Safety, Pharmacokinetics (PK) and Hemodynamic Effects of Ambrisentan in Single Ventricle Pediatric Patients
Phase: PHASE2
Conditions: Hypoplastic Left Heart Syndrome, Hypoplastic Right-sided Heart Complex
Sponsor: Kevin Hill

03-21-2016 
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Safety, Pharmacokinetics (PK) and Hemodynamic Effects of Ambrisentan 
in Single Ventricle Pediatric Patients 
 
NCT02080637 
 
Document Date: March 21, 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Title: Safety, Pharmacokinetics (PK) and Hemodynamic Effects of Ambrisentan in 
Single Ventricle Pediatric Patients. 
 
1. Protocol Synopsis 
 
Protocol Title 
Safety, Pharmacokinetics (PK) and Hemodynamic Effects of Ambrisentan in 
Single Ventricle Pediatric Patients. 
Product 
ambrisentan 
Objective: 
To evaluate the safety, PK and hemodynamic effect of ambrisentan in pediatric 
patients with single ventricle heart defects. 
Study Design: 
Randomized, double blind, placebo controlled PK, safety, and hemodynamic 
efficacy study. 
Study Population: 
Up to 20 patients ages ≥ 24 months and ≤120 months with single ventricle cardiac 
lesions; Undergoing elective Fontan surgical palliation. 
Number of 
Subjects: 
Up to 20 subjects  
Duration of Subject 
Participation: 
Until 1 month after administration of the last study drug administration 
Inclusion criteria 
1. 
Age ≥ 24 months; ≤120 months. 
2. 
History of congenital heart disease with severe hypoplasia of a right 
or left ventricle. 
3. 
Undergoing Fontan surgery as part of standard clinical care. 
4. 
Availability and willingness of the parent/legally authorized 
representative to provide written informed consent and, as appropriate, 
assent from the child. 
Exclusion criteria 
1. History of serious adverse event related to ambrisentan administration. 
2. History of ambrisentan exposure within 48 hours of the study. 
3. Presence of pulmonary venous obstruction. 
4. Treatment with cyclosporin 
5. Any of the following – as determined by the attending physician 
a. Significant hemodynamic instability 
b. Sepsis. 
c. Need for ECMO support. 
6. Renal failure defined as serum creatinine > 2 times higher than the 
upper limit of normal. 
7. Liver dysfunction defined as alanine aminotransferase or aspartate 
aminotransferase > 3 times higher than the upper limit of normal. 
8. Thrombocytopenia defined as a platelet count < 50 000 cells/µL. 
9. Leukopenia defined as white blood cells < 2500 cells/µL. 
10. Anemia defined as hemoglobin < 8mg/dL 
11. Atrial hypertension (mean LA pressure > 12mm Hg) 
Dose Schedule: 
Once daily oral administration 
Estimated Start: 
Jan 2014 
Estimated Finish: 
Jan 2016 
Duration of therapy 
3 days 

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PK/PD: 
Blood samples will be obtained at various time points after drug administration. PK 
parameters will be estimated by non-compartmental analysis using WinNonLin 
software. PD parameters will include change in hemodynamic endpoints (Fontan 
pressures, calculated cardiac index, pulmonary vascular resistance and brachial 
artery flow mediated vasodilation measured by ultrasound) 
Statistical 
Consideration: 
This protocol has sufficient enrollment to provide pilot safety and PK data and to 
allow assessment of the hemodynamic effects of ambrisentan on pulmonary 
vascular resistance and Fontan pressures.  
 
2. Purpose of the Study   
The purpose of the study is to evaluate the safety, pharmacokinetics (PK) and  
pharmacodynamics (PD) of ambrisentan in children with single ventricle heart defects that are 
undergoing Fontan (stage III) surgical palliation. This is a double blind, placebo controlled study.  
The primary objective of this Phase I/II study is to assess the plasma PK, safety and PD of oral 
ambrisentan in children with surgically palliated single ventricle heart defects. A secondary 
objective will be to assess whether ambrisentan improves post-operative outcomes including 
amount and duration of chest tube drainage and hospital length of stay.  
 
