Clinical trial NCT02741115
Conditions: Single Ventricle Heart Disease
Keywords: Fontan Maximal Oxygen Consumption Vascular Function EndoPAT Myocardial Performance
Sponsor: Mezzion Pharma Co. Ltd
Start date: 2016-07-22; Completion date: 2019-04-30
Enrollment: 400 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the clinical efficacy and safety of udenafil, an orally administered, potent and selective inhibitor of PDE5, versus placebo for the treatment of adolescent subjects who have undergone the Fontan procedure.

Detailed description:
This study is a randomized, double-blinded, efficacy trial of the effects of udenafil vs. placebo on the background of standard therapy on maximal VO2 (ml/kg/min) from baseline to six months in adolescent survivors of the Fontan procedure. . The target sample size is 400 subjects (200 per group).

Arms: arm 1: Udenafil. One tablet twice daily for 26 weeks arm 2: Placebo. One tablet twice daily for 26 weeks
Interventions: intervention 1: Udenafil intervention 2: Placebo
Intervention descriptions: intervention 1: Active drug intervention 2: Matching Placebo

Protocol documents:
Prot_000.pdf: 
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Clinical Study Report 
 
1. 
TITLE PAGE 
Report Title: 
Fontan Udenafil Exercise Longitudinal Assessment Trial (FUEL) 
Protocol Number: 
PHN-Udenafil-02 
NCT Number: 
NCT02741115 
Study Phase: 
3 
Investigational 
Drug Product(s): 
Udenafil tablets 87.5 mg BID and matching placebo 
Indication Studied: 
Treatment of single ventricle heart disease in adolescents with 
Fontan physiology. 
Study Period: 
First subject consent:  
25 July 2016 
Last Week 26 visit: 
 
27 December 2018 
Clinical 
Investigator(s): 
Multicenter 
Sponsor: 
Mezzion Pharma Co. Ltd in partnership with Pediatric Heart 
Network (PHN) 
Issue Date: 
27 February 2021 
 
 
This trial was conducted in accordance with the ethical principles of Good Clinical 
Practice, according to the ICH Harmonised Tripartite Guideline. 
 
This document is the property of Mezzion Pharma Co. Ltd and must be kept in a confidential manner. No part of 
this document may be reproduced or transmitted in any form without written permission from 
 Mezzion Pharma Co. Ltd 


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2. 
SYNOPSIS 
 
Name of 
Sponsor/Company: 
Mezzion Pharma Co. Ltd in 
partnership with Pediatric 
Heart Network (PHN) 
Individual Study Table 
Referring to Part of the 
Dossier 
Volume: 
Page: 
 
(For National Authority Use Only) 
Name of Finished Product: 
Udenafil tablet 87.5 mg  
Name of Active Ingredient: 
Udenafil 
Title of Study:  
A Phase III Safety Extension Study of Udenafil in Adolescents with Single Ventricle Physiology 
After Fontan Palliation (FUEL Extension) 
Principal Investigator:  
Multicenter 
Investigators:  
A list of investigators and their curricula vitae are provided in Appendix 16.1.4. 
Study center(s):  
27 sites (25 United States, 2 Canada) 
Publications (reference):  
None 
Studied period (years):  
Date of first informed consent:  06 February 2017 
Date of data cutoff:  31 August 2020 
Phase of development:  
3 
Objectives:  
• 
Determine the safety of udenafil (87.5 mg twice daily [BID]) in an adolescent population 
with single ventricle congenital heart disease palliated with the Fontan procedure. 
• 
Evaluate the pharmacodynamic profile of udenafil. 
 
 
 


