A Phase III Extension Study of Udenafil in Adolescents With Single Ventricle Physiology After Fontan Palliation
Phase: PHASE3
Conditions: Functional Single Ventricle Heart Disease
Sponsor: Mezzion Pharma Co. Ltd

Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 1 of 37 
 
 
 
 
A PHASE III SAFETY EXTENSION STUDY OF UDENAFIL IN ADOLESCENTS WITH 
SINGLE VENTRICLE PHYSIOLOGY AFTER FONTAN PALLIATION 
(FUEL EXTENSION) 
 
 
Funded by The National Heart, Lung, and Blood Institute, NIH/DHHS and 
Mezzion Pharma Co. Ltd. 
 
 
Protocol Number:  
PHN-Udenafil-03 
 
 
Sponsor: 
 
Mezzion Pharma Co.Ltd. in Partnership with Pediatric Heart Network (PHN)  
 
 
Sponsor Contact:    Mezzion Pharma Co. Ltd.  James L. Yeager, RPh, PhD, Tel: 847-2839176 
                                  Pediatric Heart Network (PHN) Gail D. Pearson, MD, ScD Tel: 301-435-0524 
 
 
Medical Monitor:     Brian Feingold, MD, MS, FAHA University of Pittsburgh School of Medicine 
Tel: 412-692-5541 
 
 
 
Contract Research  
Organization:           New England Research Institute, Inc. 
CRO Contact:           Julie Miller, MPH, PMP, Tel: 617-972-3197 
 
 
Date of Protocol:       October 30, 2020 
 
 
 
APPROVALS: 
 
Mezzion Pharma Co. Ltd     ___________________________   Date _______________ 
                                             James L. Yeager, RPh, PhD 
 
 
 
Pediatric Heart Network     ___________________________     Date _______________ 
                                             Gail Pearson, MD, ScD 
 
DocuSign Envelope ID: A11A46EC-185A-48F7-89FA-15FACBE0DD03
23 November 2020
DocuSign Envelope ID: B71B646A-E9DC-4D72-80AC-1CABC426282D
23 November 2020

Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 2 of 37 
 
 
 
Version History 
Version Number 
Version Date 
Comment(s) 
Version 1.0 
20-Jan-2016 
SPA Re-submission 
Version 2.0 
04-May-2016 
Updated per FDA recommendations for FUEL 
Version 3.0 
31-Aug-2017 
Conversion of visits 2 and 3 to telephone visits, 
and removal of vital sign measurements at those 
time points;  Addition of inclusion criterion #4 and 
exclusion criterion #26 
Version 4.0 
19-Apr-2018 
Addition of optional Heart Monitoring; updated 
shipping of drug resupply; extension of follow-up 
period; addition of S. Korean in-person visits at 
weeks 2 and 13. Clarification of exclusion criteria 
#16. Pregnancy testing at every in-person visit. 
Version 5.0 
10-Jun-2019 
Extension of follow-up to maximum of 36 
months 
Version 6.0 
30-Oct-2020 
Extension of follow-up to maximum of 48 
months; Telephone call schedule after Week 
52 completion updated to quarterly calls; 
Removal of South Korean sites which were 
never activated 
 
TABLE OF REVISIONS  
 
March 9, 2016 
Location of Change 
Change from 
Changed to 
Comment 
----- 
----- 
----- 
Special Protocol 
Agreement Submission 
January 27, 2016 
 
May 4, 2016 
Location of Change 
Change from 
Changed to 
Comment 
----- 
----- 
----- 
Special Protocol 
Agreement 
Resubmission May 17, 
2016 
 
August 31, 2017 
Location of Change 
Change from 
Changed to 
Comment 
Title Page 
To be determined 
Brian Feingold, MD, MS, 
FAHA  
University of Pittsburgh School 
of Medicine 
Tel: 412-692-5541 
A Medical Monitor was 
identified for the study 
Section 2 Protocol 
Synopsis and Section 
7.1 Subject Inclusion 
Critiera 
----- 
4. Current anti-platelet or 
anticoagulant therapy 
Inclusion criterion 
added requiring 
potential participants 
be on anti-platelet or 
anticoagulant therapy 
to be eligible for the 
study. 
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Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 3 of 37 
 
 
Section 2 Protocol 
Synopsis and Section 
7.2: Subject Exclusion 
Criteria 
----- 
26. History of clinically 
significant thromboembolic 
event, as adjudicated by study 
Investigators that may put the 
subject at increased risk of a 
subsequent event while 
participating in the study. 
Exclusion criterion 
added excluding 
potential participants if 
they have a history of 
clinically significant 
thromboembolic 
events. 
Section 6 Trial Design 
----- 
----- 
Figure 1 was updated 
to reflect changes in 
schedule of events 
Section 6.4 Study 
Visits 
----- 
----- 
This section was 
updated to reflect 
changes in the 
schedule of events: 
removal of in-person 
visits at weeks 2 and 
13; addition of 
telephone contacts at 
weeks 2 and 13 
Section 6.4, Table 1:  
Schedule of Events 
In-Person Visits 
(Screening/Baseline, 
Weeks 2, 13) 
Telephone Call 
Visits (Day 1, Weeks 
1, 3, 4, 8, 17, 21, 30, 
34, 39, 43, 47) 
In-Person Visits 
(Screening/Baseline, Week 
52) 
Telephone Call Visits (Weeks 
1, 2, 3, 4, 8, 13, 17, 21, 30, 34, 
39, 43, 47) 
Conversion of visits 2 
and 3 to telephone 
visits, Removal of vital 
sign assessments at 
those time points 
Throughout the 
document (Title page, 
footer) 
May 4, 2016 
August 31, 2017 
Administrative edits 
(i.e., protocol date was 
updated) 
 
April 19, 2018 
Location of Change 
Change from 
Changed to 
Comment 
1. Protocol Signature 
Page 
<Section 7.2.2= 
<Section 9.2.4= 
Updated section that 
identifies reporting 
serious adverse events 
Exclusion Criteria #16 
Known intolerance to 
oral Udenafil. 
Known intolerance, including 
hypersensitivity or allergy 
history, to oral udenafil or any 
components of the 
investigational product. 
Clarification for S. 
Korean Ministry of Food 
and Drug Safety 
Efficacy Measurements 
- 
Explore the impact of udenafil 
on atrial and ventricular 
premature beats and 
arrhythmia burden – optional 
for a subset of new 
participants. 
Heart monitoring 
measurement option for 
new participants 
6.3.2 Measures of 
Secondary Aims 
(Pharmacodynamics) 
----- 
Arrhythmia Burden: Number of 
premature atrial and/or 
ventricular beats as a 
percentage of total beats over 
the course of heart-rhythm 
monitoring while on study drug 
compared to baseline. 
Measure the occurrence of 
Updated secondary 
measurements to 
include the heart 
rhythm monitoring 
option 
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Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 4 of 37 
 
 
atrial or ventricular 
arrhythmias, including duration 
and speed, and comparison to 
baseline.  
 
6.4 Study Visits 
#1 FUEL participants 
<The safety labs for 
FUEL will be accepted 
as meeting the inclusion 
criteria for FUEL 
extension.= 
<Pregnancy testing for OLE will 
be done at every in-person visit 
via a urine or serum pregnancy 
test for female participants. If 
the pregnancy test is positive 
all further testing will be 
stopped, the patient will not be 
enrolled into the trial and the 
result will be conveyed to the 
subject and/or guardians by 
the site-principal investigator in 
accordance with local IRB 
procedures.= 
Female participants will 
have pregnancy testing 
at any in-person visit. 
6.4 Study Visits 
#6 FUEL participants 
----- 
Baseline Visit: Heart Rhythm 
Monitoring procedures added 
to protocol (see details in 
section 6.4) 
Updated to include 
optional heart rhythm 
monitoring application 
for FUEL 
Extensionparticipants 
who were not in FUEL 
6.4 Study Visits 
#6 NON-FUEL 
participants 
----- 
Baseline Visit: Heart Rhythm 
Monitoring procedures added 
to protocol (see details in 
section 6.4) 
Updated to include 
optional heart rhythm 
monitoring application 
for NON-FUEL 
participants resulting in 
splitting baseline visit 
into 2 days. 
Day 1 of 2 description 
6.4 Study Visits 
#7 
----- 
Follow-Up Visit: Heart Rhythm 
Monitoring procedures added 
to protocol (see details in 
section 6.4) 
Updated to include 
Follow-up and the 2nd 
application of the heart 
rhythm monitoring at 
baseline visit day 2 of 2 
8.3 Procedures for 
Monitoring Subject 
Adherence 
<Every 2 months= and 
<...a 2 month ...= 
<Each subject will receive via 
traceable courier a resupply of 
study medication.= 
Updated to remove 
limitation for resupply 
as a result of the 
conversion of two mid-
study, in-person visits 
to phone calls 
9.1 Recording and 
Reporting Adverse 
Events 
<The contacts at weeks 
2 and 13 will be in 
person visits during 
which adverse events 
will be assessed.= 
----- 
Updated to reflect the 
replacement of in 
person visits at weeks 2 
and 13 to telephone 
calls (US/Canada). 
Adverse events are 
captured at all 
telephone encounters. 
(see Table 1) 
13.1 Potential Risks 
----- 
Heart Monitor 
The patch which secures the 
monitor to the skin may result in 
Updated to include 
potential risk of heart 
monitor patch on the 
skin 
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Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 5 of 37 
 
 
local 
skin 
irritation 
or 
discomfort. 
2. Protocol Synopsis – 
Study Duration 
Approximately 12-15 
months (recruitment plus 
study procedures and 
follow up phone calls). 
Approximately 12-15 months 
(recruitment plus study 
procedures and follow up 
phone calls).  The trial may be 
extended by up to an 
additional 12-15 months for 
those opting to continue for a 
second year. 
Adding an option for a 
second year on open 
label udenafil for those 
subjects interested in 
remaining on drug to 
allow for more robust 
safety data capture. 
4.2 Secondary Aims 
-- 
Secondary Aim 5: Evaluate the 
safety of udenafil (87.5 mg bid) 
in adolescents with Fontan 
physiology over an additional 
12 months.  
Updated to include a 
new secondary aim 
designed to allow for 
safety data collection 
over a longer time 
period.  
6.1 Overview 
This study is a 12-month 
(52 week) safety 
extension study to 
supplement the FUEL 
Phase III clinical trial… 
This study is a 12-month (52 
week) safety extension study, 
with an option for up to an 
additional 12 months, to 
supplement the FUEL Phase 
III clinical trial… 
Updated to reflect the 
addition of an option for 
a second year. 
Figure 1 Trial Schema 
- 
 
Included the Option 2 in the 
schema 
Context illustrating 
option 2 within the 
study schema 
Figure 1 Trial Schema 
- 
 
Heart monitor (optional) 
Included the option of 
heart monitoring for 
non-FUEL participants 
6.4 Study Visits 
-- 
Option for additional up to 12 
months 
Added a section 
detailing the opportunity 
to participate in FUEL-
Extension for up to an 
additional 12 months. 
Telephone Contact 
(Between Baseline and 
Week 52) 
- 
<[South Korean sites will call at 
weeks 1, 3, 4, 8, 17, 21, 30, 
34, 39, 43, 47]= 
South Korea has 
alternate call cycles 
due to in-person visits 
at weeks 2 and 13. 
Table 1 Schedule of 
Events 
- 
Post Week 52 Option 2 
Added monthly 
telephone call schedule 
for AE assessments 
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Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 6 of 37 
 
 
Table 1 Schedule of 
Events 
- 
serum or urine pregnancy test 
at baseline visit for FUEL 
participant 
pregnancy testing at 
any in-person visit. 
5.3 Rationale for the 
Study 
- 
(with an option to extend for up 
to an additional 12 months) 
Addition of the 
extension of up to 12 
months. 
9.1 Safety 
Considerations and 
Monitoring 
- 
If the subject is continuing into 
the extension of up to an 
additional 12 months the site 
study coordinator will contact 
each subject monthly until the 
subject discontinues study 
drug. 
Added statement of 
safety monitoring for 
study drug extension of 
up to 12 months. 
9.2.2 Classification of 
Adverse Events 
CTCAE Version 4 
MedDRA 12.1 Version 
4.0 
CTCAE and MedDRA 
Current versions of 
CTCAE and MedDRA 
are used as they are 
updated and reelase 
10.1 Primary Aim – 
Safety 
...over 12 months of the 
extension trial ... 
…over the duration of the 
extension trial… 
To include the option 
for up to an additional 
12 months  
Throughout the 
document (Title page, 
footer) 
August 31, 2017 
April 19, 2018 
Administrative edits 
(i.e., protocol date was 
updated) 
 