3. Background and Significance 
Complex congenital heart defects associated with underdevelopment of a ventricle account for 
~8% of congenital heart disease with a birth incidence of 4-8/10000 live births. These single 
ventricle lesions are associated with high morbidity and 5 year mortality rates that approach 50%. 
Staged surgical palliation directs returning venous blood flow directly into the lungs so that 
pulmonary blood flow occurs without the aid of a pumping chamber. The final stage of surgery 
(stage III – the Fontan procedure) incorporates inferior caval blood flow directly into the 
pulmonary arteries. Consequently pulmonary blood flow and cardiac output are directly related to 
pulmonary vascular resistance and ventricular function. The limitations of single ventricle 
surgical palliation often result in a prolonged post-operative course with pleural effusions a 
particular concern.  There is also continued long term attrition. Elevated pulmonary vascular 
resistance and impaired systemic ventricular function are important risk factors for early and late 
failure of single ventricle palliation.  
 
Ambrisentan is an endothelin receptor antagonist that improves pulmonary and possibly systemic 
endothelial function. Ambrisentan is approved for treatment of pulmonary arterial hypertension in 
adults and is used off-label for treatment of pulmonary hypertension in childen.  Children with 
single ventricle heart defects demonstrate both pulmonary and systemic endothelial dysfunction 
and may benefit from treatment with this drug. However pharmacokinetics and hemodynamic 
efficacy of ambrisentan have not been studied in single ventricle patients. The most widely used 
alternative agent, sildenafil, was recently associated with increased mortality in children.  There is 
now an FDA safety warning against use of sildenafil in children.  We have previously 
demonstrated hemodynamic benefits with use of sildenafil in these patients but ambrisentan is a 
potentially safer agent. Therefore this study would fill an unmet need to guide dosing and 
evaluate efficacy of ambrisentan in this vulnerable population.  
 
4. Design and Procedures 
This is a single-center, randomized, blinded PK study of ambrisentan in children ages ≥ 24 
months and ≤120 months with single ventricle anatomy. There will be up to 20 subjects enrolled; 
16 will receive ambrisentan and 4 will receive placebo. A small placebo control group is 
warranted to ensure that any treatment effect is not a result of post-operative improvement. 
Patients will be enrolled at the time of their routinely scheduled Fontan surgery.  

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Initial Dose: Oral ambrisentan 2.5 – 5 mg, single dose, once daily (nasogastric and gastrostomy 
tube administration will be considered only when a nasogastric or gastrostomy tube is already in 
place as part of routine post-operative care).Subjects will be randomized by Investigational Drug 
Services (IDS) to placebo (n=4) or oral ambrisentan (n=16) using permuted blocks. Subjects will 
receive either an oral suspension (2.5 or 5mg)  or a 5mg tablet depending on their ability to 
swallow a tablet.  To begin to ensure safety, the initial 5 subjects enrolled in the study (at least 4 
active drug) will receive a dose of 2.5mg in a liquid suspension prepared by IDS.  After 
enrollment of these subjects we will perform a preliminary PK/safety analysis and evaluate 
ambrisentan exposure.   If the drug is well tolerated (no grade III or greater adverse events) and 
exposure is less than the target exposure of 500-800ng/mL, then we may increase the dose to 
5mg/dL provided via tablet in those able to take a tablet or suspension for all others. If drug 
exposure is less than 100ng/mL then we will enroll additional study subjects to ensure that at least 
16 study subjects achieve adequate drug exposure. If drug exposure is in the target range then we 
will continue to enroll study subjects to receive the 2.5mg suspension. 
 
As summarized below, study drug will be discontinued for any grade 3 or greater adverse event.  
If this occurs then IDS will be permitted to unblind the study patient to allow for appropriate 
adverse event reporting.  Drug administration will start on post-operative day #1 with initiation of 
oral feeds. Study drug/placebo will be prepared and delivered to the patient bedside by 
investigational drug services and administered orally. Subjects will continue on study drug for 3 
days.  
 
The total study duration is expected to be approximately 24 months for enrollment of up to 20 
subjects.  Study participants will remain in the study until 1 month after discharge following stage 
III surgery intervention or for 6 months – whichever is shorter.  The subjects will receive routine 
care before, during and immediately after surgery and after hospital discharge. We will record all 
in-hospital adverse events and tabulate by organ system. One month after the last study drug 
administration (dose #3), we will contact patients by phone or evaluate in person if they remain 
hospitalized. 
 
Plasma PK will be evaluated using a limited sampling scheme. A preliminary safety and PK 
analysis will be performed after 5 subjects are enrolled. Ambrisentan PK will be evaluated and 
dosing may be adjusted to achieve levels consistent with those reported in the adult and pediatric 
literature. 
 
