The United States Patent Ductus Arteriosus Registry
Conditions: Ductus Arteriosus, Patent
Sponsor: Le Bonheur Children's Hospital

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Transcatheter PDA Closure Using the AMPLATZER 
PICCOLO OCCLUDER Device in Premature Infants Less 
than Two Kilograms 
Real World Registry Study 
 
 
Date: October 18, 2018 
 
 
 
 
 
 
 
 
 
 
 
National Primary Investigator 
Shyam Sathanandam, MD 

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TABLE OF CONTENTS 
1 INTRODUCTION ....................................................................................................................... 5 
1.1 STUDY OBJECTIVE ....................................................................................................... 5 
1.2 STUDY DESIGN ............................................................................................................ 5 
2 STUDY ENDPOINTS ............................................................................................................... 5 
2.1 PRIMARY ENDPOINT ................................................................................. 6 
2.2 SECONDARY ENDPOINTS ......................................................................................................... 7 
2.3 ADDITIONAL DATA ........................................................................................................ 7 
3 STUDYPOPULATION .................................................................................................. 7 
3.1 INCLUSION CRITERIA ........................................................................................................ 7 
3.2 EXCLUSION CRITERIA .............................................................................................................. 8 
4 STUDYPROCEDURES ....................................................................................................... 8 
4.1 INFORMED CONSENT ............................................................................................................. 9 
4.2 PRE-CATHETERIZATION CLINICAL ASSESSMENT ....................................................... 9 
4.3 IMPLANT/PROCEDURE ......................................................................................................................................... 10 
4.4 POST-PROCEDURE   FOLLOW-UP .......................................................................................... 10 
5 ADVERSE EVENTS .................................................................................................... 11 
5.1 ADVERSE EVENT DEFINITIONS .......................................................................................... 11 
5.2 AE REPORTING REQUIREMENTS ............................................................................................. 11 
5.3 SPECIFIC ADVERSE EVENTS …………...………………… .............................................................11 
5.4 OTHER ADVERSE EVENTS ..................................................................................................... 11 
5.5 RISK MINIMIZATION ……… ............................................................................. 12 
5.5.1 Standard Risk Minimization Strategies ........................................................................ 12 

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5.5.2 Specific Risk Minimization Strategies for Subjects < 2 Kg ........................................................ 13 
5.5.3 Aortic or Pulmonary Artery Stenosis ..................................................................................... 14 
5.6 RISK-TO-BENEFIT RATIONALE ...................................................................................... 14 
5.7 PRECAUTIONS TAKEN FOR WEB-BASED ACCESS ...................................................................................... 14 
6 STUDY COMPLETION ……………… ................................................................... 15 
6.1 SUBJECT DEATH ............................................................................................................................. 15 
6.2 UNANTICIPATED ADVERSE EVENTS ................................................................................. 15 
 
6.3 CORE LABORATORY ……………………………………………………………. 16 
 
6.4 STUDY COMMITTEES ……………………………………………………………………………… 16 
 
6.4.1 Publication Committee ………………………………………………… 16 
 
6.4.2 Clinical Events Committee ………………………………………………………….. 16 
7 STATISTICAL CONSIDERATIONS ................................................................................ 17 
7.1 PRIMARYSAFETY   ENDPOINT....................................................................................................................... 17 
7.2 PRIMARYEFFECTIVENESS ENDPOINT .............................................................................17 
7.3 SECONDARY ENDPOINTS ……………………………………………………………. 17 
7.4 ANALYSIS POPULATION ……………………………………………………………………………… 18 
7.5 OTHER ENDPOINTS ........................................................................... 18 
7.6 JUSTIFICATION OF CLINICAL STUDY DESIGN …………………………………………………………….19 
8 REQUIREMENTS FOR INVESTIGATOR RECORDS AND REPORTS …………………. 19 
8.1 DEVIATIONS FROM CLINICAL STUDY PROTOCOL (CSP) ........................................................................ 19 
8.2 SAFETY REPORTING ……………………………………………………………. 20 
8.3 SOURCE RECORDS ……………………………………………………………………………… 21 
8.4 RECORDS RETENTION ......................................................................... 21 
9 CLINICAL DATA HANDLING ....................................................................... 21 
9.1 PROTECTION OF PERSONALLY IDENTIFIABLE INFORMATION ............................................... 22 
9.2 DATAMANAGEMENT   PLAN ................................................................................................................................... 22 

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9.3 DOCUMENT AND DATA CONTROL ..................................................................................................................... 22 
9.3.1 Traceability of Documents and Data ................................... 22 
9.3.2 Recording Data .......................................................................................... 22 
10 MONITORING ............................................................................................................................................................ 22 
11 COMPLIANCE STATEMENT ...................................................................................................................................... 23 
11.1 STATEMENT OF COMPLIANCE ......................................................................................................................... 23 
11.2 QUALITY ASSURANCE AUDITS AND REGULATORY INSPECTIONS ........................................ 23 
11.3 REPEATED AND SERIOUS NON-COMPLIANCE ......................................................................................... 23 
12 SUSPENSION OR PREMATURE TERMINATIONOF THE CLINICAL INVESTIGATION ............ 24 
13 CLINICAL STUDYCONCLUSION ........................................................................................................ 24 
14 PUBLICATIONPOLICY ......................................................................................................................................... 24 
APPENDIX A: DEFINITIONS ................................................................................................................. 25 
APPENDIX B: BIBLIOGRAPHY ................................................................................................................... 29 
APPENDIX C: PDA MODULE (CASE REPORT FORM) ...................................................... 31 
APPENDIX D: ADVERSE EVENTS REPORTING FORM .................................................................. 39 
APPENDIX E: SCHEDULE OF ASSESSMENTS ......................................................................... 42 
APPENDIX F: PROTOCOL DEVIATION REPORTING FORM ................................................................. 43 
APPENDIX G: SERIOUS ADVERSE EVENTS REPORTING FORM ................................................................. 47 

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1 INTRODUCTION 
 
This observational clinical study is intended to collect real world evidence (RWE) on the safety and 
efficacy of transcatheter device closure of patent ductus arteriosus (PDA) using the Amplatzer 
Piccolo Occluder in premature infants with a weight of less than 2 kg at the time of device implant. 
This clinical study is sponsored by Abbott. 
 
All US clinical sites/physicians enrolling in the Congenital Cardiac Interventional Study Consortium 
(CCISC) are eligible to participate in the study following satisfactory completion of qualification 
requirements. 
 
 
1.1 Study Objective 
 
The objective of this study is to demonstrate the continued safety and efficacy in a real-world 
setting of transcatheter device closure of the PDA in premature infants less than 2kg in weight at 
the time of device implant performed at the CCISC participating centers. 
 
 
1.2 Study Design 
 
This is a multi-center, single arm, non-randomized, observational study designed to help assure 
continued safety and effectiveness of FDA approved Amplatzer Piccolo Occluder device for PDA 
closure in premature infants less than 2 kg at the time of device implant. The study will be conducted 
at all the CCISC participating sites. 
 
Subjects will have transcatheter PDA closure using the Amplatzer Piccolo Occluder device as part 
of standard clinical practice under fluoroscopy with or without additional echocardiographic 
image guidance. The study involves collecting and reporting of data for the ASO II AS PDA closure 
procedures into the CCISC PDA Module Database. The PDA module encompasses pre-procedure, 
procedure, 48-hoours, 1-month and 6-months post-procedure follow-up data entry. It also 
encompasses an adverse event reporting system. Data entry is expected for all attempted PDA 
closure procedures in which the Amplatzer Piccolo Occluder device is attempted in premature 
infants weighing < 2 kg at the time of the procedure. It includes pre-procedural and post-
procedural echocardiographic information as well as data from procedural echo guidance if 
utilized. Follow-up will be for a period of six months +/- 30 days after the procedure. 
 