June 10, 2019 
Location of Change 
Change from 
Changed to 
Comment 
2. Protocol Synopsis – 
Study Duration 
Approximately 12-15 
months (recruitment plus 
study procedures and 
follow up phone calls).  The 
trial may be extended by up 
to an additional 12-15 
months for those opting to 
continue for a second year. 
Approximately 12-15 months 
(recruitment plus study 
procedures and follow up 
phone calls).  The trial may be 
extended by up to an 
additional 24-27 months for 
those opting to continue for 
additional follow-up. 
Adding an option for a 
third year on open label 
udenafil for those 
subjects interested in 
remaining on drug to 
allow for more robust 
safety data capture. 
4.2 Secondary Aims 
Secondary Aim 5: Evaluate 
the safety of udenafil (87.5 
mg bid) in adolescents with 
Fontan physiology over an 
additional 12 months (study 
months 12-24). 
Secondary Aim 5: Evaluate the 
safety of udenafil (87.5 mg bid) 
in adolescents with Fontan 
physiology over an additional 
12 months (study months 12-
36).  
Updated to include 
additional 12 months of 
follow-up  
5.3 Rationale for the 
Study 
6.1 Study Overview 
Study  
6.4 Study Visits 
6.5 Data Collection 
- 
- 
Additional edits made 
to include additional 12 
months of optional 
follow-up (12-36 
months total) 
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Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 7 of 37 
 
 
9.1 Safety 
Considerations and 
Monitoring 
 
 
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Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 8 of 37 
 
 
10.1 Primary aim - 
Safety 
…over the duration of the 
extension trial… 
…over 12 months of the 
extension trial… 
The duration over 
extension trial (up to 36 
months) is added as a 
secondary safety aim 
(see below) 
10.1.2 Secondary aim - 
Safety 
- 
10.1.2 Secondary aim – Safety 
The secondary safety outcome 
will be reported similar to 
Primary safety outcome (see 
above), but over a longer 
period of time including 
additional FU period (i.e. for up 
to 36 months on the study). 
 
Additional safety 
summary for for AEs 
over the longest 
available period (up to 
36 months) 
 
October 30, 2020 
Location of Change 
Change from 
Changed to 
Comment 
2. Protocol Synopsis – 
Study Duration 
Approximately 12-15 
months (recruitment plus 
study procedures and 
follow up phone calls).  The 
trial may be extended by up 
to an additional 24-27 
months for those opting to 
continue for a second year. 
Approximately 12-15 months 
(recruitment plus study 
procedures and follow up 
phone calls).  The trial may be 
extended by up to an 
additional 36-39 months for 
those opting to continue for 
additional follow-up. 
Adding an option for a 
fourth year on open 
label udenafil for those 
subjects interested in 
remaining on study 
drug. 
4.2 Secondary Aims 
Secondary Aim 5: Evaluate 
the safety of udenafil (87.5 
mg bid) in adolescents with 
Fontan physiology over an 
additional 12 months (study 
months 12-36). 
Secondary Aim 5: Evaluate the 
safety of udenafil (87.5 mg bid) 
in adolescents with Fontan 
physiology over an additional 
12 months (study months 12-
48).  
Updated to include 
additional 12 months of 
follow-up  
5.3 Rationale for the 
Study 
6.1 Study Overview 
6.4 Study Visits 
6.5 Data Collection 
9.1 Safety 
Considerations and 
Monitoring 
- 
- 
Additional edits made 
to include additional 12 
months of optional 
follow-up (12-48 
months total) and 
quarterly telephone 
calls 
6.4 Study Visits 
Week 2 and Week 13 
Follow-Up Visits – South 
Korean Sites Only 
 
Removed references to 
South Korea as no 
South Korean study 
sites were activated for 
the FUEL OLE study 
Table 1 Schedule of 
Events 
 
 
Frequency of calls 
changed from monthly 
to quarterly; total 
number of calls 
updated  
8.3 Procedures for 
Monitoring & Subject 
Adherence 
9.1 Safety 
Considerations and 
Monitoring 
Monthly calls 
Quarterly calls 
Frequency of telephone 
calls changed from 
monthly to quarterly 
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Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 9 of 37 
 
 
10.1.2 Secondary aim - 
Safety 
The secondary safety 
outcome will be reported 
similar to Primary safety 
outcome (see above), but 
over a longer period of time 
including additional FU 
period (i.e. for up to 36 
months on the study). 
The secondary safety outcome 
will be reported similar to 
Primary safety outcome (see 
above), but over a longer 
period of time including 
additional FU period (i.e. for up 
to 48 months on the study). 
Updated to include 
additional 12 months of 
follow-up 
 
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Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 10 of 37 
 
 
1. PROTOCOL SIGNATURE PAGE 
 
I have read the foregoing protocol and agree that it contains all necessary details for carrying out 
this study. I will conduct the study in accordance with the design and specific provisions outlined 
herein; deviations from the protocol are acceptable only with a mutually agreed upon protocol 
amendment. 
 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me 
who assist in the conduct of this study. I will discuss this material with them to ensure they are fully 
informed regarding the drug and the conduct of the study. 
 
I will use the informed consent form approved by the NHLBI and will fulfill all responsibilities for 
submitting pertinent information to the Institutional Review Board or Ethics Committee responsible 
for this study. 
 
I also agree to report all information or data in accordance with the protocol and, in particular, I 
agree to report any serious adverse experiences as defined in Section 9.2.4 of this protocol. 
 
I further agree that the NHLBI and/or its designee has access to any source documents from 
which case report form information may have been generated. 
 
I also agree to handle all clinical supplies (including drugs, biologics, and/or devices) provided by 
Mezzion® and collect and handle all clinical specimens in accordance with the protocol. 
 
The below signed confirm herewith to have read and understood this study protocol and/or 
amendment and appendices; furthermore, to accomplish this study in accordance to the protocol 
and Good Clinical Practice guidelines, as well as local regulations and regulatory authorities. 
 
PRINTED or TYPED NAME(S) 
 
SIGNATURE 
 
DATE 
 
 
 
 
 
Investigator 
 
 
 
 
Investigator 
 
 
 
 
Investigator 
 
 
 
 
Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 11 of 37 
 
 
2. Protocol Synopsis 
Protocol Title 
A Phase III Safety Extension Study of Udenafil in Adolescents with 
Single Ventricle Physiology after Fontan Palliation (FUEL Extension) 
Protocol Number 
PHN-Udenafil-03 
US IND Number 
121648 
Grant Number 
NHLBI U01 HL068270, HL109741, HL109781, HL109816, HL109818, 
HL109777, HL109778, HL109673, HL109743, HL109737, HL068270 
Clinical Phase / 
Indication 
Phase 3 
Safety of udenafil in adolescents with Fontan physiology 
Study Objectives 
1) Determine the safety of udenafil (87.5 mg, twice daily) in an 
adolescent population with single ventricle congenital heart disease 
palliated with the Fontan procedure. 
2) Evaluate the pharmacodynamic profile of udenafil over a one to 
three year period. 
Significance 
The Fontan Udenafil Exercise Longitudinal Study is planned to 
evaluate the efficacy and safety of udenafil over a six-month period. 
However, an understanding of the longer-term safety profile of udenafil 
is critical prior to adopting it for use in those with Fontan physiology. 
Study Design 
Open label extension trial of udenafil (87.5 mg twice daily). 
Primary Safety 
Measurements 
Safety will be assessed by monitoring adverse events and vital signs, 
clinical laboratory test results, 12-lead ECG, and physical 
examinations. 
Other Safety 
Measurements 
The effect of treatment on the functional health status in adolescents 
following a Fontan procedure. 
The effect of treatment on the prevalence and severity of 
complications, including protein-losing enteropathy (PLE), plastic 
bronchitis, hospitalizations, cardiac transplantation, and death in 
adolescents who receive udenafil following the Fontan procedure. 
Efficacy Measurements 
Evaluate the effect of udenafil on pharmacodynamic outcomes including 
exercise capacity, echocardiographic measures of ventricular function, 
endothelial function, and serum biomarkers, as well as measures of 
functional health status / quality of life. Explore the impact of udenafil on 
atrial and ventricular premature beats and arrhythmia burden – optional 
for a subset of new participants.  
Sample Size 
All subjects enrolled in FUEL trial, with minimum of 300 subjects 
Study Duration 
Approximately 12-15 months (recruitment plus study procedures and 
follow up phone calls).  Participation in the trial may be extended up to 
an additional 36-39 months for those opting to continue for additional 
follow-up (includes 3 months of follow-up after last study dose). 
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Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 12 of 37 
 
 
Inclusion Criteria 
1. Males and females with Fontan physiology who participated in the 
FUEL trial or, if they did not participate in FUEL, those who are 12 to 
less than 19 years of age at enrollment. 
2. Participant consent or parental/guardian consent and participant 
assent. 
3. Participant fluent in English, Spanish, or Korean   
4. Current anti-platelet or anticoagulant therapy 
Exclusion Criteria 
1. Height < 132 cm. 
2. Weight < 40 kg. 
3. Hospitalization for acute decompensated heart failure within the last 
12 months. 
4. Current intravenous inotropic drugs. 
5. Undergoing   evaluation   for   heart   transplantation   or   listed for 
transplantation. 
6. Diagnosis of active protein losing enteropathy or plastic bronchitis 
within the last three years, or a history of liver cirrhosis. 
7. Known Fontan baffle obstruction, branch pulmonary artery stenosis, 
or pulmonary vein stenosis resulting in a mean gradient of > 4 mm 
Hg between the regions proximal and distal to the obstruction as 
measured by either catheterization or echocardiography. 
8. Single lung physiology. 
9. Maximal VO2 less than 50% of predicted for age and gender at 
enrollment. 
10. Severe ventricular dysfunction assessed qualitatively by clinical 
echocardiography within six months prior to enrollment. 
11. Severe valvar regurgitation, ventricular outflow obstruction, or aortic 
arch obstruction assessed by clinical echocardiography within six 
months prior to enrollment. 
12. Significant renal, hepatic, gastrointestinal or biliary disorders that 
could impair absorption, metabolism or excretion of orally 
administered medications. 
13. Inability to complete exercise testing at baseline screening. 
14. History of PDE-5 inhibitor use (with the exception of FUEL 
participation) within 3 months before study onset. 
15. Use of any other drug to treat pulmonary hypertension within 3 
months before study onset. 
16. Known intolerance, including hypersensitivity or allergy history,to oral
udenafil or any components of the investigational product. 
17. Frequent use of medications or other substances that inhibit or 
induce CYP3A4. 
18. Current use of alpha-blockers or nitrates. 
19. Ongoing or planned participation in another research protocol that 
would either prevent successful completion of planned study testing 
or invalidate its results. 
20. Noncardiac medical, psychiatric, and/or social disorder that would 
prevent successful completion of planned study testing or would 
invalidate its results. 
21. Cardiac care, ongoing or planned, at a non-study center that would 
impede study completion. 
22. For females: Pregnancy at the time of screening, pregnancy 
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Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 13 of 37 
 
 
planned before study completion, or refusal to use an acceptable 
method of contraception for study duration. 
23. Unable to abstain or limit intake of grapefruit juice during the duration 
of the trial. 
24. Refusal to provide written informed consent/assent. 
25. In the opinion of the primary care physician, the subject is likely to 
be non-compliant with the study protocol. 
26. History of clinically significant thromboembolic event, as adjudicated 
by study Investigators that may put the subject at increased risk of a 
subsequent event while participating in the study 
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Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 14 of 37 
 