5. Study medication 
 
Rationale for Dose Selection 
Preliminary data from 16 children with pulmonary hypertension using once-daily doses of 5 mg 
demonstrate similar Cmax and AUC24hr to those seen in adult patients. This PK study included 
children and adolescents ages 2 years – 18 years including 9 subjects age <= 10 years.  Weight 
ranged from 13kg to 52 kg.  The half-life of elimination was 7.6 hours (range 5.4–15.3 hours), 
and there was improvement in hemodynamic parameters (mean pulmonary arterial pressure 
55±18 mm Hg decreased to 45±20 mm Hg after initiation of ambrisentan, p=0.04). Ambrisentan 
was well tolerated in all patients with no serious adverse events. In post-operative Fontan 
patients, I anticipate decreased bioavailability due to post-operative bowel wall edema but also 
decreased hepatic elimination. I will perform a preliminary PK/PD analysis after enrolling the 
first 5 subjects (at least 4 active drug) and adjust the dosing to achieve target peak concentrations 
of 500–800 ng/mL, a range that has demonstrated therapeutic efficacy as well as safety in adults. 
To maintain blinding, we will request that ambrisentan levels be sent from the commercial 

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laboratory directly to IDS.  IDS will remove study patient identifiers and then forward the drug 
levels for PK analysis and determination of dose adjustment. 
 
Study Drug and Administration 
 
Drug Supplies 
Film coated tablets – 5mg and matching placebo. 
 
Ambrisentan is manufactured by Gilead Sciences Incorporated. The drug is marketed and 
supplied as 5 and 10mg film coated tablets. The tablets are different colors for the different 
dosages and are also labeled with the dose on the outside of the tablet. Matching placebo tablets 
are identical in appearance and are available in the 5 and 10mg forms. Ambrisentan will be 
administered as a tablet to all children that are able to take an oral tablet.  In those that are unable 
to swallow a tablet, ambrisentan/placebo will be compounded as described below and 
administered as an oral suspension. A secondary study objective is to compare bioavailability of 
the tablet versus compounded formulation. 
 
Compounding: 
• All drug compounding procedures should be performed under a safe fume hood. 
• During preparation of suspension, gloves and a mask should be worn. 
• Crush 5mg tablet,  
• Suspend in equal parts of Ora-plus (2.5 mL) and Ora-sweet (2.5 mL) 
• Stability: the suspended dose must be administered within 4 hours of preparation. 
 
Ambrisentan must be delivered to the patient room from the investigational drug service on the 
day of administration. A label containing the protocol number and patient number must be 
applied to the drug package or syringe.  The exact time of study drug administration must be 
documented on the case report form. Vital signs will be recorded per standard post-operative 
protocol for the remainder of the study.   
 
6. Selection of Subjects: 
Inclusion Criteria 
1. Age ≥ 24months and ≤ 120 months. 
2. Congenital heart disease with underdevelopment of the right or left ventricle. 
3. Presenting for elective Fontan (total cavopulmonary anastomosis) single ventricle 
palliation. 
4. Availability and willingness of the parent/legal guardian to provide written informed 
consent 
 
Exclusion Criteria 
1. History of serious adverse event related to ambrisentan administration. 
2. History of ambrisentan exposure within 48 hours of the study. 
3. Presence of pulmonary venous obstruction. 
4. Treatment with cyclosporin 
5. Any of the following – as determined by the attending physician 
a. Significant hemodynamic instability 
b. Sepsis. 
6. Renal failure defined as serum creatinine > 2 times higher than the upper limit of 
normal. 

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7. Atrial hypertension defined as a common mean atrial pressure > 12mm Hg via direct 
measurement (central line) or a Fontan mean pressure > 22mm Hg in a patient with 
no atrial line. 
 
7.  Subject recruitment and compensation: 
Children presenting for elective Fontan surgery age ≥ 24 months and ≤ 120 months will be 
identified by the research staff and screened for eligibility. A caregiver known to the family will 
introduce the study.  If the family is interested in participating, study staff will then approach 
families to review the study and get written consent at a pre-surgical clinic visit or at the time of 
pre-surgical cardiac catheterization. Approval by the subject’s healthcare provider will be 
obtained prior to enrollment. We will consent up to 50 subjects with the goal of achieving up to 
20 evaluable subjects. There will be no compensation for subject participation. 
 