 
2.  STUDYENDPOINTS 
 
Initial data collection will be limited to 500 subjects. Additional data collection beyond the initial 
cohort of 500 subjects may be done on a voluntary basis by participating sites/physicians. 

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2.1 Primary Endpoint(s) 
 
Safety Endpoint: Composite rate of major device- or procedure-related adverse events 
(AE) of interest through 6 months’ post-implantation procedure. AEs of interest are broadly 
categorized as: 
a. Vascular access complications 
b. Valvular Injury 
c. Device embolization 
d. Pulmonary or aortic vessel stenosis 
 
Access vessel complications include femoral arterial or femoral/jugular venous complications 
noted during the procedure, immediately after the procedure or delayed (>24 hours). They 
range from bleeding from access sites, arterial or venous thrombosis with or without the 
need for treatment to loss of limb secondary to arterial occlusion. 
Valvular injury includes damage to the tricuspid valve or other cardiac valve resulting in 
immediate post-procedural valvular dysfunction. 
Device embolization includes malposition of the device either during or after the procedure 
or delayed (>24 hours). The outcome of device embolization ranges from observation, 
transcatheter retrieval at time of procedure or at a separate time, surgical retrieval, other 
end organ damage, to mortality. 
 
Adjacent vessel stenosis includes a narrowing of the aorta or the left pulmonary artery 
directly as a consequence of device implantation for PDA closure. Vessel stenosis could 
happen either during or after the procedure or delayed (>24 hours). The outcome of vessel 
stenosis ranges from no intervention needed to repeated transcatheter and surgical 
therapies. 
 
For details of each AEs and definitions, refer to Appendix A. 
 
Effectiveness Endpoint: The effectiveness endpoint is the rate of effective closure of the 
PDA using a transcatheter device within six months post procedure. If more than one 
attempt is required, or multiple devices are required during the same procedure, it is still 
considered effective if there is Grade 0 or Grade 1 shunt, as defined below, at follow-up 
(within six months) by transthoracic echocardiography (TTE) or if a second procedure is 
not required following the initial attempt. If there is device embolization, adjacent vessel 
stenosis that required retrieval of the device and replacement during the same procedure 
with less than Grade 1 shunt during follow-up, it is still considered effective. Conversely, if 
an AE is noted after the procedure that requires a second procedure for treatment that 
results in greater than Grade 1 shunt, then the procedure is considered not effective, even 
if the initial attempt was effective. 
 
PDA shunt definition: 

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Grade 0—none; 
 
Grade 1—trivial (narrow jet adjacent to the device via the PDA). Note: the presence of flow   via 
existing or newly formed aortopulmonary collaterals should not be considered as representing 
a shunt via the PDA. (See references in Appendix B by Skinner and Acherman) 
Grade 2—mild (broader jet filling proximal left pulmonary artery branch and extending to 
main pulmonary artery); 
 
Grade 3/4—moderate to severe (wide jet filling the main pulmonary artery and extending 
to pulmonary valve or distal pulmonary artery branches, which also may be accompanied 
with the presence of flow reversal in the abdominal aortic Doppler pattern during 
diastole) 
 
 
2.2 Secondary Endpoints 
 
The secondary endpoint is the rate of significant obstruction of the pulmonary artery or 
aorta during follow-up (within 6 months) per the following definitions: 
 
1. Significant obstruction of the left pulmonary artery is defined as less than 30% flow to 
the left lung by lung perfusion scan or a peak instantaneous gradient in left pulmonary 
artery 
≥35 mmHg by echocardiogram if lung perfusion scan is not available. OR 
 
2. Significant obstruction of the aorta is defined as a gradient of ≥20 mmHg in the aortic 
isthmus by invasive aortic catheterization or a mean gradient ≥20 mmHg in the aortic 
isthmus by echocardiogram if invasive aortic catheterization is not available. 
 
 
2.3 Additional Data 
 
Demographics and baseline characteristics, procedure information, and adverse events. For 
additional information, refer to the PDA Module in Appendix C. 
 
 
3 STUDY POPULATION 
 
Participating subjects includes infants born prematurely (<37 weeks’ gestation) with a weight less 
than 2 kg at the time of device implant. The decision to close the PDA is entirely at the discretion of 
the refe ring/primary cardiologist or neonatologist. 
 
 
3.1 Inclusion Criteria 
 
To participate in this clinical study, subjects must meet all of the following inclusion criteria: 

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a. Diagnosis of a PDA 
b. Clinical indication for transcatheter PDA closure (discretion of the physician) 
c. Weight < 2 kg at the time of device implant 
 
All participating study sites must obtain center specific IRB approval to enter patient data in the 
case reporting form (CRF) which will be called the PDA module. Individual consents from the 
subjects (or legally authorized representative) is not required unless local laws and governing IRB 
requirements require obtaining informed consent for data entry to this registry. No deviation of 
standard clinical practice is expected for participating in this study. No special pre-procedure, post- 
procedure, and follow-up testing is required for the purpose of this clinical study. 
 
 
3.2 Exclusion Criteria 
 
Subjects who meet any of the following exclusion criteria must be excluded from the clinical 
investigation: 
 
a. Weight <700 gm or > 2kg at the time of device implant 
b. Age < 3 days at the time of device implant 
c. Pre-existing coarctation of the aorta 
d. Pre-existing left pulmonary artery stenosis 
e. Cardiac output that is dependent on right to left shunt through the PDA due to pulmonary 
hypertension 
f. Intracardiac thrombus that interferes with device implant 
g. Active infection requiring treatment at the time of implant 
 
The indication to choose transcatheter PDA closure is at the discretion of the referring and the 
implanting physician. Though the above stated exclusion criteria are standard for most patients 
undergoing transcatheter PDA closures, clinical discretion is advised for each subject selection. 
 
 
4 STUDY PROCEDURES 
 
The indication to choose transcatheter PDA closure is at the discretion of the referring and 
implanting physician. No deviation of standard clinical practice is expected to participate in this 
study. No special pre-procedure, post-procedure, and follow-up testing is required for the purpose 
of this clinical study. 
 
Enrolled subjects (as defined in section 3.1) will undergo a PDA closure procedure with the 
appropriate device size deemed suitable for that particular patient. Post-procedure, the subject will 
need a follow-up within 48-hoours, 1-month and 6-months after the procedure. The Principal 
Investigator should arrange for appropriate care of subjects following study completion. 
 
This will be a prospective data input Registry. Screen fail subjects who do not have a PDA closure 
attempt or those who have the Amplatzer Piccolo Occluder device introduced but do not retain an  
 
 

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Amplatzer Piccolo Occluder PDA closure device at the end of the procedure will be noted in the 
Registry and followed for 48 hours post procedure. 
The following sections provide a detailed description of procedures required by this clinical study. 
 
 
4.1 Informed Consent 
 
The Principal Investigator or his/her authorized designee will conduct the Informed Consent for 
performing the procedure – transcatheter PDA closure as per their hospital policy. No special 
consents are required for the purpose of this clinical study. All participating study sites must obtain 
center specific IRB approval to enter patient data in the PDA Module. Individual consents from the 
subjects or legally authorized representative (LAR) is not required unless local laws and governing 
IRB requirements require obtaining informed consent for data entry to this registry. No deviation of 
standard clinical practice is expected to participate in this study. No special pre-procedure, post- 
procedure, and follow-up testing is required for the purpose of this clinical study. 
Patients with a weight less than 2 kg will be undergoing transcatheter PDA closures and their 
protected health information (PHI) will be entered into the PDA module. If there are local IRB rules 
that involves the need for individual consents from the LAR for sharing PHI, then a separate 
Informed consent must be obtained using the local IRB approved informed consent in accordance 
with IRB requirements. The patient under the age of 18 will also be informed about the clinical 
study within his/her ability to understand. Per state, local, and/or IRB requirements, processes will 
be followed and documented to collect assent for minor children. The consent will allow for the 
sharing and transfer of raw patient level data to the sponsor. 
 