 
3. Table of Contents 
 
TABLE OF REVISIONS ................................................................................................................................... 2 
1. 
PROTOCOL SIGNATURE PAGE ..........................................................................................................10 
2. 
Protocol Synopsis ...................................................................................................................................11 
3. 
Table of Contents ...................................................................................................................................14 
List of Abbreviations .......................................................................................................................................16 
4. 
STUDY AIMS AND HYPOTHESES ........................................................................................................17 
4.1 Primary Aim ............................................................................................................................................17 
4.2 Secondary Aim(s) ...................................................................................................................................17 
5. 
BACKGROUND INFORMATION ............................................................................................................18 
5.1 The circulation after the Fontan procedure and potential role for PDE5 inhibitors .................................18 
5.2 PDE5 inhibitors in patients with Fontan physiology ................................................................................18 
5.4 Rationale for Study Outcomes ................................................................................................................19 
6. 
STUDY / TRIAL DESIGN ........................................................................................................................21 
6.1 Overview .................................................................................................................................................21 
Figure 1 Trial Schema ....................................................................................................................................21 
6.2 Study Design ..........................................................................................................................................21 
6.3 Study Measures ......................................................................................................................................21 
6.3.2 
Measures of Secondary Aims (Pharmacodynamics) .....................................................................21 
6.3.3 
Covariate Measures .......................................................................................................................22 
6.4  Study Visits ..............................................................................................................................................22 
Table 1. Schedule of Events ...........................................................................................................................26 
6.5 Data Collection .......................................................................................................................................27 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ...............................................................................28 
7.1 Subject Inclusion Criteria ........................................................................................................................28 
7.2 Subject Exclusion Criteria .......................................................................................................................28 
7.3 Recruitment/Enrollment Procedures .......................................................................................................29 
7.4 Indications for Discontinuation of Study Drug .........................................................................................29 
7.5 Subject Withdrawal from Study ...............................................................................................................29 
8. 
TREATMENTS TO BE ADMINISTERED ...............................................................................................29 
8.1 Description of Study Treatments ............................................................................................................30 
8.2 Concomitant Medications .......................................................................................................................30 
8.3 Procedures for Monitoring Subject Adherence .......................................................................................30 
8.4 Study Completion ...................................................................................................................................31 
9. 
SAFETY ASSESSMENTS ......................................................................................................................31 
9.1 Safety Considerations and Monitoring ...................................................................................................31 
9.2.  Recording and Reporting Adverse Events .............................................................................................31 
9.2.1 
Definitions of Adverse Event, Suspected Adverse Reaction and Adverse Reaction .....................31 
9.2.2 
Classification of Adverse Events ....................................................................................................31 
9.2.3 
Identification of and Data Collection Procedures for Adverse Events ............................................33 
9.2.4 
Reporting Procedures ....................................................................................................................33 
9.2.5 
Reporting Adverse Events to Institutional Review Boards for NIH-Supported Multi- Center Clinical 
Trials .......................................................................................................................................................33 
9.2.6 
Follow-up of Subjects after Adverse Events ...................................................................................33 
9.3  Safety Monitoring ....................................................................................................................................34 
10. STATISTICS ...........................................................................................................................................34 
10.1 Primary Aim - Safety ...............................................................................................................................34 
10.2 Secondary Aims - Efficacy ......................................................................................................................34 
10.3 Interim analyses ......................................................................................................................................35 
10.4 Potential Biases .......................................................................................................................................35 
11. DATA MANAGEMENT ...........................................................................................................................35 
11.1 Data Entry ...............................................................................................................................................35 
11.2 Data Validation and Monitoring...............................................................................................................35 
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Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 15 of 37 
 
 
11.3 Data Security and Integrity .....................................................................................................................36 
11.4 Biospecimen Tracking ............................................................................................................................36 
12. QUALITY CONTROL AND QUALITY ASSURANCE .............................................................................36 
13. ETHICS AND HUMAN SUBJECTS CONSIDERATIONS .......................................................................36 
13.1 Potential Risks ........................................................................................................................................36 
13.3 Potential Benefits ...................................................................................................................................41 
13.4 Risk/Benefit Ratio and Importance of Information to Be Obtained .........................................................41 
14. STUDY LIMITATIONS ............................................................................................................................42 
15. REFERENCES .......................................................................................................................................43 
 
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IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
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List of Abbreviations 
 
AE 
Adverse event 
ADL 
Activities of daily living 
BNP 
Brain-type natriuretic peptide 
CRF 
Case report form 
CTCAE 
Common terminology criteria for adverse events 
DCC 
Data coordinating center 
DSMB 
Data and Safety Monitoring Board 
EDC 
Electronic data capture 
FDA 
Food and drug administration 
ID 
Identification 
IND 
Investigational new drug 
IRB 
Institutional Review Board 
MedDRA 
Medical dictionary for drug regulatory activities 
MM 
Medical monitor 
MPI 
Myocardial performance index 
NHLBI 
National Heart, Lung, and Blood Institute 
NIH 
National Institutes of Health 
OLE 
Open label extension 
PAT 
Pulse amplitude tonometry 
PCQLI 
Pediatric Cardiac Quality of Life Inventory 
PD 
Pharmacodynamic 
PDE5 
Phosphodiesterase type 5 
PHN 
Pediatric Heart Network 
PI 
Principal investigator 
PK 
Pharmacokinetic 
QA 
Quality assurance 
QC 
Quality control 
RCT 
Randomized clinical trial 
REB 
Research Ethics Board 
SAE 
Serious adverse event 
sGC 
Soluble guanylate cyclase 
VO2 
Oxygen consumption 
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Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 17 of 37 
 
 
4. STUDY AIMS AND HYPOTHESES 
 
4.1 Primary Aim 
Evaluate the safety of udenafil (87.5 mg bid) in adolescents with Fontan physiology over a 12- 
month period. 
 
Hypothesis: Udenafil will be safe and well tolerated over the 12-month study period. 
 
Primary outcome: Adverse events will be collected and recorded. Adverse events will be 
categorized by severity and relationship to drug.  
 
Secondary Outcome 
Death, hospitalization, and heart transplantation information will be collected and evaluated. 
 
4.2 Secondary Aim(s) 
Secondary Aim 1: Evaluate the effect of udenafil on pharmacodynamic (PD) outcomes 
including: exercise capacity, echocardiographic measures of ventricular function, endothelial 
function, and biomarkers associated with heart failure over a 12-month period. 
 
Hypothesis: PD outcomes will improve following administration of udenafil. 
 
Primary Outcomes: 
• 
Exercise: Change in maximal oxygen consumption from baseline to Week 52 testing 
measured using a standardized exercise test. 
• 
Echo: Change in myocardial performance index as measured by pulse wave Doppler 
echocardiography from baseline to Week 52 testing. 
• 
Endothelial Function: Change in log-transformed Reactive Hyperemia Index derived 
from the EndoPAT® device. 
• 
Biomarkers: Change in serum BNP level from baseline to Week 52. 
 
Secondary Outcomes: 
• 
Exercise: Submaximal measures of exercise capacity will be collected and evaluated. 
• 
Echo:  Measure  of  systolic  and  diastolic  function  will  be  collected  from  a  targeted 
echocardiogram. 
 
Secondary Aim 2: Determine if 12 months of treatment with oral udenafil will alter functional 
health status in adolescents following the Fontan procedure as measured by standardized quality 
of life surveys. 
 
Hypothesis: Functional health status will improve following administration of udenafil. 
 
Primary Outcome: Change in functional health status from baseline to Week 52 as measured by 
the full scale PedsQL. 
 
Secondary Outcomes: 
12- month change in: 
• 
Peds QL physical functioning Score 
• 
Peds QL psychosocial functioning Score 
• 
Peds QL cardiac-specific module quality of life score 
• 
Pediatric Cardiac Quality of Life Inventory (PCQLI) Score 
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Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 18 of 37 
 
 
 
Secondary Aim 3: Establish a collection of genetic material to identify genetic determinants 
of response to udenafil after the Fontan procedure in persons with single-ventricle lesions, and 
for unspecified future studies. [This aim will only apply to those who did not provide a sample 
for the FUEL study]. 
 
Secondary Aim 4: Determine the prevalence and severity of complications, including protein-
losing enteropathy (PLE), plastic bronchitis, hospitalizations, cardiac transplantation and death, 
in adolescents who receive udenafil following the Fontan operation. 
 
Secondary Aim 5: Evaluate the safety of udenafil (87.5 mg) bid in adolescents with Fontan 
physiology over an additional follow-up period (study months 12-36).  [This aim is an opt-in aim 
for those who choose to remain on drug for up to an additional 36 months]. 
 
Primary outcome: Adverse events will be collected and recorded. Adverse events will be 
categorized by severity and relationship to drug.  
 
Secondary Outcome 
Death, hospitalization, and heart transplantation information will be collected and evaluated. 
 
Secondary Aim 6: Assess arrhythmia burden before and after taking study drug at baseline visit 
(for non-FUEL subjects only; patient participation is optional) 
Outcome: Occurance, duration and speed of atrial or ventricular arrhythmias, as well as number 
of premature beats will be collected and evaluated.  
 
 
5. BACKGROUND INFORMATION 
5.1 The circulation after the Fontan procedure and potential role for PDE5 inhibitors 
The Fontan operation is a palliative procedure for children born with functional single ventricle 
congenital heart disease1,2. This operation, which creates a total cavopulmonary connection, 
separates the systemic and pulmonary circuits and eliminates both hypoxemia and ventricular 
volume overload. However, following the Fontan operation there is no ventricular pump to 
propel blood into the pulmonary arteries. Instead blood returns to the lungs via passive flow 
from the systemic veins. This results in a circulation characterized by elevated central venous 
pressure, abnormal pulmonary vascular resistance, and a chronically low cardiac output. Over 
time, these inherent characteristics of Fontan physiology result in a predictable, persistent 
deterioration of cardiovascular efficiency, as marked by a progressive decline in exercise 
performance that begins after puberty3-6. This decline in exercise capacity correlates with an 
increase in symptoms from cardiovascular dysfunction and may result in the need for 
hospitalization, escalation of heart failure management, or transplant7-10. The threshold at which 
significant impairment is reached is variable among patients, but typically occurs sometime in 
the third decade of life. 
 
A medication that addresses the central deficiencies of Fontan physiology may help to allow for 
a longer duration of efficient function of this circulation, and may therefore increase the duration 
and quality of transplant-free survival. Short-term pilot data evaluating the use of sildenafil, a 
PDE5 inhibitor, suggest a potential role for this class of medication for patients with the Fontan 
circulation11, 12. 
 
5.2 PDE5 inhibitors in patients with Fontan physiology 
PDE5 inhibitors are a unique class of medication that have demonstrated utility in reducing 
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Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 19 of 37 
 
 
pulmonary vascular resistance and improving ventricular performance in patients with 
pulmonary hypertension and myocardial dysfunction13-17. These characteristics make them 
potentially attractive as a therapy for the Fontan population in which cardiac output, and thus 
exercise, are limited by the absence of a sub-pulmonary ventricle18. In limited short-term 
studies in children and adolescents with Fontan physiology, treatment with sildenafil, a three- 
times daily PDE5 inhibitor, has been safe and has shown a modest benefit in exercise 
performance and ventricular function11, 19. 
 
Given this background the FUEL trial, a large-scale randomized clinical trial (RCT), was designed 
and is expected to begin in the second quarter of 2016. The primary aim of the RCT is to evaluate 
the impact of udenafil (a twice-daily PDE5 inhibitor new to the United States) on exercise 
capacity in adolescents with Fontan physiology. Regardless of the outcome of the efficacy 
trial, longer-term safety data is imperative prior to wide-scale usage of this medication. 
 
5.3 Rationale for the Study 
While the six-month treatment with long-term utility of udenafil in adolescents with Fontan 
physiology is being evaluated in the FUEL trial, the novel nature of this drug in this specific 
population calls for a more thorough investigation of longer-term safety. Indeed, the Food and 
Drug Administration requires additional safety data before an indication for this drug in this 
population will be issued. With that need in mind, we propose a 12-month open label FUEL 
Extension Study (with an option to extend for up to an additional 36 months) to evaluate the safety 
of longer-term use of udenafil in adolescents with Fontan physiology. 
 
We will collect and record adverse events throughout the duration of the extension trial with 
specific attention on the composite endpoint of death, heart failure associated hospitalization, 
and heart transplantation. We will also collect PD data to mirror that which is being collected in 
the FUEL trial to evaluate whether any potential PD improvements are maintained over a longer 
period of time. If udenafil is demonstrated to provide a sustained improvement in PD parameters, 
this would have important implications for guiding duration of therapy. 
 
5.4 Rationale for Study Outcomes 
Safety Data: The short-term safety data of PDE5 inhibitors in those with Fontan physiology has 
been established by a number of previous studies including the recently concluded Fontan 
Udenafil Phase I/II Trial, undertaken by a subset of PHN core sites. These data suggest that 
PDE5 inhibitors in general, and udenafil specifically, are safe in this population with side effects 
limited to those known to be associated with PDE5 inhibitor use. In the Fontan Udenafil Trial 
there were no serious adverse events associated with udenafil. 
 