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Methodology:  
This was a Phase 3, open-label extension, 12-month, multicenter study, with an option for up to 
an additional 36 months, to supplement the Phase 3 Fontan Udenafil Exercise Longitudinal 
Assessment Trial (FUEL study) by providing a more robust safety and side-effect profile of the 
use of udenafil in adolescents with Fontan physiology. An attempt was made to recruit all 
participants who completed the FUEL study (approximately 400 adolescents). If recruitment from 
the FUEL study was less than 300 subjects, additional adolescents with Fontan physiology (De 
Novo subjects) were identified through the review of clinical data records at each participating 
site until the minimum of 300 total subjects were enrolled.  
Those who were interested were enrolled and consented at the first study visit by the study 
coordinator from each participating site. Screening and identification of potential subjects 
continued until enrollment was complete.  
Subjects who agreed to participate had baseline testing performed to determine eligibility with 
inclusion/exclusion criteria. For subjects who participated in the FUEL study and continued on to 
this extension study, safety laboratory results from FUEL were accepted as meeting the inclusion 
criteria for FUEL Extension. For De Novo subjects, the baseline visit consisted of 2 parts, 
baseline testing and study drug initiation. These parts may have been combined into a single day 
or split into 2 days so long as the duration between the visits was no more than 7 days. Safety 
laboratory testing and pregnancy testing for female participants were performed. After safety 
laboratory testing, subjects performed an exercise test to maximal effort to be eligible for study 
drug initiation.  
All enrolled subjects were provided with udenafil, at a dose of 87.5 mg BID, for the duration of 
the study. The first dose of study drug was administered at the clinic (Visit 1). Approximately 
2 hours (±30 minutes) post dosing, resting heart rate and blood pressure were measured, and the 
subject performed a self-limited 6-minute walk. A repeat heart rate and blood pressure were 
measured immediately following and approximately 2 hours (±30 minutes) following the 6-
minute walk. Subjects who had a drop in systolic blood pressure >20 mmHg from the pre- to 
post-6-minute walk measurement, or had a drop in systolic blood pressure below the 5th 
percentile for age, were excluded from receiving any further study drug. Continuing subjects were 
dispensed their initial supply of study medication and instructed to take 1 tablet orally BID. 
 
 
 
 


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Methodology (continued):  
All subjects returned to the clinic at Week 52. In addition to clinic visits, study coordinators 
contacted each subject by telephone the day after the baseline visit to discuss any adverse events 
(AEs). Subjects were also contacted by telephone at Weeks 1, 2, 3, 4, 8, 13, 17, 21, 30, 34, 39, 43, 
and 47 to ensure the study drug was well tolerated, to monitor study drug adherence, record AEs 
and concomitant medications, and offer pregnancy counseling, if needed. Subjects were 
encouraged to notify the study coordinator between scheduled contact dates with any new onset 
symptoms or complications.  
For subjects continuing in FUEL Extension beyond Week 52, telephone contact occurred monthly 
and 30 and 90 days following study drug discontinuation to ensure the study drug was well 
tolerated and record AEs. 
In-clinic study visits included assessments of safety (AEs, concomitant medication use, vital 
signs, and clinical safety laboratory evaluations), efficacy (exercise testing, echocardiogram, 
EndoPAT®, brain natriuretic peptide, and quality of life measurements), and pharmacokinetics. 
The duration of study drug dosing was 12 months, with an option to extend for up to an additional 
36 months. When an individual subject completed the study, the subject’s primary cardiologist 
was notified, and the study drug was stopped.  
De Novo subjects who were not participants in the FUEL trial were given the opportunity to 
participate in the heart rhythm-monitoring subset of FUEL Extension. Optional heart rhythm 
monitoring was to include a 3- to 7-day baseline monitor and a 3-day steady-state monitor.  
Number of patients (planned and analyzed):  
Planned: 300 to 400 adolescents. 
Analyzed: 301 adolescents for safety (at interim analysis). 
Diagnosis and main criteria for inclusion:  
1. Males and females with Fontan physiology who participated in the FUEL trial or, if they 
did not participate in FUEL, were 12 to less than 19 years of age at enrollment. 
2. Current anti-platelet or anticoagulant therapy. 
 
 
 