8. Consent Process:  
The research staff will conduct the consent process as outlined by GCP guidelines. Consent will 
be obtained from each child’s parent or legal guardian when they are identified by study staff as 
an eligible candidate for study enrollment. Consent is indicated on the study-specific consent 
form with the signature of the parent or guardian. The process will take about 1 hour and the 
parent/guardian will be allowed as much time as they need to decide whether or not to enroll 
their baby in the study. 
 
9. Subject’s capacity to give legally effective consent: N/A 
 
10. Study Interventions:   
 
Baseline/Pre-Dose Assessment 
After the parent or legally authorized representative has signed the IRB-approved 
informed consent form, and after it has been determined that the patient satisfies all 
inclusion and exclusion criteria, the following evaluations will be performed and 
recorded in the CRF: 
1. 
Baseline demographics, medical history and medical baseline conditions. 
2. 
Physical examination. 
3. 
Preoperative laboratory assessment (obtained as part of usual clinical care for 
pre-operative assessment: 
a. Hematology: hematocrit, hemoglobin, white blood cell count with differential, 
platelet count. 
b. Serum chemistry: creatinine, blood urea nitrogen, sodium, potassium, calcium. 
c. Liver function tests:  aspartate transaminase (AST), alanine transaminase (ALT), 
alkaline phosphatase, total bilirubin, conjugated bilirubin, serum albumin. 
 
Study Procedures  
1. Record the start and stop time of ambrisentan administration and all concomitant 
drugs.  
2. Hemodynamic evaluation performed during pre-operative cardiac catheterization 
(obtained as part of usual clinical care), prior to initiation of study drug, and at 0-
1,1-6,18-30 and 40-60hrs after administration of the first ambrisentan dose 
(blood samples will be collected only if central monitoring lines remain or if they 
can be timed with a routine lab collection) 

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a. Record Fontan, common atrial, and systemic arterial pressures from 
existing central lines that are placed as part of routine post-operative 
care.  
b. Collect study labs (coincident with scheduled PK levels – see below): 
i. plasma samples for biomarkers (endothelin 1 [ET1], brain 
natriuretic peptide [BNP]).   
c. Record oxygen saturation from routinely collected arterial and venous 
blood gases.  
3. PK blood samples (500 µL, up to 7 per patient) and pressure measurements will 
be obtained at baseline and at 1–2, 3–4, 5–6, 8–12, 12–16, 24, and 48 hours post-
initial drug administration.  
4. Adverse events will be collected during and for 1 month after the last study drug 
administration. Results will be tabulated by organ system. 
5. Physical examination will be performed within 24 hours after administration of 
study drug and once daily during study enrollment. 
6. Record all AEs and SAEs.   
7. Record all concomitant medication administered 24 hours after administration of 
study drug. 
8. Up to 4 scavenge samples will be obtained from the clinical laboratory from 
samples collected in the 24 hours following ambrisentan administration.  
Scavenged samples are left over heparinized plasma samples from these children 
that are collected from the clinical laboratory prior to discarding. 
 
PK Sampling  
A limited PK sampling scheme will be employed such that no more than 3000 μl of blood 
is obtained.   
 
Hospitalization Procedures 
1. Any of the following clinical laboratories performed as standard of care during the study will 
be recorded.  We will use the laboratory values closest to study dose if there have been 
multiple tests.   
a. Hematology: hematocrit, hemoglobin, white blood cell count with differential, platelet 
count 
b. Serum chemistry: creatinine, blood urea nitrogen, sodium, potassium, calcium 
c. Liver function tests:  aspartate transaminase (AST), alanine transaminase (ALT), alkaline 
phosphatase, total bilirubin, conjugated bilirubin 
2. Physical examination will be performed daily during the post-operative hospitalization. 
3. Record all AEs for 24 hours after the last dose of study drug 
4. Record all SAEs for 1 month after the last dose of study drug   
5. Record duration of mechanical ventilation 
6. Record hospital length of stay 
7. Record intensive care unit length of stay 
8. Record duration and volume of chest tube drainage 
 
 
Plasma PK Sampling and Handling 
Timing of samples will treat the start time of oral administration of the first dose as time zero (0). 
The date and time will be recorded for the start/stop time of oral drug administration and for the 
acquisition time of the PK sample.  The pharmacokinetic samples will be obtained in sodium 
heparin collection tubes.  
 

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11. Trial registration: 
The trial will be registered on clinicaltrials.gov before study enrollment begins pursuant 
with FDAAA trial registry requirements. 
 