 
4.2 Pre-catheterization Clinical Assessment 
 
The following assessments, diagnostic tests and evaluations and must be included in the PDA 
module, please see Appendix C for the CRF to be used: 
 
a. Demographics- including subject’s age, gender, ethnicity, birth weight, gestational age 
b. Medical History- 
 
o Indicate subject’s primary symptom, associated heart defects and co-morbidities, genetic 
syndromes if any, ongoing medical support, current medications, history of prior 
attempted medical or surgical therapy for the PDA 
 
c. Transthoracic echo (TTE) - 
 
o PDA measurements, color and spectral Doppler findings, estimates of pulmonary 
hypertension, left ventricular function and dimensions, pulmonary and aortic flow 
and dimensions, aortic arch sidedness, presence of other heart defects, and pulmonic 
and tricuspid valve regurgitation 

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Baseline assessments must be obtained within 2 weeks of the procedure 
 
 
 
4.3 Implant/Procedure 
 
The Amplatzer Piccolo Occluder device can be implanted either transvenously via the femoral 
vessels. To minimize complications in small infants (< 2 kg) it is recommended to utilize the 
anterograde transvenous approach via the femoral vein as the preferred approach. The use of 
invasive hemodynamic measurements and angiograms are not required in this study to minimize 
complications, and instead whenever possible hemodynamic assessments and visualization of the 
anatomy may be performed using intra-operative echocardiography. The recommended use of 
Heparin is considered optional, and not required if the subject is at high risk for bleeding 
complications, including children 
< 2kg. 
 
The following procedural data must be recorded in the PDA module: 
 
a. Demographics- including subject’s age and procedure weight 
b. Procedure data- 
 
o Primary indication for the procedure, anesthesia type, image guidance techniques used, 
access vessels, hemodynamic assessment, sheath/catheter sizes, PDA morphologic types, 
intra-procedural PDA measurement by angiography, heparin administration, device 
delivery technique, contrast and radiation doses, adverse events 
c. Device/implant data- 
 
o Device(s) implanted, device size, residual shunting by angiography, grade of residual 
shunting, peak/mean gradient across left pulmonary artery and aorta (optional) 
 
d. Intra-procedure Transthoracic echo (optional)- 
 
o Baseline PDA size, residual PDA shunting post device implantation, peak/mean gradient 
across left pulmonary artery and aorta, left ventricular function and dimensions, pericardial 
effusion, increased tricuspid or pulmonary valve regurgitation. 
 
4.4 Post-Procedure Follow-up 
 
The follow-up assessment must be obtained within 48-hoours, 1-month and 6-months after the 
procedure. The schedule of all assessments is provided in Appendix E. The following post- 
procedure follow-up assessments, diagnostic tests and evaluations and must be included in the PDA 
module: 
a. Demographics- including subject’s age, weight 
b. Transthoracic echo (TTE) – including checking for the presence of the device within the 
PDA, degree of residual shunting if any, spectral Doppler findings, estimates of pulmonary 

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hypertension, left ventricular function and dimensions, pulmonary and aortic flow and 
dimensions, pulmonic and tricuspid valve regurgitation 
Subjects should be on appropriate endocarditis prophylaxis according to the American Heart 
Association recommendations for prophylaxis. 
 
 
5 ADVERSE EVENTS 
 
Risks associated with the procedure are managed in accordance with ISO 14971. The risk analysis 
included an objective review of published and available unpublished medical and scientific data. 
The sections below provide an overview of residual risks identified in the risk management report 
and anticipated benefits of the medical device. The additional tests and assessments required by the 
clinical investigation were analyzed for additional risks to subjects of this clinical investigation, and 
are incorporated in the sections below. 
5.1 Adverse Event Definitions 
 
For details of each adverse events (AE) and definitions, refer to Appendix A. 
 
5.2 AE Reporting Requirements (Adverse Event Form) 
 
Procedural adverse events must be documented carefully. If there is an adverse event that arises 
directly as a result of the procedure or the device, or noted during follow-up, an Adverse Event 
Form (Appendix D, G) must be filled out separate from the PDA Module and reported to their IRB 
and Industry Sponsor. 
 
5.3 Specific Adverse Events 
 
The adverse event form includes specific risks associated with transcatheter device closures that 
needs to be followed. They include: 
 
a. Access complications: Include site, timing and type of complication, and outcome 
b. Valvular injury: Include site, timing and type of complication, and outcome 
c. Device embolization: Include timing of embolization, embolization site and outcome 
d. Vessel stenosis: Include timing of vessel stenosis, site of vessel stenosis and outcome 
 
5.4 Other Adverse Events 
 
Other risks associated with the implant procedure are similar to those of other cardiac 
catheterization procedures in infants and children and are documented below: 
 
 
 
Air embolism 
Allergic  dye reaction 
 
Allergic drug reaction 
Anesthesia reactions 
 
Apnea 
Arrhythmia 

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Arteriovenous fistulae 
Hematoma 
Pericarditis 
Air embolism 
Hemodynamic compromise 
Peripheral embolism 
Bacterial endocarditis 
Hemolysis 
Peripheral pulse loss 
Bleeding at the access site 
Hypertension 
Pleural effusion 
Brachial plexus injury 
Hypotension 
Pseudoaneurysm 
Bruising 
Infection 
Reintervention for device 
 
Cardiac perforation 
Cardiac tamponade 
Chest pain 
Death 
 
Deep venous thrombosis 
Device erosion 
Dissection 
Embolism 
Fever 
Headache/migraine 
 
Myocardial infarction 
Nickel sensitization 
Nickel toxicity 
Palpitations 
Partial obstruction of the 
Aorta 
 
Partial obstruction of the 
Pulmonary Artery 
 
Perforation 
Pericardial effusion 
removal 
 
Radiation injury/burn 
Respiratory distress 
Stroke 
Transient ischemic attack 
 
Thrombosis   
Valve damage 
Vascular occlusion 
Vessel damage/perforation 
Thrombus f o r m a t i o n 
 
 
 
5.5 Risk Minimization 
 
Every possible effort should be taken to minimize risks. This begins with physician training and 
proctoring. In addition, each site is encouraged to follow their routine clinical strategies to 
minimize procedural risks. These guidelines are merely to help physicians to prevent adverse 
events, recognize risks especially is very small children and treat appropriately. 
5.5.1 Standard Risk Minimization Strategies 
 
Standard risk minimization strategies include: 
 
I. 
Cardiologists with training and education in pediatric cardiology and with expertise in 
using the Amplatzer Piccolo Occluder device to close PDAs 
II. 
Prior experience with transcatheter closure procedures using similar devices with a 
minimum of 10 cases in subjects < 2 kg. 
III. 
Institutions will have the necessary infrastructure to support study procedures: 

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a. Cardiac catheterization lab or NICU bedside capability to perform intra-procedural 
echocardiography and fluoroscopy 
b. Anesthesiology support, as needed 
c. Catheterization laboratory, operating room, post anesthesia recovery, intensive care 
and step down unit spaces to accommodate cases with and without complications 
d. On-site emergency cardiac surgery services 
e. Adequate monitoring for each clinical investigation site 
f. 
Conducting the clinical investigation in accordance with the study, all applicable  laws 
and regulations and any conditions of approval imposed by the appropriate IRB or 
applicable regulatory authorities where the clinical investigation is performed 
g. Preparation of the device and implant procedure in accordance with the device 
IFUs 
h. Training of Investigators both on the study protocol and implant procedure 
i. 
All site staff will participate and complete a raining module 
j. Implanting physicians with no prior successful transcatheter PDA closure experience in 
small infants (<2 kg) will receive proctoring for a minimum on one case. 
k. Assessment of continuing safety of subjects in the clinical investigation by an 
independent Clinical Events Committee (CEC). 
l. Physicians are required to follow The American Heart Association 
Recommendations for endocarditis prophylaxis during the clinical study. 
m. Sites should follow patients per their standard of care for any reported adverse events. 
 
