
lead to radiographic imaging demonstrating an acute ischemic event are 
considered to have sustained a stroke.   
 
• Transient Ischemic Attack (TIA):  Fully reversible symptoms of short duration.  If 
radiographic imaging demonstrates an acute central neurologic lesion (“cerebral 
infarction with transient symptoms”), however, such subjects are reclassified as 
having sustained a stroke. 
 
Noncerebral: 
 
A thromboembolism documented operatively, at autopsy, or clinically that produces signs 
or symptoms attributable to complete or partial obstruction of a peripheral artery.     
 
Valvular Thrombosis 
 
Any thrombus not caused by infection attached to or near the study valve that occludes part of 
the blood flow path, interferes with valve function, or is sufficiently large to warrant treatment.  
Valvular thrombosis found at autopsy in a subject whose cause of death was not valve related 
or found at operation for an unrelated indication should also be counted as valvular 
thrombosis.