12. Risk/Benefit assessment:  
Blood volume: In order to minimize the amount of blood sampling, hematology and chemistry 
laboratory measures will be obtained per local standard of care; and a limited PK sampling 
scheme will be employed such that no more than a total of 3000 μl of blood is obtained from each 
patient for PK analysis.  Blood samples will be collected in 500 µL aliquots.  In addition a total of 
4 samples will be obtained for biomarker assessment.  Blood samples will again be collected in 
500 µL aliquots.  No more than 2000 μl will be collected for biomarker assessment. During the 
study samples will be obtained from indwelling central venous catheters. If central venous lines 
are not available then samples will be obtained from a peripheral IV if present.  If no IV is present 
then every effort will be made to time the PK sampling with line draws or heel sticks for normal 
laboratory monitoring including chemistries, blood gases, and accuchecks.  This should result in 1 
or 2 additional line draw or possibly heel sticks specifically for PK sampling in any given child.   
 
Drug related adverse effects: 
 
Below is a summary of adverse events associated with ambrisentan use from the pivotal trials as 
reported on the drug label: 
 
Table. Adverse Reactions with Placebo-Adjusted Rates >3% 
 
Placebo (N=132) 
Letairis (N=261)  
 
Adverse reaction  
n (%)  
n (%)  Placebo-adjusted (%)  
Peripheral edema  
14 (11)  
45 (17)  
6  
Nasal congestion  
2 (2)  
15 (6)  
4  
Sinusitis  
0 (0)  
8 (3)  
3  
Flushing  
1 (1)  
10 (4)  
3  
 
Peripheral edema was similar in younger patients (>65 years) receiving Letairis (14%; 
29/205) or placebo (13%; 13/104), and was greater in elderly patients (<65 years) receiving 
Letairis (29%; 16/56) compared to placebo (4%; 1/28).  In a retrospective report of 
ambrisentan use in 38 children ages 2-18 years with pulmonary hypertension, no patient 
developed peripheral edema. We will assess for peripheral edema daily in our patients and 
ambrisentan will be discontinued in patients demonstrating significant worsening of 
peripheral edema. 
 
Ambrisentan use is contra-indicated in patients with pulmonary venous obstruction as use can 
cause pulmonary edema. Theoretically patients with single ventricle diastolic dysfunction 
and associated elevated left atrial pressures might also be at risk for pulmonary edema. 
Elevated common atrial pressures at the time of drug initiation (mean >12mm Hg) will be 
considered a contraindication to study enrollment. If an atrial line is not in place then a 
Fontan mean pressure > 22mm Hg will be considered as a surrogate estimate of LA 
hypertension. 
 
A preclinical study in a juvenile rat model showed decreased brain weight following chronic 
treatment (> 1 year) with high doses (at least several times the recommended high dose limit 

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in adults). In a study of 38 children (ages 2- 18) there were no neurologic side effects. We 
will assess neurologic status with all vital sign checks per routine post-operative protocol. 
 
Long term ambrisentan use has been associated with a mean lowering of hemoglobin of 
0.8mg/dL.  These changes have not been seen until after several weeks of therapy.  In the 
post-operative setting it is not uncommon to see some blood loss after surgery.  We will 
monitor daily labs obtained as part of routine post-operative care.  If there is a decline in 
hemoglobin beyond that expected as part of the normal post-operative course, then we will 
consult with the physicians caring for the child and discontinue ambrisentan if use is possibly 
contributing to worsening anemia. 
 
Other risks: Subjects will be closely monitored in an ICU setting during the first drug 
administration.  They may be transferred to the floor service for the 2nd and 3rd doses but 
will continue to be monitored with routine vital signs.  
 
Drug interactions: Ambrisentan has the potential for drug interactions with cyclosporine 
 
Potential for benefit: Ambrisentan is a selective pulmonary vasodilator with potential benefit in 
this patient population. Use in the post-operative setting may improve post-operative course with 
the potential to decrease duration of chest tube drainage as well as ICU or hospital length of stay. 
Whatever the findings may conclude, this study will provide additional information about 
ambrisentan to physicians and may provide preliminary data for a multi-center pK study 
in this population. Therefore, future children may benefit from the increased knowledge 
of physicians who treat them. Participation in this research study is optional; if parents 
decide not to allow their child to participate in the study their child’s routine standard of 
care will not be altered.  
 
12. Costs to the subject and compensation:  
The subject will incur no charges or fees for participating in the study. Gilead will supply 
the study drug.  The remaining study costs will be covered by the Gilead Sciences 
Research Scholars Program in Cardiovascular Disease, including cost of pK and 
biomarker analysis.  
 