 
5.5.2 Specific Risk Minimization Strategies for Subjects < 2kg 
 
The following measures should also be taken to reduce the risks at the time of the 
procedure: 
 
a. The use of heparin is optional in children < 2 kg in order to decrease the risk of bleeding. 
b. Implanting physicians with no prior successful transcatheter PDA closure experience in 
children< 2 kg will be trained on the Amplatzer Piccolo Occluder device, specifically 
device size selection and placement, to reduce the risk of device embolization, partial 
obstruction of the aorta or pulmonary artery and hemolysis which could be potentially 
caused by the device. 
c. The physicians will be instructed to use their clinical judgement to monitor subjects for 
potential adverse events related to nickel and to report such events with the goal of 
protecting the welfare of the subject if the root cause of the adverse event is determined to 
be nickel related, paying special attention to subjects weighing < 2 kg. 
d. Physicians are encouraged to utilize an anterograde implant approach, while avoiding the 
need for arterial access in children < 2 kg. 
e. Acquisition of invasive hemodynamic measurements is not required in children < 2 kg 
unless there is suspicion for pulmonary hypertension in order to minimize 
complication and shorten procedure time. 

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f. 
Device implant is recommended to be performed based on echocardiographic and 
fluoroscopic guidance with judicious utilization of intravenous contrast agents as 
necessary for best imaging of the PDA. 
 
 
 
5.5.3 Aortic or Pulmonary Artery Stenosis 
 
If stenosis of the aorta or pulmonary artery is suspected or noted during the procedure or 
during follow-up, the following measures are recommended: 
 
a. Perform aortic catheterization to obtain invasive measurement of the gradient if the mean 
gradient by echocardiogram in the aortic isthmus is ≥ 20mmHg. 
b. If aortic catheterization is contraindicated, then an alternative imaging study, such as  
computed tomography (CT) aortic angiography imaging or magnetic resonance (MR) aortic 
angiography imaging may be utilized. 
c. CT aortic angiography or MR aortic angiography may be used to confirm a significant aortic 
obstruction whenever there is ≥ 50% diameter narrowing at the aortic isthmus. 
d. Alternatively, a clinical exam may be used to confirm aortic obstruction. 
e. Exam criteria = 1) Diminished lower extremity pulses or a blood pressure discrepancy of ≥ 
20mmHg between the upper and lower extremities AND 2) an abnormal abdominal aortic 
Doppler pattern (blunted profile with diminished upstroke, holo-diastolic antegrade flow, 
or flow reversal during diastole). 
f. If a new significant gradient in the pulmonary artery or the aorta is identified on follow-up 
echocardiograms, a lung perfusion scan or CT/MR/aortic catheterization will be required to 
determine  if  the  result  meets the secondary endpoint. 
 
 
5.6 Risk-to-Benefit Rationale 
 
Risks associated with participating in this clinical study are not anticipated to be any different from 
risks associated with participating in any other large web-based registry. There is a small risk of a 
loss of confidentiality and every effort will be made to prevent this type of breach. The potential 
benefit of participating in this clinical study will allow for a large data registry to be compiled. 
Advantage of having this registry will include the possibility of future prospective, observational 
and cohort studies. The PDA module, though initially for the Amplatzer Piccolo Occluder device, 
will also provide a method for tracking and oversight for all PDA device procedures in the United 
States. 
 
5.7 Precautions Taken for Web-Based Access 
 
All paper research records will be stored in locked file cabinets and will be accessible only to    
research personnel. All electronic research records will be computer password protected and 
accessible only to research personnel. All research records will be transmitted to CCISC, will be 
labeled with a code, and will not contain any identifiable information about the subjects.  A m a s t e r  

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key/list which links with the subject’s PHI, such as the patient’s name with the code on the research 
records and specimens will be maintained at individual participating institutions. Information 
about any subject’s participation in this study or the results of procedures performed in this study 
will be placed in the subjects’ medical record; as such, this information could be made available to 
your employer or insurer. While individual details about a particular case might be provided in 
publications or presentations, they will not be discussed in a way that would allow any subject to 
be individually identified as a participant. 
Protecting data and patient privacy is of great importance to this study. All research records will be 
saved in a password protected computer at individual participating centers.  Access to the records 
will be limited to research personnel alone. Anti-virus software will be used to protect every      
computer network. Several different hardware and software solutions will be used to ensure that 
unauthorized users cannot access our computer systems. Data Encryption will be used that      
transposes the PHI which is sent from each participating sited to our server and browser into a 
code that cannot be understood or altered without using a "key". The "key" deciphers the 
information from our server to be able to display on any browser. Data transmitted between 
participating sites will be protected using Message Authentication Codes (MACs). The MAC will be 
based on the actual data itself, and provides a quick way to verify that the data wasn't changed or 
tampered with in route. 
6 Study Completion 
 
Subject participation in the clinical investigation will conclude upon completion of the follow-up 
visit at 6 months’ post device implantation procedure. If a subject misses the scheduled follow-up 
visit within the 6-month window, the subject will be considered as having missed the visit (which 
will be deemed a deviation from the clinical study protocol and the applicable form will be 
completed). 
 
A subject will be considered ‘Lost to Follow-up’ after two missed scheduled visits within the 6- 
month window, a minimum of two unsuccessful phone calls from investigational site personnel to 
the subject. These two phone calls must be documented in the subject’s research records. If the 
subject is deemed lost to follow-up, a certified letter will be sent to the subject’s last known address 
or to the subject’s general practitioner (GP). A copy of the letter must be maintained in the subject’s 
research records. 
 
 
6.1 Subject Death 
 
Subject deaths will be  documented and reported  to the CCISC  PDA Module  PI as soon  as possible 
(but no later than 3 business days) after becoming aware of the event via the applicable case report 
form (CRF)  within the PDA module. In the event an autopsy is performed whenever possible   data 
on the histopathology of the Amplatzer Piccolo Occluder device should be submitted within the 
case report form including any photographs of the gross and microscopic findings. 

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6.2 Unanticipated Adverse Events 
 
If an unanticipated adverse event occurs, the investigator must notify the CCISC PDA Module PI and 
the IRB immediately, but no later than 10 working days of the investigator’s knowledge of the 
event, as required by 21 CFR §812.150. CCISC Scientific Committee will perform a Root Cause 
Analysis (RCA)to investigate the cause of the event, and, as appropriate, will be responsible for 
notifying FDA and all other participating IRBs and investigators. 
 
6.3 Core Laboratory 
 
A Core Lab will not be used to review and adjudicate patient’s clinical information, angiograms and 
transthoracic echocardiography. However, the CCISC will randomly audit up to ten percent of the 
patients’ data entered in the PDA module from each institution. Service details are previously 
outlined in the applicable Service Agreement between the CCISC participating site and the CCISC. 
 
 
6.4 Study Committees 
 
6.4.1 Publication Committee 
 
A Publication Committee may be established to oversee study publications. Publication Committee 
membership may include the national coordinating investigator, Principal Investigators, a   
representative of CCISC, and a statistician. The Publication Committee will be responsible for 
identifying, selecting and approving publication proposals and determining authorship according to 
a Publication Plan. A Publication Committee charter will define membership of the committee and 
outline  the roles and responsibilities of the  committee,  as well as rules  to  define   authorship. 
 