Pharmacodynamics: The primary and secondary PD aims of the FUEL trial are designed to 
evaluate the efficacy of udenafil on a number of important PD parameters. These include 
measures of exercise capacity, ventricular function (as measured by echocardiography), 
endothelial function, and biomarkers associated with heart failure. In the FUEL extension trial 
we will evaluate these parameters at study entrance (using end-of-study measures for those 
who participated in FUEL) and again at end-of-study. The durability of any improvement noted 
in FUEL is important, as it may help to inform clinical decisions regarding long-term therapy. 
 
Biorepository: The response to udenafil may also be influenced by variants influencing the 
vascular response to udenafil. Variants in the endothelial nitric oxide synthase gene have been 
reported to influence the response to sildenafil in patients with erectile dysfunction, although this 
has not been studied for udenafil20. Variation in genes that regulate the vascular, inotropic and 
chronotropic response to exercise may influence the exercise capacity of patients after the 
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Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 20 of 37 
 
 
Fontan procedure as well as the response to udenafil. DNA will be stored to perform future 
genotyping studies to analyze the genetic contribution to the response to udenafil. 
 
Functional Health Status: In the PHN Fontan Cross-Sectional Study, physical and psychosocial 
functional statuses were significantly reduced across almost all domains21, 22. It is clear that 
overall functional status is significantly reduced in this population compared to a healthy control 
population23. Given these findings, a highly desirable goal of any therapy to improve or maintain 
function in the population with the Fontan procedure would be maintenance or improvement in 
overall health status. However, in the PHN study, none of the evaluated measures of exercise 
performance including percent of predicted maximal VO2 significantly correlated with measures 
of physical functioning or psychosocial domains22.  Given these findings, even a positive effect 
of udenafil therapy on aerobic capacity may not necessarily result in improved functional status. 
Under these circumstances, any change in functional status over time that is associated with 
udenafil therapy would be an extremely important outcome. 
 
 
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Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 21 of 37 
 
 
6. STUDY / TRIAL DESIGN 
6.1 Overview 
This study is a 12-month (52 week) safety extension study, with an option for up to an additional 
36 months, to supplement the FUEL Phase III clinical trial to provide a more robust safety and 
side-effect profile of the use of udenafil in adolescents with Fontan physiology. We will attempt 
to recruit all participants who completed the FUEL trial, a potential of approximately 400 subjects, 
and will supplement, if needed, with additional adolescents with Fontan physiology until the 
minimum of 300 total subjects have been enrolled. 
Figure 1 Trial Schema 
 
 
 
 
6.2 Study Design 
This will be an open-label extension study. All enrolled subjects will be provided with udenafil, 
at a dose of 87.5 mg bid, for the duration of the study. Importantly, once the results of FUEL are 
known, these will be presented to the DSMB which will then provide a recommendation as to 
whether the FUEL extension trial should continue. If a total lack of efficacy is determined, the 
extension trial may be discontinued. 
 
6.3 Study Measures 
 
6.3.1 Measures of Primary Aim (Safety) 
All adverse events will be collected and recorded for the duration of the trial. 
 
6.3.2 
Measures of Secondary Aims (Pharmacodynamics) 
 
Primary Outcomes: 
• 
Exercise: Change in maximal oxygen consumption from FUEL extension baseline (will 
be end-of-study testing for FUEL participants) to testing at 12 months measured using 
a standardized exercise test. 
• 
Echo: Change in myocardial performance index as measured by pulse wave Doppler 
echocardiography from baseline to testing at 12 months. 
• 
Endothelial Function: Change in log-transformed Reactive Hyperemia Index derived 
from the EndoPAT® device. 
• 
Functional Health Status: Change in full scale Peds QL 
• 
Biomarkers: Change in serum BNP level from baseline to  testing at 12 months. 
 
Secondary Outcomes: 
• 
Exercise: Submaximal measures of exercise capacity will be collected and evaluated. 
• 
Echo:  Measure  of  systolic  and  diastolic  function  will  be  collected  from  a  targeted 
echocardiogram. 
• 
Functional Health Status: Change in Peds QL physical functioning score, psychosocial 
functioning score, and cardiac-specific quality of life score. Change in Pediatric Cardiac 
Quality of Life Inventory (PCQLI) score. 
• 
Arrhythmia Burden (limited to  non-FUEL subjects; participation is optional) will be 
assessed at 2 time points: pre-study drug and post-study drug (both during  the baseline 
visit): Number of premature atrial or ventricular beats (2 outcomes) as a percentage of total 
beats over the course of heart-rhythm monitoring from pre-study drug measurements 
compared to taking study drug. Occurrence, duration and speed of atrial or ventricular 
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Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 22 of 37 
 
 
arrhythmias (2 outcomes), and comparison between the two time points.  
 
6.3.3 Covariate Measures 
We will attempt to identify possible associations between a variety of clinical factors and both 
safety and PD outcomes.  Examples of clinical factors include: 
• 
Age 
• 
Gender 
• 
Race/ethnicity 
• 
Height/weight 
• 
Ventricular morphology 
• 
Resting oxygen saturation 
• 
Baseline pharmacodynamic test results 
• 
Current medication use 
 
6.4  Study Visits 
 
Baseline Visit – For those subjects who WERE participants in the FUEL Trial: 
 
1. Baseline screen 
Prior to study enrollment, patients will be screened to ensure that all inclusion criteria are 
met and none of the exclusion criteria are present.   The safety labs for FUEL will be 
accepted as meeting the inclusion criteria for FUEL extension. Pregnancy testing for OLE 
will be done at every in-person visit via a urine or serum pregnancy test for female 
participants. If the pregnancy test is positive all further testing will be stopped, the patient 
will not be enrolled into the trial and the result will be conveyed to the subject and/or 
guardians by the site-principal investigator in accordance with local IRB procedures.   
 
2. Informed consent 
Informed consent and assent for FUEL Extension will be obtained (if not obtained prior) 
as per local IRB/REB requirements during the end-of-study visit for FUEL. 
 
3. Baseline PD testing 
End-of-study pharmacodynamic testing for FUEL will serve as baseline testing for FUEL 
Extension. 
 
4. Quality of life surveys 
End-of study quality of life survey results (Peds QL, Peds QL cardiac specific module, 
PCQLI), HAES for FUEL will serve as baseline testing for FUEL Extension 
 
5. Initiation of study drug (See Table 2) 
Subjects will return to their study center in the shortest period of time deemed practical, 
following FUEL study completion, for study drug initiation under direct observation.  During 
this visit, a resting blood pressure and heart rate will be obtained just prior to dosing.  One 
dose of the study medication will be administered to the subject.  At approximately 2 hours 
(+/- 30 minutes) post dosing, an additional resting heart rate and blood pressure will be 
measured and the subject will asked to perform a self-limited 6-minute walk.  A repeat heart 
rate and blood pressure will be measured immediately following the 6 minute walk and a 
blood sample will be obtained for determination of udenafil and metabolite concentration.  At 
approximately 2 hours (+/- 30 minutes) following the 6-minute walk, a final resting heart rate 
and blood pressure will be obtained, adverse events will be recorded, and the subject will be 
dispensed their initial supply of study medication.  The subject will be instructed to take the 
medication twice a day and to bring back the medication bottle for their next in-person visit.  
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Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 23 of 37 
 
 
The subject will then be discharged from the clinic. Importantly, if the subject has a drop in 
systolic blood pressure > 20 mmHG from the pre- to post-6 minute walk measurement, or if 
the systolic blood pressure drops below the 5th percentile for age (calculated by 2 x age + 
65), they will be excluded from receiving any further study drug. These subjects will be 
followed for 90 days per the FUEL protocol for adverse event monitoring. 
 
 
Baseline Visit - For those subjects who WERE NOT participants in the FUEL Trial: 
The baseline visit consists of two parts, baseline testing and study drug initiation.  These parts 
may be combined into a single day, or split into two days so long as the duration of time between 
the visits is no more than 7 days. 
 
1. Baseline screen 
Prior to study enrollment, patients will be screened to ensure that all inclusion criteria are 
met and none of the exclusion criteria are present. 
 
2. Informed consent 
On the day of the first study visit, informed consent and assent will be obtained (if not 
obtained prior) as per local IRB requirements. 
 
3. Baseline PD testing and safety labs  
The EndoPAT® vascular assessment will be completed as the first PD test following 
consent. This must be performed in a fasting (from midnight until after the test), non- 
caffeinated state. 
After the vascular assessment, subjects will have a targeted 
echocardiogram to assess ventricular function. A short break will be given, either after the 
vascular assessment or after the echocardiogram, and a light snack will be provided. Safety 
labs will be performed following the vascular assessment, echocardiogram, and break. 
These will include collection of blood to evaluate serum creatinine and liver enzyme 
(aspartate transaminase and alanine transaminase) levels for all participants, and a urine or 
serum pregnancy test for female participants. If the pregnancy test is positive all further 
testing will be stopped, the patient will not be enrolled into the trial and the result will be 
conveyed to the subject and/or guardians by the site-principal investigator in accordance 
with local IRB procedures. After the safety labs, an exercise test will be administered using 
a braked cycle ergometer following a ramp protocol previously published in the PHN Fontan 
Cross-Sectional Study3.  As with the FUEL study, subjects who fail to achieve a maximal 
effort on a baseline exercise test will be offered an opportunity to repeat the test within a 
2 week time window. After exercise testing, subjects will have completed the baseline 
testing. 
 
4. Quality of life surveys  
The Peds QL, cardiac specific Peds QL, H A E S  and PCQLI will be administered 
during the baseline testing visit. 
 
5. Initiation of study drug (see Table 2) 
Study drug initiation will occur under direct observation.  A resting blood pressure and heart 
rate will be obtained just prior to dosing.  One dose of the study medication will be 
administered to the subject.  At approximately 2 hours (+/- 30 minutes) post dosing, an 
additional resting heart rate and blood pressure will be measured and the subject will asked 
to perform a self-limited 6-minute walk.  A repeat heart rate and blood pressure will be 
measured immediately following the 6 minute walk and a blood sample will be obtained for 
determination of udenafil and metabolite concentration.  At approximately 2 hours (+/- 30 
minutes) following the 6-minute walk, a final resting heart rate and blood pressure will be 
obtained, adverse events will be recorded, and the subject will be dispensed their initial 
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Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 24 of 37 
 
 
supply of study medication.  The subject will be instructed to take the medication twice a day 
and to bring back the medication bottle for their next in-person visit.  The subject will then 
be discharged from the clinic. Importantly, if the subject has a drop in systolic blood pressure 
> 20 mmHG from the pre- to post-6 minute walk measurement, or if the systolic blood 
pressure drops below the 5th percentile for age (calculated by 2 x age + 65), they will be 
excluded from receiving any further study drug. These subjects will be followed for 30 days 
for adverse event monitoring.  
 
6. Baseline Visit Day 1 of 2: Heart Rhythm Monitoring pre-study drug dose 
At study initiation, a subset of FUEL Extension subjects who were not in the FUEL Trial 
will have the opportunity to enroll in a heart rhythm-monitoring study. Heart rhythm 
monitoring will include a 3 to 7-day baseline monitor followed by a 3-day steady state 
monitor. Enrollment in the heart rhythm-monitoring arm will require that subjects split the 
baseline visit such that baseline testing is performed 3 to 7 days prior to drug initiation. At 
the conclusion of baseline testing on day 1 of 2, the heart monitor will be placed on the 
subject. The device will be worn for 3 to 7 days and removed when the patient returns for 
study drug initiation (baseline visit day 2 of 2). The device, identified only by the subject’s 
study identification number, will then be sent to the vendor for generation of a report..   
 
7. Baseline Visit Day 2 of 2: Heart Rhythm Monitoring after study drug dose 
For those who opted to participate in the heart rhythm-monitoring subset and completed a 
minimum of three days of baseline monitoring (day 1 of 2), a second device will be placed 
on the subject at the conclusion of the second day of the baseline visit (day 2 of 2) after 
study drug initiation. The device will be worn for 72 hours after which the subject will be 
instructed to mail the device, identified only by their study subject number, to the vendor 
for download and generation of a report. 
The report will be returned to the enrolling site and any change in the frequency of 
premature beats or arrhythmias will be shared with the DSMB as summary data in 
accordance with standard reporting. A change in arrhythmias felt to rise to the level of a 
serious adverse event will be reported to the Medical Monitor in accordance with serious 
adverse event reporting (section 9.3). 
 
 
Week 52 Testing 
At  Week 52, the subject will undergo testing for primary and secondary efficacy endpoints. Testing 
for this visit will include an exercise test, an echocardiogram, EndoPAT®, BNP, quality of life 
questionnaires and safety labs. To minimize any potential effect of the timing of administration of 
the study drug on testing outcomes, the time of the study drug dosing on the visit day will be 
standardized. Additionally, if a subject is unable to achieve a maximal effort on exercise testing, 
they will be offered the opportunity to repeat the EST within two weeks (14 days) of the first test. 
During this time period, the subject should remain on udenafil.  If they achieve a maximal effort on 
this second study, the results of the second study will be used in the analyses. 
 