13. Data Analysis & Statistical Considerations: 
There will be up to 50 subjects enrolled and receiving drug in this study.  Additional subjects will 
be enrolled to ensure that at least 20 subjects have at least 4 evaluable PK samples and that at 
least 16 subjects have ambrisentan peak exposure > 100ng/dL. Subjects who have only 1 
evaluable sample will be included in the analysis. Descriptive statistics such as number of 
observations, mean, median, 95% confidence interval, standard deviation, standard error, 
minimum, and maximum will be presented for continuous variables (such as age, weight, etc). 
Other descriptive statistics such as counts, proportions, and/or percentages will be presented to 
summarize discrete variables (such as race, sex, etc.). Pharmacokinetic parameters will be 
calculated using non-compartmental analysis using WinNonlin software (Pharsight Corporation, 
Mountain View, CA). As previously mentioned, there will be an interim PK analysis that may 
alter the dosage. 
 
14. Data & Safety monitoring: 

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Laboratory data, such as hematology and serum chemistry data will be tabulated by dosage group. 
Summary statistics for changes from baseline will be presented.  Hemodynamic measurements 
will be described using univariable descriptive statistics (mean median, etc.); observed values and 
changes from baseline will be summarized.  
 
Safety 
Adverse events will be collected during study participation.  
 
Study termination 
Adverse events will be defined based on the Common Terminology Criteria for Adverse 
Events (CTCAE) v4.03 (1). 
 
In accordance with the CTCAE guidelines, adverse events will be evaluated by organ 
system and broadly defined as follows: 
 
Grade 1:  
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2:  
Moderate; minimal, local or non-invasive intervention indicated; limiting 
age appropriate instrumental activity of daily living. 
Grade 3:     
Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self care ADL. 
Grade 4:     
Life threatening consequences; urgent intervention indicated. 
Grade 5:     
Death related to AE. 
 
Study drug  must be discontinued and the patient will be withdrawn from the study 
if one of the following occurs: 
• Patient develops a grade 3 or greater adverse event thought to be related to study 
drug.  
• The study team decides it is in the patient’s best interest to discontinue study drug 
 
The study will be stopped if one of the following occurs: 
• Any 3 participants experience a grade 3 adverse event. 
• Any single participant experiences a grade 4 or grade 5 adverse event. 
 
Serious Adverse Events 
Serious adverse events (SAE) will be defined as Grade 3 or greater adverse events. 
Investigators will submit safety reports of all SAE as required by the Institutional Review 
Board (IRB) and Pfizer Inc.  
 
 
Dose Interruptions for Serious Adverse Events 
If the patient experiences an AE felt to be related to study drug, the drug will be held at 
the discretion of the investigator. For an AE felt to be at least possibly related to study 
drug, study drug can be held until the AE resolves. Resume drug at the original dose. If 
the same AE recurs, study drug should be held. For an AE not felt to be due to study 
drug, no interruption is necessary. 

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All patients who receive study medication will be followed for safety. Peer investigators 
including Dr. Michael Cohen-Wolkowiez and Dr. Jennifer Li will conduct an internal 
review of study safety following the completion 6 subjects.  The safety review will 
include all SAEs, all AEs thought to be possibly or probably related to the study drug, 
and all patients who discontinued participation in the study early. Enrollment will be 
allowed to continue during the safety evaluation. 
 
15. Data storage & confidentiality: 
Data generated by this study will be available for inspection by any regulatory 
authorities, by the sponsor, and by the Duke IRB, as appropriate, although no routine 
monitoring is planned. Medical information obtained from subjects during the course of 
this study is confidential and disclosure to third parties other than those noted above is 
prohibited. Data will be collected from the medical record and identified with a code 
number. The link between this subject’s identity and the code number will be kept locked 
in a research office at Duke and in a password protected computer. All study data will be 
securely stored. Data about subjects and their samples will be maintained on case report 
forms under lock and key in the Pediatric cardiology offices.  De-identified pK samples 
(using study code number) will be sent to an external laboratory for analysis.  No PHI 
will leave Duke.  If  data resulting from this protocol is presented at scientific meetings or 
published in scientific journals, the subjects will not be identified.   Study records will be 
retained until subjects reach 21 years of age. 
 
 
1. 
U.S. National Institutes of Health: Common Terminology Criteria for Adverse Events v4.03: Published June 14, 
2010. http://ctep.info.nih.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40_conversion.