 
6.4.2 Clinical Events Committee (CEC) 
 
An independent CEC will be responsible for providing review and adjudication of pre-defined 
clinical events, including major and minor complications, deaths, or other events or endpoints as 
outlined in the CEC Charter. The CEC is responsible for reviewing all reportable Adverse Events as 
defined in section 5. 
 
The CEC will also advise the site PIs on the continuing validity and scientific merit of the clinical 
study. CEC members could be investigators in the clinical study. At any time during the study, the 
CEC may offer opinions or provide formal recommendations concerning aspects of the study that 
impact subject safety (e.g. safety-related protocol changes or input regarding study-related adverse 
event rates). 
 
The primary function, responsibilities and membership of the CEC will be described in detail in a 
CEC charter. 

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7 STATISTICAL CONSIDERATIONS 
 
 
 
The following section describes the statistical methods for the clinical investigation and justification 
of the clinical study protocol. 
 
 
7.1 Primary Safety Endpoint 
 
The primary safety endpoint is the rate of major adverse events through up to six-months after an 
attempted device implant (refer to Appendix A for definition). 
 
 
The proportion of subjects experiencing a major AE through up to six-months will be estimated. 
The 95% confidence interval for the percent of major AE will be calculated using the exact 
binomial method. The numerator  for  the event rate is the  number  of subjects  who  experienced  an 
event through up to six-months. The denominator is the number of subjects in the analysis population 
(As detailed in Section 7.4). The primary safety endpoint rate will be descriptively compared with the 
rate reported in the Amplatzer Piccolo Occluder IDE and Continued Access Protocol studies. The 
overall estimated rate for major complications based on published literature ranges between 4.0 to 
10.0%. 
 
 
7.2 Primary Effectiveness Endpoint 
 
The primary effectiveness endpoint is the rate of effective closure of the PDA among subjects with a 
successful device implant as assessed by the presence of either a Grade 0 or Grade 1 shunt (see 
Appendix A for definition) at the 6 month follow-up visit by transthoracic echocardiography. 
 
 
The proportions of subjects who have effective closure of the PDA at follow-up will be calculated 
along with the 95% confidence interval. The numerator for the event rate is the number of subjects 
who have effective closure of the PDA at follow-up. The denominator is the number of subjects in 
the analysis population (As detailed in Section 7.4). The primary effectiveness endpoint will be 
compared with the rate reported in the ADO II AS and Continued Access Protocol studies. 

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Among subjects successfully implanted with any device, the PDA occlusion rate is estimated to be 
approximately 99%. 
 
 
7.3 Secondary Endpoints 
 
The secondary endpoint is the rate of significant obstruction of the pulmonary artery or aorta 
through the follow-up visit per the following definitions: 
 
1. Significant obstruction of the left pulmonary artery is defined as less than 30% flow to the left 
lung by lung perfusion scan or a peak instantaneous gradient in left pulmonary artery ≥35 mmHg 
by echocardiogram if lung perfusion scan is not available. OR 
 
2. Significant obstruction of the aorta is defined as a gradient of ≥20 mmHg in the aortic isthmus by 
invasive aortic catheterization or a mean gradient ≥20 mmHg in the aortic isthmus by 
echocardiogram if invasive aortic catheterization is not available. 
 
 
The proportions of subjects experiencing an obstruction of the pulmonary artery or aorta through 
the of low-up visit will be calculated along with the 95% confidence interval. The numerator for the 
event rate is the number of subjects who experience an event by the follow-up visit. The 
denominator is the number of subjects in the analysis population (As detailed in Section 7.4). 
 
 
7.4 Analysis Population 
 
The analysis of the primary and secondary endpoints will include all subjects who achieve a 
successful implant, which is defined as leaving the catheterization lab with a device implanted in 
the PDA. If a subject has multiple devices attempted during the same procedure, but leaves 
procedure with at least one device within the PDA the procedure is considered successful. Subjects 
without an implanted device in the PDA will be excluded. Additionally, subjects who had no 
follow- up visits up to the six-months +/- one-month window, or lost to follow-up will be excluded. 
 
 
7.5 Other Endpoints 
 
 
 
The following endpoints will be summarized using descriptive statistics. 
 
 
 
a. Implant success: The frequency and percentage of implant success (defined in Section 7.4) 
will be reported. This analysis will include all subjects entered in the PDA module. 

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b. PDA shunt status at follow-up visit: The frequency and percentage of PDA shunt status at 
the 6 month follow-up visit, as assessed by the TEE, will be reported. Shunt sizes 
categories are: Grade 0/1, 2, and Grade 3/4. This analysis will include subjects who 
achieve a successful implant. 
 
c. Obstruction measurements at follow-up visit: The frequency and percentage of 
significant obstruction of the left pulmonary artery and the frequency and percentage of 
significant aortic obstruction (defined in Section 7.3) at the 6 month follow-up visit will be 
reported. Both analyses will include subjects who achieve a successful implant. 
 
d. Major and Minor Complications: The frequency and percentage of major and minor 
complications (refer to Appendix A for definition) from the time of the implant procedure 
will be reported. 
 
e. Death: The frequency and percentage of death will be reported. 
 
f. Additional data: Demographics and baseline characteristics, procedure information, left 
ventricular function and dimensions, pulmonic and tricuspid regurgitation, adverse events, 
subjects lost to follow-up will also be summarized. 
 
 
7.6. Justification of Clinical Study Design 
 
Based on the IMPACT registry, there are over 6000 transcatheter device closures of PDA that occurs 
in the United States annually. However, there are no comprehensive data collection tools for this 
procedure. The current  databases  do  not include multiple  data  points,  or follow-up  data,  or a 
section for specific adverse events to be documented.  Moreover, until now, there has been no      
approved devices for PDA closure in children < 2kg.  This clinical study is the first of its kind to 
collect data from all transcatheter device closure of PDA in children < 2kg performed at the CCISC 
participating centers.   This study will  be  limited to children between 700 to 2000  grams  who are 
the most vulnerable population undergoing this procedure. This will allow us to understand the 
real world experience (efficacy and safety) of using the Amplatzer Piccolo Occluder device in an 
extremely vulnerable, yet highly underserved population. The study will allow for standardization 
of this procedure throughout the country for the small children (<2 kg) with a PDA. This is a multi-
center, single arm, observational data collection study. This will be a large population study to help 
analyze outcomes in subjects <2 kg. The trial has two primary endpoints for safety and effectiveness 
without formal hypothesis. The safety and effectiveness results will be compared with data 
reported in the Amplatzer Piccolo Occluder IDE and Continued Access Protocol studies. 
 
 
8 REQUIREMENTS FOR INVESTIGATOR RECORDS AND REPORTS 

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8.1 Deviations from Clinical Study Protocol (CSP) 
 
A deviation is defined as an instance(s) of failure to follow, intentionally or unintentionally, the 
requirements of the CSP. The investigator should not deviate from the CSP. In some cases, failure to 
comply with the CSP may be considered failure to protect the rights, safety and well-being of 
subjects; such non-compliance exposes subjects to unreasonable risks. Examples: failure to adhere 
to the inclusion/exclusion criteria, failure to safeguard protected health information (PHI) failure to 
perform safety assessments intended to detect adverse events. Investigators should seek to 
minimize such risks by adhering to the CSP. 
 
If certain assessments such as details of the echocardiogram, RSS, etc., is not performed or completed 
within the CRF, it may not be considered as a deviation as determined by the National PI. The PI 
must maintain accurate, complete, and current records, including documents showing the date of and 
reason for each deviation from the CSP. Relevant information for each deviation will be documented as 
soon as possible on the applicable CRF within the PDA module. The site will submit the CRF to the 
CCISC PDA Module PI. The PI is required to adhere to local regulatory requirements for reporting 
deviations to IRB. An investigator shall notify the CCISC PDA Module PI and the reviewing IRB of 
any deviation from the investigational plan to protect the life or physical well- being of a subject in 
an emergency. Such notice shall be given as soon as possible, but in no event later than10 working 
days after the emergency occurred. The protocol deviation reporting form and a log are provided 
in Appendix F. 
 