At Week 52, vital signs (Resting Blood Pressure/Heart rate) will be obtained; assessment of 
adverse events, concomitant medications, drug accountability and a blood sample will be drawn 
for determination of udenafil and metabolite concentration immediately following the exercise 
test. For female subjects, serum or urine pregnancy test will be administered. 
. 
Telephone Contact (Between Baseline and Week 52) 
Study coordinators will call each subject the day after drug initiation to ensure the study drug is 
well tolerated. Subjects will be called at weeks 1, 2, 3, 4, 8, 13, 17, 21, 30, 34, 39, 43, 47 to monitor 
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DocuSign Envelope ID: B71B646A-E9DC-4D72-80AC-1CABC426282D

Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 25 of 37 
 
 
adherence, to collect medical history data, and record adverse events through 52 weeks.  They 
will also be called 30 and 90 days after Week 52 to record adverse events.  Subjects will be 
encouraged to notify the study coordinator between scheduled contact dates with any new onset 
symptoms or complications. 
 
Post-Week 52 Follow-up 
 
Option 1: discontinuation of study drug  
If a participant chooses to discontinue study drug after Week 52, a study coordinator will call the 
subject at 30 (week 56) and 90 days (week 64) to record any additional adverse events possibly 
or probably related to study drug that may have occurred in the 90 days following completion of 
the study protocol. 
 
Option 2: continuation of study drug for up to 36 additional months 
Following the Week 52 visit, participants will have the option of continuing on in FUEL-Extension 
for  up to 36 months.  During this time, safety data will be collected.  Participants will be contacted 
by the study coordinator on a quarterly basis to monitor and record adverse events.  Once study 
drug has been discontinued (maximum of 36 months following Week 52), subjects will be 
contacted at 30 days and 90 days following cessation of study drug to monitor for additional 
adverse events after discontinuation of drug. 
 
For participants who have completed the 24-month extension and have stopped taking study 
drug for any period of time perior to re-consenting to version 6, the only testing needed prior to 
re-initiating study drug is a pregnancy test for female participants. 
 
 
 
DocuSign Envelope ID: A11A46EC-185A-48F7-89FA-15FACBE0DD03
DocuSign Envelope ID: B71B646A-E9DC-4D72-80AC-1CABC426282D

Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 26 of 37 
 
 
Table 1. Schedule of Events 
 
Visit Number 
1 
1 
TC1 TC 2-15 
2 
TC 16-
17 
TC 16 - 28 
Subject Status 
New subject  
(no FUEL)  
Former FUEL 
subject 
 
 
 
Post 
week 52 
Option 
1 
Post Week 52 Option 
2 
Time point 
Screening/ 
Baseline 
Day 0 
Screening/ 
Baseline 
Day 0 
Day 
1 
Weeks  
1, 2, 3, 
4, 8, 13, 
17, 21,  
30, 34, 
39, 43, 
47 
Week 
52 
Day 30, 
90 post-
study 
(Weeks 
56 and 
64) 
 
Quarterly 
Day 30, 90 
post-drug 
discontinue 
Visit Window(s) 
 
 
 
± 3 
days 
± 10 
days 
± 10 
days 
 
 
Type of Visit(s) 
In-Person 
In-Person 
Call 
Calls* 
In-
Person 
Calls 
Calls 
Calls 
Informed Consent/Assent 
X 
X 
 
 
 
 
 
 
Subject ID# assigned 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
Physical Measurements 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Demographics/expanded demo 
X 
 
 
 
 
 
 
 
Prior/Concomitant Meds 
X 
 
 
X 
X 
 
 
 
EndoPAT® 
X 
 
 
 
X 
 
 
 
Serum or urine pregnancy test 
X 
X 
 
 
X 
 
 
 
Clinical Laboratory tests (creatinine, 
ALT, AST) 
X 
 
 
 
X 
 
 
 
Biomarker (BNP) sample 
X 
 
 
 
X 
 
 
 
Genetic repository sample (optional) 
X 
 
 
 
 
 
 
 
Heart Monitor (optional) 
X 
 
 
 
 
 
 
 
Echocardiogram 
X 
 
 
 
X 
 
 
 
Exercise test (EST) 
Xa 
 
 
 
Xa 
 
 
 
Dispense Open Label Udenafilb 
X 
X 
 
 
 
 
 
 
Resting BP and HRc 
X 
X 
 
 
X 
 
 
 
Administer first dose of study drugc 
X 
X 
 
 
 
 
 
 
Peds QL generic and cardiac modules; 
PCQLI; HAES 
X 
 
 
 
X 
 
 
 
Drug Accountabilityb 
X 
 
 
 
X 
 
 
 
Pregnancy counseling (if appl) 
X 
X 
 
X 
 
 
 
 
Adverse events assessment 
 
X 
X 
X 
X 
X 
X 
X 
Morisky Scale (MMAS) 
 
 
 
X 
 
 
 
 
Schedule/Confirm next visit 
X 
X 
X 
X 
X 
 
 
 
a If failed 1st exercise test, exercise testing can be repeated w/in 14 days. Pregnancy testing must also be repeated. 
b For detailed Drug Accountability procedures, consult the Manual of Operations (MOO) 
c For specific timing of procedures, see Additional Procedures and Measurements in Table 2 
 
DocuSign Envelope ID: A11A46EC-185A-48F7-89FA-15FACBE0DD03
DocuSign Envelope ID: B71B646A-E9DC-4D72-80AC-1CABC426282D

Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 27 of 37 
 
 
 
 
 
Table 2.  Initiation of Study Drug  
 
 
Time from administering first dose of study medication 
Procedure 
<1 hour 
prior to 
dose 
0 hour 
2 hours ± 30 
minutes 
4 hours ± 30 
minutes 
Vital Signs (Resting blood pressure and 
heart rate) 
X 
 
 
X                
before discharge 
from clinic 
Administer First Dose of Study Drug  
 
X  
 
 
Vital Signs Immediately before and 
Following a 6-minute Self-Limiting Walk 
 
 
X 
 
Blood Sample for determination of 
udenafil and metabolite concentration 
immediately after the 6-minute walk. 
 
 
X  
 
Record Adverse Events 
 
X 
X 
X 
Dispense Initial Study Drug for Home 
Administration and Discharge from Clinic 
 
 
 
X 
 
6.5   Data Collection 
 
1. Demographic information 
The following demographic data will be collected: age, gender, race, ethnicity, cardiac 
anatomy, date of Fontan, presence of a fenestration, degree of atrioventricular valve 
regurgitation, grade of ventricular function, concomitant medications, and significant co- 
morbidities. 
 
2. Safety data 
Adverse events will be reviewed with each subject at each study visit and during 
telephone encounters. These events will be recorded and graded by severity and 
relationship to study drug based on established criteria.  Two additional telephone 
encounters will take place 30 days and 90 days following  cessation of study drug [either 
at Week 52 or up to Week 208 if the subject opts to continue study drug] to assess for 
any adverse events possibly or probably related to study drug in the period following the 
completion of study procedures. 
 
3. Exercise stress test 
Data from the braked cycle ergometry exercise stress tests will be collected according to 
protocol established in the PHN Fontan Cross-Sectional Study3. 
 
4. Assessment of ventricular performance 
Each study echocardiogram will be stored in a de-identified manner and sent to a core 
laboratory, which will perform the data analysis and submit the measurements to the 
PHN Data Coordinating Center (DCC). 
 
5. Vascular function testing 
De-identified data from EndoPAT® testing will be collected according to a standardized 
protocol.  These data will be sent to a vascular core lab, which will perform the analysis 
and submit the measurements to the PHN DCC. 
DocuSign Envelope ID: A11A46EC-185A-48F7-89FA-15FACBE0DD03
DocuSign Envelope ID: B71B646A-E9DC-4D72-80AC-1CABC426282D

Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 28 of 37 
 
 
 
6. Biomarkers 
Serum for measurement of BNP level will be sent to a core clinical lab.  Results will be 
sent directly to the PHN DCC. 
 
7. Quality of life survey 
Results of the Quality of life surveys will be submitted to the PHN DCC. 
 
8. Samples for the biorepository 
Samples collected for the biorepository will be shipped directly to the biorepository for 
future analysis. 
 
 
7. SELECTION AND WITHDRAWAL OF SUBJECTS 
 
7.1 Subject Inclusion Criteria 
1. Males and females with Fontan physiology who participated in the FUEL trial or, if they did 
not participate in FUEL, those who are 12 to less than 19 years of age at enrollment. 
2. Participant consent or parental/guardian consent and participant assent 
3. Participant fluent in English or Spanish  
4. Current anti-platelet or anticoagulant therapy 
 
 
7.2 Subject Exclusion Criteria 
1. Height < 132 cm. 
2. Weight < 40 kg. 
3. Hospitalization for acute decompensated heart failure within the last 12 months. 
4. Current intravenous inotropic drugs. 
5. Undergoing   evaluation   for   heart   transplantation   or   listed for transplantation. 
6. Diagnosis of active protein losing enteropathy or plastic bronchitis within the last three years, 
or a history of liver cirrhosis. 
7. Known Fontan baffle obstruction, branch pulmonary artery stenosis, or pulmonary vein 
stenosis resulting in a mean gradient of > 4 mm Hg between the regions proximal and distal 
to the obstruction as measured by either catheterization or echocardiography. 
8. Single lung physiology. 
9. Maximal VO2 less than 50% of predicted for age and gender at enrollment. 
10. Severe ventricular dysfunction assessed qualitatively by clinical echocardiography within six 
months prior to enrollment. 
11. Severe valvar regurgitation, ventricular outflow obstruction, or aortic arch obstruction assessed 
by clinical echocardiography within six months prior to enrollment. 
12. Significant renal, hepatic, gastrointestinal or biliary disorders that could impair absorption, 
metabolism or excretion of orally administered medications. 
13. Inability to complete exercise testing at baseline screening. 
14. History of PDE-5 inhibitor use (with the exception of FUEL participation) within 3 months 
before study onset. 
15. Use of any other drug to treat pulmonary hypertension within 3 months before study onset. 
16. Known intolerance, including hypersensitivity or allergy history,to oral udenafil or any 
components of the investigational product. 
17. Frequent use of medications or other substances that inhibit or induce CYP3A4. 
18. Current use of alpha-blockers or nitrates. 
19. Ongoing or planned participation in another research protocol that would either prevent 
DocuSign Envelope ID: A11A46EC-185A-48F7-89FA-15FACBE0DD03
DocuSign Envelope ID: B71B646A-E9DC-4D72-80AC-1CABC426282D

Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 29 of 37 
 
 
successful completion of planned study testing or invalidate its results. 
20. Noncardiac medical, psychiatric, and/or social disorder that would prevent successful 
completion of planned study testing or would invalidate its results. 
21. Cardiac care, ongoing or planned, at a non-study center that would impede study completion. 
22. For females: Pregnancy at the time of screening, pregnancy planned before study 
completion, or refusal to use an acceptable method of contraception for study duration. 
23. Unable to abstain or limit intake of grapefruit juice during the duration of the trial. 
24. Refusal to provide written informed consent/assent. 
25. In the opinion of the primary care physician, the subject is likely to be non-compliant with 
the study protocol. 
26. History of clinically significant thromboembolic event, as adjudicated by study Investigators that 
may put the subject at increased risk of a subsequent event while participating in the study. 
 
7.3 Recruitment/Enrollment Procedures 
All subjects enrolled in the FUEL Trial will be offered participation in the FUEL Extension Trial. 
This number is anticipated to be approximately 400 subjects. If recruitment from the FUEL subjects 
is less than 300, additional subjects will be identified through the review of clinical data records 
at each participating PHN and auxiliary site. Those who are interested will be enrolled and 
consented at the first study visit by the study coordinator from each participating site. We plan to 
continue to screen and identify potential subjects until enrollment is completed. If consent is 
obtained for study participation but a subject is excluded on the basis of safety labs or a 
pregnancy test (Section 5.2), an additional subject will be recruited to replace the excluded subject. 
 
7.4 Indications for Discontinuation of Study Drug 
Study drug may be discontinued temporarily or permanently, but subjects should remain in the trial 
and complete all study data collection and follow-up measures, including exercise performance 
testing.  Study drug may be discontinued for the following reasons: 
• 
An adverse experience including failure to tolerate study medication that, in the judgment of 
the investigator or primary physician requires drug discontinuation. 
• 
Voluntary discontinuation of study drug by subject. 
 