 
8.2 Safety reporting 
 
Safety surveillance within this study (and the safety reporting performed by the investigator), 
starts as soon as the subject is referred for PDA closure. The safety surveillance and the safety 
reporting will continue until the follow-up visit has been performed, the subject is deceased, the 
subject/investigator concludes his/her participation into the clinical study or the subject is deemed 
lost to follow-up. All adverse event data required to be reported will be collected throughout the 
clinical study and will be reported to the CCISC PDA Module PI. 
 
 
For the purposes of this clinical study the following events will be reported (see Appendix A for 
definitions): 
 
 
a. Unanticipated adverse device effects 
b. All adverse events viewed/interpreted by investigator to be potentially related to either 
i) the implant procedure or ii) the device regardless of seriousness 
 
 
 
Note – If relatedness is unknown or cannot be determined, then the event must be reported. 

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Note – if a procedure is abandoned and surgical ligation is used to close the PDA, adverse events 
associated with the surgical ligation will not be reported. 
Records relating to the subject’s subsequent medical course must be maintained and submitted (as 
applicable) to the CCISC PDA Module PI until the event has subsided or, in case of permanent 
impairment, until the event stabilizes and the overall clinical outcome has been   ascertained. 
Adverse events will be monitored until they are adequately resolved. The status of the subject’s 
condition should be documented at periodic intervals. 
 
 
 
Subject deaths will be documented and reported to the CCISC PDA Module PI as soon as possible 
(but no later than 3 business days) after becoming aware of the event via the applicable CRF. If an 
unanticipated adverse device effect  occurs, the investigator must notify the CCISC PDA Module PI 
and the IRB immediately, but no later than 10 working days of the investigator’s knowledge of the 
event, as required by 21 CFR §812.150. The CCISC will take any steps necessary to investigate the 
event, and, as appropriate, will be responsible for notifying FDA and all other participating IRBs and 
investigators. 
 
 
8.3 Source records 
 
Source documents will be created and maintained by the investigational site team throughout the 
clinical study. The data reported on the PDA module will be derived from, and be consistent with, 
these source documents, and any discrepancies will be explained in writing. 
 
 
 
8.4 Records retention 
 
The CCISC PDA Module coordinator and Principal Investigators will maintain the clinical study 
documents as required. Measures will be taken to prevent accidental or premature destruction of 
these documents. The Principal Investigator or the CCISC may transfer custody of records to 
another person/party and document the transfer at the investigational site or the CCISC site, as 
appropriate. These documents must be retained by the investigational site for a period of 2 years 
after the conclusion of the clinical study and made available for monitoring or auditing by the 
CCISC or representatives of the applicable regulatory agencies. All original source documents must 
be stored for the maximum time required by the regulations at the hospital, research institute, or 
practice in question. If original source documents can no longer be maintained at the site, the 
investigator will notify the CCISC PDA Module PI. 
 
 
9 Clinical Data Handling 

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The CCISC PDA Module will be responsible for the data handling. The CCISC and/or its affiliates will 
be responsible for compiling and submitting all required reports to governmental agencies. Data 
will be analyzed by the CCISC and maybe transferred to the any other worldwide regulatory 
authority in support of a market-approval application. CCISC will have the ability to send raw data 
and data analysis scrubbed of all PHI and institution information to industry, government agency or 
other worldwide regulatory authorities. 
 
 
9.1 Protection of Personally Identifiable Information 
 
The CCISC respects and protects personally identifiable information collected or maintained for this 
clinical study. The privacy of each subject and confidentiality of his/her information will be 
preserved in reports and when publishing any data. Confidentiality of data will be observed by all 
parties involved at all times throughout the clinical investigation. All data will be secured against 
unauthorized access. 
 
 
9.2 Data Management Plan 
 
A Data Management Plan (DMP) will describe procedures used for data review, database cleaning, and 
issuing and resolving data queries. If appropriate, the DMP may be updated throughout the clinical 
investigation duration. All revisions will be tracked and document controlled. Subject data will be 
captured in a validated electronic data capture (EDC) system hosted by the CCISC. Only authorized 
site personnel will be permitted to enter the CRF data through the EDC system deployed by CCISC. 
An electronic audit trail will be used to track any subsequent changes of the entered data. 
 
9.3 Document and Data Control 
 
9.3.1 Traceability of Documents and Data 
 
The investigator will ensure accuracy, completeness legibility and timeliness of the data 
reported to the CCISC PDA Module on the CRFs and in all required reports. 
 
9.3.2 Recording Data 
 
The CRF will be reviewed by the authorized site personnel. An appropriate comment will be 
provided to explain changes to data reported on the CRF. 
 
 
10 Monitoring 
 
It is the responsibility of the CCISC PDA Module PI to ensure the clinical study is conducted, 
recorded and reported according to the approved CSP, subsequent amendment(s), applicable 
regulations and guidance documents. Monitoring will be conducted according to CCISC’s Clinical 
Monitoring work instruction. Prior to beginning the clinical investigation, the CCISC will contact the 

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Investigator or designee to discuss the clinical study and data requirements. A designated monitor 
will periodically review the subject records and associated source documents. The investigator of 
each site shall make subject and clinical study records available to the clinical monitor. The 
percentage of data that the monitor decides to verify will be according to the discretion of the 
monitor. The CCISC will randomly audit ten percent of the patients entered in the PDA module from 
each institution. Service details are previously outlined in the applicable Service Agreement 
between the CCISC participating site and the CCISC. 
 
 
11 Compliance Statement 
 
11.1 Statement of Compliance 
 
In addition to applicable regional or local laws and regulations, this clinical study will be 
conducted in compliance with the most current version of the World Medical Association (WMA) 
Declaration of Helsinki and 21 CFR Parts 50, 54, 56 and 812. In the event of any conflicts, local 
laws and regulations will have precedence and in such cases, good faith efforts will be made to 
adhere to the intent of the other documents. Each participating site will sign a Clinical Study 
Agreement by appropriate personnel and agree to be compliant with it. Sites will not start 
entering data on subjects undergoing PDA closures prior to obtaining IRB approval and relevant 
Regulatory Authority approval, if applicable, and authorization from the CCISC in writing for the 
clinical study. If additional requirements are imposed by the IRB or relevant Regulatory Authority, 
those requirements will be followed. If any action is taken by an IRB or a relevant Regulatory 
Authority with respect to the clinical study, that information will be forwarded to the CCISC. 
 
11.2 Quality Assurance audits and Regulatory Inspections 
 
The investigator and/or delegate should contact the CCISC immediately upon notification of a 
regulatory authority inspection at the site. A monitor or designee will assist the investigator and/or 
delegate in preparing for the audit. The CCISC may perform quality assurance audits, as required. 
 
The Principal Investigator or institution will provide direct access to source data during and after 
the clinical investigation for monitoring, audits, IRB review and regulatory authority inspections, as 
required. The Principal Investigator or institution will obtain permission for direct access to source 
documents from the subject, hospital administration and national regulatory authorities before 
starting the clinical study. 
 
11.3 Repeated and Serious Non-Compliance 
 
In the event of repeated non-compliance or a one-time serious non-compliance, as determined by 
the CCISC, a monitor or designee will attempt to secure compliance by one or more of the following 
actions: 
a. Visiting the investigator, 
b. Contacting the investigator by telephone, 
c. Contacting the investigator in writing, 

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d. Retraining of the investigator. 
 
If an investigator is found to be repeatedly non-compliant with the signed agreement, the CSP or 
any other conditions of the clinical investigation, the CCISC will either secure compliance or, at its 
sole discretion, terminate the investigator’s participation in the clinical investigation. In case of 
termination, the CCISC will inform the responsible regulatory authority, as required, and ensure 
that the IRB is notified, either by the Principal Investigator or by the CCISC. 
 
 
12 Suspension or premature termination of the clinical investigation 
 
The CCISC reserves the right to terminate the clinical investigation at any stage, with appropriate 
written notice to the investigators, IRB and relevant regulatory authorities, if required. 
A Principal Investigator, IRB or regulatory authority may suspend or prematurely terminate 
participation in a clinical study at the investigational sites for which they are responsible. The 
investigators will follow the requirements specified in the Clinical Study Agreement. 
 
If suspicion of an unacceptable risk to subjects arises during the clinical study or when so 
instructed by the IRB or regulatoryauthority, the CCISC may suspend the clinical study while the 
risk is assessed. The CCISC will terminate the clinical study if an unacceptable risk is confirmed. If   
the CCISC completes an analysis of the reasons for the suspension, implements the necessary 
corrective actions, and decides to lift the temporary suspension, the CCISC will inform the Principal 
Investigators, IRB, or regulatory authority, where appropriate, of the rationale, providing them 
with the relevant data supporting this decision. Approval from the IRB or regulatory authority, 
where appropriate, will be obtained before the clinical study resumes. If the CCISC suspends   or 
prematurely  terminates the  clinical  study at an individual  investigational  site in the  interest  of 
safety,  the CCISC  will inform all  other  Principal Investigators. 
 
 
13 Clinical Study Conclusion 
 
Initial data collection will be limited to 500 subjects. Additional data collection beyond the initial 
cohort of 500 subjects may be done on a voluntary basis by participating sites/physicians. It is 
anticipated to take a minimum of three years to have the 500 Subjects needed for the conclusion of 
the study. 
 
 
14 Publication Policy 
 
Publications or presentations of clinical study methods or results will adhere to CCISC’s publication 
policy, which is based on Good Publication Practices and International Committee of Medical 
Journal Editors (ICMJE) guidelines. A copy of the policy will be provided upon request of the 
investigator. 

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Publication planning and authorship determinations will be overseen by the Publications 
Committee (see section 6.4.1), and investigators will be notified via email about the dissemination 
of study data and opportunities for involvement as authors on publications/presentations. 
 
 
 
 
 
APPENDIX A: DEFINITIONS 
 
 
 
NON-STUDY SPECIFIC DEFINITIONS 
 
 
 
Adverse Event (AE) 
 
Any untoward medical occurrence, unintended disease or injury or untoward clinical signs 
(including abnormal lab findings) in subjects, users, or other persons, whether or not related to the 
device under clinical investigation. This definition includes events related to the device as well as 
events related to the procedure. 
 
 
Serious Adverse Event (SAE) 
 
An adverse event that led to: 
 
a. Death 
b. A serious deterioration in the health of the subject that either resulted in: 
i. 
A life threatening illness or injury 
ii. 
A permanent impairment of body structure or function 
iii. 
Prolonged hospitalization 
iv. 
A medical or surgical intervention to prevent life threatening illness or injury 
v. 
A malignant tumor 
c. Fetal distress, fetal death or a congenital abnormality or birth defect 
d. A planned hospitalization for a pre-existing condition or a procedure required by the CSP 
 
 
 
Adverse Device Effect (ADE) 
 
An adverse event related to the use of an investigational medical device. This definition includes 
adverse events resulting from insufficient or inadequate implantation, installation or operation, or 
any malfunction of the investigational medical device. This definition includes any event resulting 
from the use error or from intentional misuse of the  investigational  medical device. 

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Serious Adverse Device Effect (SADE) 
 
Adverse device effect that has resulted in any of the consequences characteristic of a serious 
adverse event. 
 
 
Unanticipated Adverse Device Effect (UADE) 
 
As defined in 21 CFR§812.3, Unanticipated Adverse Device Effect (UADE) are defined as 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 CSP or application (including supplementary plan or application), or any 
other unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of subjects. 
 
 
STUDYSPECIFIC   DEFINITIONS 
 
 
 
Related 
 
The adverse event is related to the study device/procedure – i.e. an event that follows a reasonable 
temporal sequence from administration of the study intervention, follows a known or expected 
response pattern to the suspected intervention, that is confirmed by improvement on stopping and 
reappearance of the event on repeated exposure and that could not be reasonably explained by the 
known characteristics of  the  subject’s  clinical state. 
 
In summary, the AE is related to any study device or procedure if the event satisfies all of following 
criteria: 
 
a. Has a reasonable temporal relationship to intervention (e.g. device implant) 
b. Could not readily have been produced or explained by the subject’s clinical state or have 
been due to environmental or other interventions 
c. Follows a known pattern of response to intervention 
d. Disappears or decreases with reduction in dose or cessation of intervention and recurs with 
re-exposure 
 
 
Major Complication 
 
Major complications are defined as device or procedure-related adverse events resulting in any of 
the following: 

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a. Death 
b. Life-threatening adverse event, 
c. Persistent or significant disability/incapacity, and/or 
d. A major open surgical intervention which is performed by a surgeon under 
general anesthesia 
 
 
Examples of Major Complications: 
 
a. Device or procedure related events leading to death 
b. Cardiac perforation requiring percutaneous (e.g., pericardiocentesis) or open surgical 
intervention 
c. Cardiac tamponade 
d. Embolization requiring open surgical procedure (e.g., open heart surgery or femoral vessel 
cut down procedure) to retrieve the device 
e. Persistent hemodynamic instability requiring emergency cardioversion/defibrillation 
therapy or emergency blood transfusion and/or institution of inotropic therapy 
f. Excessive blood loss or hemolysis requiring transfusion > 20 cc/kg 
g. Persistent or worsening respiratory instability 
h. Cerebral or pulmonary embolism 
i. Persistent cardiac arrhythmia requiring a pacemaker 
j. Arteriovenous fistula requiring open surgical intervention 
k. False aneurysm of the femoral artery requiring surgical intervention 
l. 
Femoral vessel thrombophlebitis treated with intravenous antibiotics 
m. Infection of the device (bacterial endocarditis) 
 
Minor Complication 
 
Minor complications are defined as device or procedure-related adverse events that do not fit the 
definition of a major complication. These will include adverse events which may require medical 
intervention but are not life threatening, are not likely to have long-term (> 6 months) sequelae, 
and do not require long term (> 6 months) therapy. The following are examples of adverse events 
considered to be minor complications: 
 
a. Embolization that occurs intra-operatively where the device is retrieved using a 
transcatheter approach (e.g., using a snare) without needing to perform an open surgical 
procedure, such as open heart surgery or an open femoral vessel cut down procedure. 
b. Reduced peripheral pulse (reversible) that can be managed with anti-thrombotic therapy 
(e.g., heparin, Aspirin) 
c. Cardiac perforation not requiring percutaneous (e.g., pericardiocentesis) or open surgical 
intervention 
d. Transient cardiac arrhythmia that is managed successfully with cardioversion 
or medication 
e. Hematoma of the groin not requiring open surgical intervention 

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PDA Residual Shunt Grades Definitions 
 
Grade 0—none; 
 
Grade 1—trivial (narrow jet adjacent to the device via the PDA). Note: the presence of flow via 
existing or newly formed aortopulmonary collaterals should not be considered as representing 
a shunt via the PDA. (see references in Appendix  B by  Skinner  and Acherman) 
 
Grade 2—mild (broader jet filling proximal left pulmonary artery branch and extending to 
main pulmonary artery); 
Grade 3/4—moderate to severe (wide jet filling the main pulmonary artery and extending to 
pulmonary valve or distal pulmonary artery branches, which also may be accompanied with 
the presence of flow reversal in the abdominal aortic Doppler pattern during diastole) 
 
 
Definitions of significant adjacent vessel stenosis (narrowing/obstruction) 
 
1. Significant obstruction of the left pulmonary artery is defined as less than 30% flow to the 
left lung by lung perfusion scan or a peak instantaneous gradient in left pulmonary artery 
≥35 mmHg by echocardiogram if lung perfusion scan is not available. OR 
 
2. Significant obstruction of the aorta is defined as  a gradient of ≥20  mmHg in the  aortic 
isthmus by invasive aortic catheterization or a mean gradient ≥20 mmHg in the aortic isthmus 
by echocardiogram if invasive aortic catheterization is not available. 