When possible, the subject will undergo an exercise test, EndoPAT®, and echocardiogram before 
permanent discontinuation of the study drug.  All information regarding any temporary stop and 
restart of study drug will be recorded. 
 
7.5 Subject Withdrawal from Study 
The <Week 52= testing will be obtained whenever possible on subjects who withdraw early.  The 
reason for withdrawal will be documented for all subjects withdrawn from the study.  A subject 
may be withdrawn from trial participation for the following reasons: 
• 
Subject (or legal guardian) declines further study participation. 
• 
Lost to follow-up despite repeated, multiple attempts by the site investigator and study 
coordinators to contact the subject. 
• 
In the investigator’s or other physician’s judgment, it is in the subject’s best interest. 
 
If the subject refuses to continue with the study visits, every attempt will be made to continue 
contact by telephone, written communication, or record review to determine if outcome events 
(death, hospitalizations and major complications) have occurred, unless the subject specifically 
refuses such follow-up.  If the withdrawing subject is unwilling to have his/her medical records 
reviewed until the end of the study period (to document vital status and cause of death), he/she 
must submit a written refusal. 
8. TREATMENTS TO BE ADMINISTERED 
DocuSign Envelope ID: A11A46EC-185A-48F7-89FA-15FACBE0DD03
DocuSign Envelope ID: B71B646A-E9DC-4D72-80AC-1CABC426282D

Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 30 of 37 
 
 
 
8.1 Description of Study Treatments 
All enrolled subjects will receive udenafil at a dose of 87.5 mg twice daily for the duration of the 
study. 
 
8.2 Concomitant Medications 
Subjects will be treated with other medications at the discretion of their physicians. At study 
visits, current medications will be recorded on the study forms. If a subject begins open-label 
use of any other PDE-5 inhibitor at any time during the study, withdrawal from study drug is 
required. 
 
The following drug interactions have been observed with PDE-5 inhibitors including udenafil: 
 
• 
Medications or other substances that strongly inhibit CYP3A4 including but not limited to 
erythromycin, indinavir, nelfinavir, clarithromycin, fluconazole, itraconazole, nefazodone, 
ketoconazole, posaconazole, and voriconazole. 
• 
Medications or substances that strongly induce CYP3A4 including but not limited to 
carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin and St. John’s Wort. 
• 
Alpha blockers 
• 
Intravenous inotropic drugs 
• 
Bosentan 
• 
Ritonavir 
• 
Medications with a drug interaction that should be avoided: 
- 
Boceprevir 
- 
PDE-5 inhibitors other than udenafil 
- 
Telaprevir 
- 
Organic nitrates including isosorbide dinitrate, isosorbide mononitrate and 
nitroglycerin 
- 
Soluble guanylate cyclase (sGC) stimulators 
 
8.3 Procedures for Monitoring Subject Adherence 
Study drug adherence will be assessed at each scheduled study contact by the study 
coordinator. Additionally, adherence will be calculated bi-monthly by comparing the expected 
versus actual consumption of study drug tablets. The study coordinator will remind the subject 
to return study drug bottles to the site during each call contact. Each subject will receive via 
traceable courier a resupply of study medication. Subjects will have the option to return all 
remaining study drug from previous supply to the site using a pre-paid envelope from a service 
provider with the capability to track the shipment (e.g. FedEx or UPS). The study coordinator 
or pharmacist will measure and record the number of remaining tablets. Once the pill count is 
complete, the pharmacy may then destroy the returned study medication according to standard 
operating procedure. 
 
The study coordinator or pharmacist will measure and record the number of remaining tablets, 
and a study drug supply will be dispensed. Once the pill count is complete and the study drug 
has been monitored, the pharmacy may then destroy the returned study medication according to 
standard operating procedure. 
 
Self-report of study drug compliance will be assessed with administration of the Morisky scale24. 
The Morisky scale is a questionnaire used to predict adherence to medication therapies. The 
scale will be administered during each quarterly contact call. 
 
DocuSign Envelope ID: A11A46EC-185A-48F7-89FA-15FACBE0DD03
DocuSign Envelope ID: B71B646A-E9DC-4D72-80AC-1CABC426282D

Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 31 of 37 
 
 
8.4 Study Completion 
When an individual subject completes the study, the subject’s primary cardiologist will be 
notified, and the study drug will be stopped; there is no need to wean subjects off of the study 
drugs. The decision of whether to continue the use of an off label PDE-5 inhibitor for individual 
subjects will be decided by the subjects and their primary cardiologist, and will be at the 
subject’s expense or that of their third-party payer.  Udenafil may also be available to study 
participants after the conclusion of the study through the manufacturer. 
 
9. SAFETY ASSESSMENTS 
 
9.1 Safety Considerations and Monitoring 
The site study coordinators will contact each subject the day after the baseline visit, then weekly 
for four weeks and monthly until 52 weeks (12 months), and then at 30 and 90 days from the week 
52 visit. If the subject is continuing into the extension of up to an additional 36 months then the site 
study coordinators will contact each subject quarterly until the subject discontinues study drug. At 
withdrawal or discontinuation, site study coordinators will contact each subject at 30 and 90 days 
from withdrawal or discontinuation to record adverse events.  
 
9.2.  Recording and Reporting Adverse Events 
A major component of safety monitoring is ascertainment and reporting of AEs, including adverse 
drug reactions. The approach to these activities for this study is summarized in the sections 
that follow. 
 
9.2.1 Definitions of Adverse Event, Suspected Adverse Reaction and Adverse Reaction 
 
The FDA Final Rule on IND Safety Reporting Requirements provides the following definitions: 
• 
Adverse event: any untoward (e.g. unfavorable, negative, or harmful) medical occurrence 
associated with the use of a drug in humans, whether or not the event is considered 
drug related. An event can be any unfavorable and unintended sign, symptom, or disease 
temporally associated with the use of the product. 
• 
Suspected Adverse Reaction: any AE for which there is a reasonable possibility that the 
drug caused the event, meaning the event is possibly, probably related to the study 
drug. 
• 
Adverse Reaction: an AE for which there is a greater degree of certainty regarding 
causality; meaning the event is probably or definitely related to the study drug. Adverse 
reactions are a subset of Suspected Adverse Reactions. 
 
9.2.2 Classification of Adverse Events 
 
Monitoring AEs requires that they be classified as to seriousness, expectedness, and potential 
relationship to the study drugs, all of which drive the reporting process. 
 
a. Seriousness 
An SAE is one that: 
• 
Results in death, 
• 
Is life-threatening (the subject was, in the view of the Principal Investigator, in immediate 
danger of death from the event as it occurred), 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
• 
Results in persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions, 
• 
Is a congenital anomaly/birth defect in the offspring of a participant, or 
• 
Is  an  Important  Medical  Event  that  may  jeopardize  the  subject  or  may  require 
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DocuSign Envelope ID: B71B646A-E9DC-4D72-80AC-1CABC426282D

Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 32 of 37 
 
 
medical/surgical intervention to prevent one of the serious adverse event outcomes. 
 
The Common Terminology Criteria for Adverse Events (CTCAE) a n d  MedDRA 
(http://ctep.cancer.gov) provide a grading system a n d  t e r m i n o l o g y  that is used to 
i d e n t i f y  a n d  categorize the severity of adverse events, as follows: 
 
Grade Severity 
Definition 
1 
Mild 
Asymptomatic  or  mild  symptoms;  clinical  or  diagnostic  observations 
only; intervention not indicated. 
2 
Moderate 
Minimal,  local  or  noninvasive  intervention  indicated;  limiting  age- 
appropriate instrumental activities of daily living (ADL). 
3 
Severe 
Severe  or  medically  significant  but  not  immediately  life-threatening; 
Hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL. 
4 
Life- 
threatenin
Life-threatening consequences; urgent intervention indicated. 
5 
Death 
Death related to AE 
 
An SAE, as defined above, encompasses CTCAE grades 4 and 5, and any Grade 3 event that 
requires or prolongs hospitalization, or that substantially disrupts the ability of the subject to 
conduct normal life functions. 
 
b. Expectedness 
The purpose of reporting is to provide new, important information on serious reactions or events 
previously unobserved or undocumented.  Therefore, all AEs will be evaluated as to whether 
their occurrence was unexpected, using the following definitions: 
• 
Unexpected: An unexpected AE or adverse reaction is one for which the nature 
or severity is not consistent with information in the protocol, consent form, or 
product brochure.   An AE or adverse reaction also may be categorized as unexpected 
if the event has not previously been observed at the same specificity and/or severity. 
There may be unexpected adverse events in female participants in whom this class of 
medication has not been extensively studied. 
• 
Expected:  An event is considered expected if it is known to be associated with the study 
drug(s) and/or the disease state.  According to the product brochure (attached; English 
translation from Korean) and for this protocol, expected events include: 
o Spontaneous penile erection 
o Facial flushing (> 10%)Headache (1-10%) 
o Eye redness (1-10%) 
o Dyspepsia (1-10%) 
o Nasal congestion (1-10%) 
 
c. Causality 
Causality assessment is required to determine which events require expedited reporting. The 
following criteria will be used to determine causality: 
• 
Not Related:  The event is clearly related to other factors, such as the subject’s clinical 
state, or non-study drugs or interventions. 
• 
Possibly Related:  The event follows a compatible temporal sequence from the time of 
administration of the study drug, but could have been produced by other factors such as 
the subject’s clinical state or non-study drugs or interventions. 
• 
Probably Related:  The event follows a reasonable temporal sequence from the time of 
drug administration, and cannot be reasonably explained by other factors such as the 
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DocuSign Envelope ID: B71B646A-E9DC-4D72-80AC-1CABC426282D

Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 33 of 37 
 
 
subject’s clinical state, or non-study drugs or interventions. 
 
9.2.3 Identification of and Data Collection Procedures for Adverse Events 
 
AEs will be identified when they are reported to the clinical center or during scheduled study 
visits by study coordinators and investigators. AEs will be assessed using self-report, physical 
examination data, and medical record review. 
 
9.2.4 Reporting Procedures 
 
Fatal or life-threatening AEs are to be reported to the data coordinating center (DCC) within 24 
hours of first knowledge of the event. Those that are unexpected and considered possibly, 
probably, or definitely related to the study drug (udenafil) will be reported by the DCC to the 
FDA, the DSMB Chair, the medical monitor (MM), the National Heart, Lung, and Blood Institute 
(NHLBI), and all study Investigators as soon as possible, but no later than 7 calendar days after 
first knowledge of the event, followed by a complete report within 15 calendar days. All other 
fatal or life threatening events that are unrelated to study drug (udenafil) will be reported 
semiannually to the DSMB and the NHLBI, and annually to the FDA. 
 
 
Seriousness 
Reporting Timeframe 
Notification Timeframe 
Fatal or life threatening 
Within 24 hour of learning of
the event 
Within 7 calendar days after 
report 
Serious,  but  not  fatal  or  life 
threatening, and pregnancy 
Within 24 hours of learning of
the event 
Within 15 calendar days after 
report 
All other 
Within  7  calendar  days  of 
learning of the event 
Within 15 calendar days after 
report 
 
All other SAEs (i.e., non-fatal or not life-threatening) that are unexpected and considered 
possibly, probably, or definitely related to the study drug will be reported to the DCC within 24 
hours of learning of the event. The DCC will report the event to the FDA, NHLBI, DSMB and all 
study Investigators within 15 calendar days after first knowledge of the event. 
 
All other AEs not meeting the criteria for expedited reporting will be reported to the DCC within 7 
calendar days of first knowledge of the event. The DCC will report these AEs quarterly to 
NHLBI and annually to the FDA. 
 
 
9.2.5 Reporting Adverse Events to Institutional Review Boards for NIH-Supported Multi- 
Center Clinical Trials 
 
The site Investigator or designee is responsible for reporting all serious adverse events to the 
local IRB in accordance with local policies and procedures. 
 
A Data and Safety Monitoring Board (DSMB) Summary Report will be prepared within 30 days 
of each meeting and distributed by NHLBI staff to each Principal Investigator and Study 
Coordinator. The Summary Report will include information that the DSMB met, they reviewed 
the study for safety, and which recommendations were made related to the study. The report is 
to be forwarded to the local IRB. 
 
 
9.2.6 Follow-up of Subjects after Adverse Events 
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Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 34 of 37 
 
 
 
For AEs with a causal relationship to the study product, follow-up by the Investigator is required 
until the event or its sequelae resolve or stabilize at a level acceptable to the Investigator. 
 