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APPENDIX B: BIBLIOGRAPHY 
 
1. Tashiro, Jun, Eduardo A. Perez, and Juan E. Sola. "Reduced Hospital Mortality with Surgical 
Ligation of Patent Ductus Arteriosus in Premature, Extremely Low Birth Weight Infants: A 
Propensity Score-matched Outcome Study."Annals of surgery (2015). 
2. Schneider, Douglas J. "The patent ductus arteriosus in term infants, children, and adults." In 
Seminars in perinatology, vol. 36, no. 2, pp. 146-153. WB Saunders, 2012. 
 
3. Mahoney LT, Coyell KG, Laurer RM: The Newborn Transitional Circulation: Two-dimensional 
Doppler Echocardiographic Study. J Am Coll Cardiol 1985;6:623. 
 
4. Philip, Ranjit, B. Rush Waller, Vijaykumar Agrawal, DenaWright, Alejandro Arevalo, David 
Zurakowski, and Shyam Sathanandam. "Morphologic characterization of the patent ductus 
arteriosus in the premature infantand the choice of transcatheter occlusion device." 
Catheterization and Cardiovascular Interventions (2015). 
5. Krichenko A, Benson LN, Burrows P, et al: Angiographic classification of the isolated, persistently 
patent ductus arteriosus and implications for percutaneous catheter occlusion. Am J of Card 
1989;63:877-80. 
 
6. Pass R: AMPLATZER Duct Occluder Device: A New Technologyfor the Closure of the Moderate- to-
large-sized Patent Ductus Arteriosus. Expert Rev Med Devices 2006;3:291-296. 
 
7. Schneider, Douglas J. "The patent ductus arteriosus in term infants, children, and adults." In 
Seminars in perinatology, vol. 36, no. 2, pp. 146-153. WB Saunders, 2012. 
 
8. Moore JW, Levi DS, Moore SD, Schneider DJ, Berdjis F. Interventional Treatment of Patent Ductus 
Arteriosus in 2004. Catheter Cardiovasc Interv 2005;64:91-101. 
 
9. Perlo f, Joseph K.The Clinical Recognition of Congenital Heart Disease. Philadelphia: Saunders. 
Print. 
 
10. Gross RE, Hubbard JP. Surgical ligation of a patent ductus arteriosus: report of first successful 
case. Congenital Heart Disease, Hutchinson Ross Pub Co., 1982, p 253. 
 
11. Kabra,Nandkishor S., etal. "Neurosensory impairment after surgical closure of patent ductus 
arteriosus in extremely low birth weight infants: results from the Trial of Indomethacin Prophylaxis 
in Preterms." The Journal of pediatrics 150.3 (2007): 229-234. 
 
12. Chorne, Nancy, etal. "Patent ductus arteriosus and its treatment as risk factors for neonatal and 
neurodevelopmental morbidity." Pediatrics 119.6 (2007): 1165-1174. 
 
13. Teixeira, L. S., et al. "Postoperative cardiorespiratory instability following ligation of the preterm 
ductus arteriosus is related to earlyneed forintervention." Journal of Perinatology 28.12 (2008): 
803-810. 

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14. Portsmann W, Wierny L, Warnke H, etal: Catheter closure of patent ductus arteriosus: 62 cases 
treated without thoracotomy. Radiol Clin North Am 1971;9:203-218. 
15. Weisz, Dany E., and Patrick J. McNamara. "Patent ductus arteriosus ligation and adverse 
outcomes: causality or bias?." Journal of clinical neonatology 3.2 (2014): 67. 
16. Philip, Ranjit, B. Rush Waller, Vijaykumar Agrawal, DenaWright, Alejandro Arevalo, David 
Zurakowski, and Shyam Sathanandam. "Morphologic characterization of the patent ductus 
arteriosus in the premature infantand the choice of transcatheter occlusion device." 
Catheterization and Cardiovascular Interventions (2015). 
 
17. 17. Gruenstein, Daniel H., et al. "Transcatheter closure of patent ductus arteriosus using the 
AMPLATZER™ duct occluder II (ADO II)." Catheterization and Cardiovascular Interventions 89.6 
(2017): 1118-1128.Agnoletti, Gabriella, D. Marini, A.  M. Villar, R.  Bordese,  and F.  Gabbarini.  "Closure 
of  thepatent ductus  arteriosus  with  the new duct occluder  II additional  sizes device." 
Catheterization and Cardiovascular Interventions 79, no. 7 (2012): 1169-1174. 
18. Kenny, Damien, Gareth J. Morgan, James R. Bentham, Neil Wilson, Robin Martin, Andrew 
Tometzki, Paul Oslizlok, and Kevin P. Walsh. "Early clinical experience with a modified Amplatzer 
ductal occluder for transcatheter arterial duct occlusion in infants and small children." 
Catheterization and Cardiovascular Interventions 82, no. 4 (2013): 534-540. 
 
19. Sungur, Metin, Cemsit Karakurt, Nazan Ozbarlas, and Osman Baspinar. "Closure of patent ductus 
arteriosus in children, small infants, and premature babies with Amplatzer duct occluder  
additional sizes: multicenter study."Catheterization and Cardiovascular Interventions 82, no. 2 
(2013): 245-252. 
 
20. Bruckheimer, Elchanan, Max Godfrey, Tamir Dagan, Michael Levinzon, Gabriel Amir, and Einat 
Birk. "The Amplatzer duct occluder additional sizes device for transcatheter PDA closure: Initial 
experience." Catheterizationand Cardiovascular Interventions 83, no. 7 (2014): 1097-1101. 
 
21. Baspinar, Osman, Derya Aydin Sahin, Ayse Sulu, Ahmet Irdem, Gokhan Gokaslan, Ercan Sivasli, 
and Metin Kilinc. "Transcatheter Closure of Patent Ductus Arteriosus in Under 6 kg and Premature 
Infants." Journal ofinterventionalcardiology 28, no. 2 (2015): 180-189. 

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APPENDIX C: PDA MODULE/CASE REPORTING FORM (CRF) 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX D: ADVERSE EVENT REPORTING FORM 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential 
40 

Confidential 
41 
 
 
 

Confidential 
42 
 
APPENDIX E: SCHEDULEOF ASSESSMENTS 
 
 
 
 
 
Pre- 
Catheterizatio
Device 
Implan
Follow up 
within 48 hours 
Follow up at 
30 ± 7 days 
Follow up at 
6 ± 1months 
Demographic Data 
X 
Physical Exam Data 
X 
X 
X 
X 
Medical History 
Data 
X 
Procedure Data 
X 
Device Data 
X 
Transthoracic 
Echocardiogra
m Data 
X 
X * 
X 
X 
X 
Adverse Event Data 
X 
X 
X 
X 
Death Data 
X 
X 
X 
X 
* optional Intra-procedure Transthoracic Echocardiogram 

Confidential 
43 
 
 
 
APPENDIX F 
 
 

Confidential 
44 
 
 
 
 

Confidential 
45 
 
 
 

Confidential 
46 
 
 
 
 
 
 
 

Confidential 
47 
 
APPENDIX G 
 
 

Confidential 
48