9.3  Safety Monitoring  
The Data and Safety Monitoring Plan for this trial will follow standard PHN monitoring principles. 
Oversight of data and safety is provided by the PHN DSMB, appointed by NHLBI. The DSMB 
meets at least twice a year to review data on AEs, adverse reactions, suspected adverse 
reactions, patient-reported outcomes, data quality, and study recruitment at regular intervals, 
and makes recommendations about study conduct to the Director of the Division of 
Cardiovascular Sciences, NHLBI. 
 
The DSMB and NHLBI are assisted by a MM in reviewing serious adverse events in PHN 
studies. The PHN MM is the NHLBI’s designee for determining causality and expectedness of 
all SAEs. 
 
10. STATISTICS 
 
10.1 Primary Aim - Safety 
The primary safety outcome is adverse events. The adverse events will be reported by 
seriousness, severity and relationship with the study drug. Additionally, the number of 
subjects experiencing a composite outcome of death, heart failure associated hospitalization, 
or heart transplant will be reported. The overall assessment of safety will be made on the 
basis of all available adverse events and safety outcome data over the duration of the 12 
months extension trial and an additional 90 days following completion of the study protocol. 
 
10.1.2 Secondary aim – Safety 
The secondary safety outcome will be reported similar to Primary safety outcome (see above), but 
over a longer period of time including additional FU period (i.e. for up to 48 months on the study). 
 
10.2 Secondary Aims - Efficacy 
Primary outcomes for secondary aims 
Changes in myocardial performance index as measured by pulse wave Doppler 
echocardiography over 12 months of the follow-up from the extension trial baseline till end-of-
study testing will be calculated. Student’s t-test for location will be used to determine if mean 
change is different from zero.  A similar approach will be applied to maximal oxygen consumption 
determined by exercise testing for subjects who reached maximal effort at both time points. 
 
Similarly, changes in serum BNP level and pulse amplitude tonometry ratio derived from the 
EndoPAT device over 12 months of the follow-up from the extension trial baseline till end-of- 
study testing will be calculated. The Wilcoxon signed rank test for location will be used to 
determine if median change of each of these outcomes is different from zero. 
 
For secondary efficacy aim focused on maximal oxygen consumption, estimated power to test 
potential secondary hypothesis is calculated conditional on the target sample size of 250 subjects 
(a conservative estimate for number of subjects with paired max effort exercise measurements). 
The estimate below is provided strictly as an illustration, since there will be no formal hypotheses 
testing for secondary outcomes. 
 
Assuming 250 subjects with paired max effort exercise measurements, baseline mean value of 
maximal VO2: 28.0±6.25 ml/kg/min and correlation between baseline and 12-month 
measurements for maximal VO2: 1/3 (based on historical data; a conservative assumption), 
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Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 35 of 37 
 
 
we’ll have 85% power to detect change of 1.4 ml/kg/min (or 0.2 of standard deviation) with type 
1 error of 0.05. 
 
Secondary outcomes for secondary aims 
Secondary outcomes include submaximal measures of exercise capacity (based on exercise 
testing), measures of systolic and diastolic function (based on echocardiograms), and results of 
quality of life surveys measured at baseline and 12-month follow-up visit. Descriptive statistics 
will be provided for each outcome at both time points. Mean change values of the outcomes will 
be assessed by a paired t-test. 
 
Missing data 
Since the main goal of the follow-up study is to assess safety of the patients, imputation of 
missing data is not planned. 
 
10.3 Interim analyses 
No formal stopping rules for safety or efficacy are planned. However, the trial data will be 
reviewed on a periodic basis, at least twice per year, by the DSMB. The DSMB report will 
include information on safety, data quality and data completeness, overall and by center. The 
DSMB has the jurisdiction to recommend stopping of the trial early due to safety concerns at 
any time. The DSMB can recommend stopping the trial after reviewing the results of the FUEL 
trial if the results of FUEL suggest that continuing with FUEL extension is not necessary. 
 
10.4 Potential Biases 
Enrollment to the open label extension trial (OLE) will have two sources: rollover subjects who 
were previously enrolled in one of the FUEL arms (udenafil, placebo) and new subjects who 
didn’t participate in FUEL. Since inclusion/exclusion criteria are identical for the FUEL and OLE, 
we don’t expect differences between the rollover and new subjects. 
 
OLE subjects will not include FUEL subjects who dropped-out or didn’t consent to OLE, creating 
the theoretical potential for one arm of FUEL (placebo or study drug) to be over-represented in 
OLE. Incidence of AEs and key patient characteristics of FUEL subjects not participating in OLE 
will be compared by treatment arm to assess potential bias.  
 
11. DATA MANAGEMENT 
A customized data management system will be developed for the study using the DCC’s secure 
web-based e-Clinical Operating System (eCOS). This system integrates all aspects of study 
data collection including: subject screening and enrollment data; real time accrual reporting; 
tracking of subject study appointments for follow-up; all study follow-up data collection; 
censoring/loss to follow-up data; and monitoring timeliness and quality of data collection. 
 
11.1 Data Entry 
The eCOS system allows direct data entry from multiple study sites via a secure web-based 
application. Data are entered by subject study identification number; names will not be linked 
with subject data in the database. Study sites will maintain local records in secure areas linking 
the subject name with the identification number assigned for the study. Study sites will have full 
access to their own data in eCOS and be able to view these data remotely. Study staff will not 
be able to view subject-level data associated with other sites. 
 
11.2 Data Validation and Monitoring 
Integrated into the data entry system are real time validations, including both inter- and intra- 
instrument data checks. Inconsistent or questionable values are flagged during entry, and an 
edit report is automatically generated to the data entry client. These edit reports provide the 
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IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 36 of 37 
 
 
information necessary to investigate any data entry errors or resolved questions regarding out- 
of-range or questionable values. The eCOS system tracks data entry quality and missing data 
rates by instrument and data collector. 
 
11.3 Data Security and Integrity 
The Web-based components of the data management system utilize several levels of security to 
ensure privacy and integrity of the study data. Access to data from both inside and outside the 
DCC is controlled by extensive security features. The archiving and back-up system ensures 
minimal data loss, even in the most catastrophic system failure. The eCOS database is backed 
up nightly with backups rotated to a secure offsite facility on a routine basis. Data will not be 
stored on laptop computers. 
 
11.4 Biospecimen Tracking 
Specimen tracking is started from the time of receipt at the site, through shipment to the core 
laboratory that will assess udenafil plasma concentrations. Each specimen will be labeled with 
the study code, time of collection, a unique specimen number that is different from the subject’s 
unique study identification (ID) number, and the aliquot number (1 or 2). The master list linking 
the specimen identification numbers to the subject study ID numbers will be maintained under 
password protection in the data management system at the DCC. This blinding code system 
will maintain the confidentiality of the specimens yet allowing linkage of the specimens with 
clinical study data for analyses. 
 
12. QUALITY CONTROL AND QUALITY ASSURANCE 
 
The DCC has primary responsibility for quality control (QC) / quality assurance (QA) activities of 
the data. The DCC also requires that the sites complete certain QC activities, most of which are 
monitored by the DCC. The key QC/QA activities are: 
 
• 
Development of a Study Manual; 
• 
Clearly formatted and carefully constructed Data Forms with clear, up-to-date manuals 
of instruction; 
• 
Sign-Off Procedures for all CRFs; 
• 
Central protocol training and tracking of all site data collection staff with the use of 
standardized checklists; 
• 
Data management  training  and certification of site personnel completing  data entry 
and/or data management; 
• 
Verification of patient eligibility; 
• 
On-going monitoring of all protocols/data collection activities; 
• 
Inclusion of repeat measurements, as feasible, in the course of the study; and 
• 
Monitoring visits to sites as required with pre-specified goals and/or remote monitoring 
activities. 
 
The DCC may conduct site visits to the Core Laboratories and/or Biorepository to review QA 
and QC procedures and data transfer to the DCC. Review of central laboratory-related reports 
will be conducted at least monthly to identify overall or site-specific problems in data or specimen 
acquisition and reporting of results. 
 
13. ETHICS AND HUMAN SUBJECTS CONSIDERATIONS 
 
13.1 Potential Risks 
 
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IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 37 of 37 
 
 
Clinical data collection 
There are no significant procedural risks associated with physical examination or testing by 
ECG or echocardiography. These evaluations, however, may rarely reveal previously unknown 
cardiac abnormalities. 
 
Exercise Testing 
Exercise testing is part of the routine care of children and young adults and will be performed 
with coverage by a pediatric cardiologist. In this study, the subject’s heart rate, rhythm, blood 
pressure, and arterial oxygen saturation will be monitored throughout the exercise test. The 
subjects will exercise on a cycle ergometer, which minimizes the risk of falling or 
musculoskeletal injury. The physician or subject may stop the test at any time they feel unable 
or uncomfortable proceeding. To minimize risk, subjects with either clinical heart failure or a 
recent history of heart failure or clinically significant arrhythmia will be excluded from the study. 
In patients with Fontan physiology, the risks of exercise testing in this are low. In the PHN 
Cross-sectional Fontan Study, there were no complications of exercise testing in 411 subjects3. 
 
Echocardiogram and EndoPAT® Testing 
Echocardiograms are part of routine care for children and young adults with Fontan physiology. 
Subjects  may  have  minor  skin  irritation  from  the  patches  placed  on  the  skin  during  the 
echocardiogram. Additionally, subjects may experience minimal discomfort related to the 
performance of the echocardiogram and EndoPAT® testing as a result of pressure on the chest 
or arm during the testing procedures. 
 
Plasma Collection 
Minor temporary discomfort may be associated with the removal of blood by venipuncture or 
through a blood drawing intravenous catheter.  There is a risk of bruising, lightheadedness, and 
a very small amount of bleeding associated with the blood draw. 
 
Heart Monitor 
The patch which secures the monitor to the skin may result in local skin irritation or discomfort. 
 
Study Drug: Udenafil 
Sildenafil was the first PDE-5 inhibitor approved by the FDA for treatment of pulmonary 
hypertension in adults. This approval was based on the results of the SUPER 1 study published 
in 200513. This study included 278 subjects followed for one year. There were two serious 
adverse events felt to be potentially related to the study drug: left ventricular dysfunction and 
postural hypotension in one subject each. The most common side effects were headache and 
flushing. The incidence of side effects is listed in the table below. There was no significant 
alteration in any monitored laboratory value associated with any dose of sildenafil used in this 
study. 
 
Incidence of side effects by dosage in adults with pulmonary hypertension SUPER1 Study13 
Side Effect 
Placebo (N=70) 
Sildenafil 
20 mg 
40 mg 
80 mg 
(N=69) 
(N=67) 
(N=71) 
Headache 
27 (39) 
32 (46) 
28 (42) 
35 (49) 
Flushing 
3 (4) 
7 (10) 
6 (9) 
11 (15) 
Dyspepsia 
5 (7) 
9 (13) 
6 (9) 
9 (13) 
Back pain 
8 (11) 
9 (13) 
9 (13) 
6 (8) 
Diarrhea 
4(6) 
6 (9) 
8 (12) 
7 (10) 
Limb pain 
4 (6) 
5 (7) 
10 (5) 
6 (8) 
Myalgia 
3 (4) 
5 (7) 
4 (6) 
10(14) 
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Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 38 of 37 
 
 
Cough 
4 (6) 
5 (7) 
3 (4) 
6 (8) 
Epistaxis 
1 (1) 
6 (9) 
5 (7) 
3 (4) 
Pyrexia 
2 (3) 
4 (6) 
2 (3) 
7 (10) 
Insomnia 
1 (1) 
5 (7) 
4 (6) 
3 (4) 
Influenza 
2 (3) 
4 (6) 
4 (6) 
3 (4) 
Visual disturbance 
0 
0 
3 (4) 
5 (7) 
Gastritis 
0 
2 (3) 
2 (3) 
3 (4) 
Data presented as N (%) 
 
Tadalafil was approved more recently based on a study of 405 young adults with pulmonary 
hypertension from multiple causes. At the 40 mg daily dosage, side effects were similar to 
SUPER 1 study, only headaches occurred at a significantly higher rate than placebo. There 
was no clinically significant change in any safety laboratory values. Serious adverse events 
were equally distributed throughout all treatment arms25. 
 
There are fewer data on the safety of PDE-5 inhibitor use in children and adolescents12, 26, 27. A 
recent review of pediatric studies by Huddleston et.al. showed that the side effect profile in this 
population was similar to that reported in the SUPER1 Study. However, the incidence of side 
effects appears to be significantly lower26. Similarly to SUPER1, there was no significant 
change in any monitored laboratory testing with PDE-5 inhibitors in the pediatric population in 
these small pediatric studies. The recently published STARTS-1 and STARTS-2 trials evaluated 
three escalating doses of sildenafil in pediatric patients with pulmonary arterial hypertension. 
Increased mortality was observed in the higher dosage cohorts of the STARTS-2 extension 
trial28. 
 
Incidence of side effects of sildenafil in the pediatric population. Pooled data from 15 studies 
in children26 
Adverse Event 
Description 
n 
Incidence (%) 
Hypotension 
Significant   blood   pressure   reduction   and   impaired 
oxygenation with IV, transient with PO 
15 
5.9 
Erection 
Mostly short-lived erection, recurrent 
6 
2.6 
Nasal 
congestion 
 
Transient, resolved upon discontinuation 
6 
2.3 
Headache 
Persistent (sildenafil suspended 4 mo); 
one only with dose > 125 mg 
4 
1.6 
Dizziness 
Resolved with dose reduction; 
one only with dose > 125 mg 
3 
1.2 
Flushing 
Resolved with dose reduction; 
one only with dose > 125 mg 
3 
1.2 
Bleeding 
Circumferential oozing after circumcision 
requiring cauterization and sutures; 
penis was erect 
1 
< 1 
Body ache 
Mild, self-limiting 
1 
< 1 
Epistaxis 
Self-limiting 
2 
< 1 
GI upset 
Not otherwise described 
2 
< 1 
Heavy 
menstrual flow 
 
With menarche, responded to progesterone therapy 
2 
< 1 
Optic 
neuropathy 
 
Monocular visual loss 
1 
< 1 
Pneumothorax 
Questioned relatedness 
1 
< 1 
Retinopathy 
Retinopathy of prematurity 
1 
< 1 
Rhinorrhea 
Resolved with dose reduction 
2 
< 1 
Intestinal 
pneumatosis 
Temporarily discontinued, safety restarted without other 
documented adverse event (continued 688 days) 
1 
< 1 
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IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 39 of 37 
 
 
Abdominal 
discomfort 
 
Not otherwise described 
NR 
IV intravenous; PO by mouth, NR not reported 
% incidence calculated by utilizing sum of all pediatric studies and case reports 
 
The largest controlled trial of a PDE-5 inhibitor in the pediatric congenital heart disease 
population, and the only study to assess its use in the Fontan population, is the Sildenafil After 
the Fontan Operation Study (SAFO Study), which served as the pilot study for this proposal11. 
In this study, 31 subjects underwent a double-blind 6-week cross over study of sildenafil and 
placebo. Headache and facial flushing were the only 2 side effects that occurred significantly 
more in the sildenafil treatment arm compared to the placebo. Interestingly, both of these side 
effects were only more common in the female subjects. Dizziness and vomiting were the only 
other side effects that occurred in more than 1 percent of the study subjects and were equally 
common in both treatment arms. These findings are summarized in the table below. Of note, 
there were no cases of priapism or visual disturbance in this population. These data suggest 
that PDE-5 inhibitors are well tolerated in the pediatric population with a side effect profile at 
least as safe as that seen in adults. Summary of Side Effects for the SAFO Study11. 
 
Event 
Sildenafil (n = 27) 
Placebo (n = 28) 
Headache 
9 (33%) 
5 (18%) 
Flushing 
5 (19%) 
0 (0%) 
Dizziness 
2 (7%) 
2 (7%) 
Nausea/Vomiting 
2 (7%) 
0 (0%) 
Abdominal Pain 
1 (4%) 
0 (0%) 
Kidney Stone 
1 (4%) 
0 (0%) 
Photosensitivity 
1 (4%) 
0 (0%) 
Rash 
1 (4%) 
0 (0%) 
Diarrhea 
0 (0%) 
1 (4%) 
Hypotension 
0 (0%) 
1 (4%) 
Muscle Pain 
0 (0%) 
1 (4%) 
Tinnitus 
0 (0%) 
1 (4%) 
Tremors 
0 (0%) 
1 (4%) 
Any Event 
19 (70%) 
18 (64%) 
 
We are aware of three previous Phase I studies of Udenafil, all performed in healthy adult male 
populations designed to investigate the safety, tolerability, PK, and PD of Udenafil. In these 
three studies, there were no serious adverse events. Adverse events were primarily limited to those 
expected for PDE5 inhibitors and included facial flushing, headache, and spontaneous erection. 
All of the observed adverse events appeared to occur in a dose responsive manner, with the 
majority of events occurring at doses of 200 mg or more. The side effect profile reported in 
these three studies is similar to that reported in the pilot trial of sildenafil (20 mg three-times 
daily) in the Fontan population, in which the most common adverse events were headache and 
flushing
11
. In studies of PDE5 inhibitors in the Fontan population, there were no unanticipated side 
effects. It is important to confirm that the short-term safety and tolerability of udenafil before starting 
a RCT in this cohort. For this reason a Phase I/II dose escalation trial of udenafil in adolescents with 
Fontan palliation has been completed prior to this study to establish safety and dosage for this 
study. The adverse events associated with the escalated dosages in this study are presented in 
Table 3. For the 87.5 mg BID dose to be used in the current study, headache, flushing, and 
spontaneous penile erection were present in percentages similar to the previous pediatric studies 
reported above. 
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Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 40 of 37 
 
 
 
Table 3.  Drug-related *adverse events that occurred more than once in one subject or in more than 
one subject in at least one cohort 
Preferred 
Term, 
#Events (#Subjects) 
37.5 
mg 
daily 
(N=6) 
37.5 
mg 
twice daily 
(N=6) 
87.5 
mg 
daily 
(N=6) 
125 
mg 
daily 
(N=6) 
87.5 
mg 
twice 
daily 
(N=6) 
Abdominal discomfort 
0 (0) 
0 (0) 
0 (0) 
3 (1) 
1 (1) 
Back pain 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
4 (1) 
Flushing 
2 (1) 
2 (2) 
4 (4) 
1 (1) 
7 (2) 
Headache 
8 (3) 
6 (4) 
9 (4) 
13 (4) 
12 (4) 
Nasal congestion 
1 (1) 
2 (2) 
1 (1) 
1 (1) 
3 (1) 
Nausea 
1 (1) 
2 (1) 
0 (0) 
0 (0) 
1 (1) 
Spontaneous penile erection 
0 (0) 
2 (1) 
1 (1) 
2 (2) 
6 (2) 
*Probably or possibly; definitely related 
 
13.2 Confidentiality, Protection against Risks 
 
Investigators will take all reasonable measures to protect the confidentiality of subjects and their 
families, including the following: 
 
Use of Subject ID numbers 
Each subject is assigned a subject identification number (SID). All interview and clinical research 
data are stripped of identifiers and labeled with the study number. The enrollment log with 
participant identifiers will be maintained at each site in a secured, locked location available only 
to the study staff. Samples for DNA will be stripped of the study SID at the laboratory and 
assigned distinct specimen numbers without other identifying information. The informed consent 
form states that study data will be made available to the DCC and NIH/NHLBI to ensure study 
safety and quality control. The subject’s name and any other identifying information will not 
appear in any presentation or publication resulting from this study. 
 
Reporting of Test Findings 
The results of future tests on biological specimens will not be released to the subject/family. At 
the end of the study, the results of the genetic testing may be published for all the subjects as a 
group, but it will not be possible to provide results for an individual subject and medical 
management will not be changed based on individual results. There is a reasonable possibility 
that no findings will result from this research effort. If findings are detected, it may be years 
before any utility of these findings is realized. Further, if samples are <anonymized= prior to 
release to other investigators for research, it may not be possible to trace the results back to the 
subject. 
 
If an incidental finding is found on a study clinical test, the PI or other qualified member of the 
research team will take full responsibility for disclosing the findings to the patients/parents, 
communicating with their primary cardiologist with permission, or making appropriate cardiology 
referrals as indicated. The subject may choose to seek a second opinion and/or appropriate 
clinical care. This might change the subject's insurability and employability as it relates to the 
clinical finding only. The presumption is that detection of a potentially clinically significant 
finding will prove to be beneficial. 
 
Certificate of Confidentiality 
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IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
Page 41 of 37 
 
 
To help us protect the privacy of subjects who provide biological specimens and to be compliant 
with current NIH policy, we will obtain a Certificate of Confidentiality from the National Institutes 
of Health (NIH). With this Certificate, the researchers of this study cannot be forced to disclose 
information that may identify a subject, even by a court subpoena, in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings. The Certificate cannot be used 
to resist a request for information from the United States government when it is used for 
evaluating federally funded study projects or for information that must be disclosed to meet the 
requirements of the Food and Drug Administration (FDA). A Certificate of Confidentiality does 
not prevent a subject or his/her family from voluntarily releasing information about the subject’s 
involvement in this research. If an insurer, employer, or other person obtains a subject’s or 
family’s written consent to receive research information, then the researchers will not use the 
Certificate to withhold that information. 
 
Information from DNA analyses and phenotypic data from clinical studies or medical records 
may be placed into a central data repository in the future, such as the National Center for 
Biotechnology Information repository. Data and samples will be de-identified before submission 
to this or any other central repository. 
 
Exercise Testing 
Exercise testing will be performed in the presence of a cardiologist. The subject’s heart rate, 
rhythm, blood pressure, and arterial oxygen saturation will be monitored throughout the study. 
The subjects will exercise on a cycle ergometer which minimizes the risk of falling or muscular- 
skeletal injury.   The physician or subject may stop the test at any time they feel unable or 
uncomfortable proceeding. To minimize risk, subjects with either clinical heart failure or a 
recent history of heart failure will be excluded from the study. 
 
Risk of Udenafil 
Any subject with a previous serious adverse reaction to a PDE-5 inhibitor or a known 
contraindication to its use will be excluded from this study. Incidence of side effects will be 
monitored at every study visit. Subjects and families will be encouraged to report any serious 
event to study personnel as soon as the event occurs, rather than waiting for scheduled visits or 
phone calls. 
 
13.3 Potential Benefits 
 
There are potential benefits to participating in this study. The observed decline in exercise 
capacity in adolescents with Fontan physiology is substantial and well documented. It is clear 
that a significant percentage of this population will have an aerobic capacity with exercise testing 
that is below 45% - 50% of predicted by their third decade of life. When this level of exercise 
intolerance is reached, the risk of overt heart failure, hospitalization, and death or transplantation 
rises significantly. If udenafil improves aerobic capacity, this may prolong by years the time to 
onset of overt symptoms in this population. However, udenafil can only be used clinically if it is 
determined to be safe. 
 
Currently, there is no known direct benefit from provision of biospecimens by the subject and 
family. The indirect benefit comes from the potential knowledge about the relationship between 
genetic factors or biomarkers and longer-term cardiac and neurodevelopmental outcomes. This 
information may help physicians provide better answers to families’ questions regarding causes, 
risk, and recurrence risks.  It may also inform development of future interventions and/or 
treatments. 
 
13.4 Risk/Benefit Ratio and Importance of Information to Be Obtained 
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Ventricle Physiology after Fontan Palliation (FUEL Extension) 
30 Oct 2020 
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The risk/benefit ratio of the study is favorable. The risk of adverse drug reactions is low, and 
most are relatively minor in nature and reversible with a decrease in the dose of study drug or 
cessation of therapy. The results of this study and the information that it provides will allow for 
the design of a randomized clinical trial to study the impact of udenafil in the Fontan population. 
 
14. STUDY LIMITATIONS 
 
This study will evaluate the safety of udenafil in a large cohort of adolescents over a one-year 
time period and may therefore fail to identify side effects that occur over a longer period of time. 
As such, ongoing surveillance of udenafil in the population is recommended if this drug were to 
be adopted for routine clinical use. 
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15. REFERENCES 
1. 
Fontan F and Baudet E. Surgical repair of tricuspid atresia. Thorax. 1971;26:240-8. 
2. 
Kreutzer G, Galindez E, Bono H, De Palma C and Laura JP. An operation for the 
correction of tricuspid atresia. The Journal of thoracic and cardiovascular surgery. 
1973;66:613-21. 
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Pediatric Heart Network/Mezzion Pharma Co. Ltd. 
IND 121648 Udenafil Tablets Phase III Safety Extension Study of Udenafil in Adolescents with Single 
Ventricle Physiology after Fontan Palliation (FUEL Extension) 
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