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Test product, dose and mode of administration, batch number:  
Udenafil tablets 87.5 mg orally BID 
Dr. Reddy’s Laboratories Ltd.: Batches UDBT15-11 and UDBT15-12  
Halo Pharmaceutical Canada, Inc.: Batch MP0220 
Duration of treatment:  
52 weeks, with an option to extend for up to an additional 36 months 
Reference therapy, dose and mode of administration, batch number:  
None 
Criteria for evaluation at interim analysis: 
Efficacy endpoints: 
• 
Change in maximal VO2 from baseline to Week 52 
• 
Change in VO2 at ventilatory anaerobic threshold (VAT) from baseline to Week 52 
• 
Change in ventilatory equivalents of carbon dioxide (VE/VCO2) at peak exercise from 
baseline to Week 52 
• 
Change in VE/VCO2 at VAT from baseline to Week 52 
• 
Change in minute ventilation at peak exercise 
• 
Change in work rate at peak exercise from baseline to Week 52 
• 
Change in work rate at VAT from baseline to Week 52 
• 
Change in myocardial performance index (MPI) from baseline to Week 52 
Safety: 
Adverse events, vital signs (blood pressure and heart rate), and concomitant medication use. 
Statistical methods at interim analysis: 
The Safety population included all subjects who took at least 1 dose of study drug. The Efficacy 
population included all enrolled subjects who had baseline and Week 52 exercise capacity data for 
which site-based data quality assurance process was complete at data cut-off.  
Three treatment groups were defined: 
• 
Udenafil-Udenafil, which included subjects who received udenafil in the FUEL and 
FUEL Extension studies 
• 
Placebo-Udenafil, which included subjects who received placebo in the FUEL study and 
udenafil in FUEL Extension  
• 
De Novo: Subjects who did not participate in the FUEL study and received udenafil in 
FUEL Extension 
For efficacy and safety summaries, the Placebo-Udenafil and De Novo groups were combined 
(denoted as Placebo/De Novo-Udenafil). 
All summaries were descriptive. Descriptive statistics for categorical endpoints included the 
number and percent of subjects in each treatment group and category. Quantitative endpoints were 
summarized for each treatment group with the mean, median, standard deviation, minimum value, 
and maximum value. Missing data were not imputed. 
Baseline was defined as the last measurement before receipt of udenafil in FUEL Extension. For 
the Udenafil-Udenafil group, change to Week 52 of FUEL Extension measures change in exercise 
capacity between 26 weeks and 78 weeks of udenafil treatment. This change represents 
persistence of initial effectiveness beyond 26 weeks. For the Placebo-Udenafil and De Novo 
groups, change to Week 52 of FUEL Extension measures change in exercise capacity from pre-
udenafil to following 52 weeks of udenafil treatment. 
 


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Statistical methods (continued): 
For each efficacy endpoint, descriptive statistics were summarized for baseline, Week 52, and 
Week 52 change from baseline. A 2-sided, 95% confidence interval was calculated for change 
from baseline for each group. 
Safety analyses were descriptive with no formal hypothesis testing. All AEs were classified by the 
Medical Dictionary for Regulatory Activities with respect to system organ class and preferred 
term. Subject incidence of all treatment-emergent adverse events (TEAEs), and TEAEs that are 
treatment-related, serious, serious treatment-related, and any TEAE leading to study 
discontinuation were tabulated. Number (%) of subjects who were hospitalized, had a cardiac 
transplant, or died were tabulated. 
Incidence of potentially clinically significant changes from pre dose values in blood pressure and 
heart rate were tabulated at i) post first study dose but before the self-limited 6-minute walk, ii) 
after the 6-minute walk, and iii) at any time after dosing. 
SUMMARY – CONCLUSIONS 
EFFICACY RESULTS: 
For the Udenafil-Udenafil group, change to Week 52 of FUEL Extension measures change in 
exercise capacity between 26 weeks and 78 weeks of udenafil treatment. This change represents 
persistence of initial effectiveness beyond 26 weeks. For the Placebo/De Novo-Udenafil group, 
change to Week 52 of FUEL Extension measures change in exercise capacity from pre-udenafil to 
after 52 weeks of udenafil treatment. 
In the Placebo/De Novo-Udenafil group, mean exercise capacity and myocardial performance 
improved between pre-udenafil and after 52 weeks of udenafil treatment: 
• 
Mean increase at peak exercise effort in VO2 (58.00 mL/min), work rate (5.78 watts), and 
minute ventilation (2.41 L/min). When VO2 was standardized by each subject’s body 
weight, a mean decrease was observed (-0.93 mL/kg/min; 95% CI: -1.7 to -0.2 
mL/kg/min). 
• 
Mean increase in VO2 at VAT of 12.90 mL/min (95% confidence interval [CI]: -23.1 to 
48.9 mL/min). When standardized by each subject’s body weight, a mean decrease was 
observed (-0.93 mL/kg/min; 95% CI: -1.5 to -0.4 mL/kg/min). 
• 
Mean decrease in VE/VCO2 at VAT of -0.77 (95% CI: -1.4 to -0.2). 
• 
Mean increase in work rate at VAT of 0.58 watts (95% CI: -2.6 to 3.7 watts). 
• 
Mean decrease in MPI of -0.04 (95% CI: -0.1 to 0.0). 
In the Udenafil-Udenafil group, mean exercise capacity was improved while myocardial 
performance did not deteriorate between 26 weeks and 78 weeks of udenafil treatment: 
• 
Mean increase at peak exercise effort in VO2 (38.00 mL/min), work rate (2.99 watts), and 
minute ventilation (2.56 L/min). When VO2 was standardized by each subject’s body 
weight, a mean decrease was observed (-1.45 mL/kg/min; 95% CI: -2.3 to -0.6 
mL/kg/min). 
• 
Mean increase in VO2 at VAT of 6.57 mL/min (95% CI: -47.9 to 61.0 mL/min). When 
standardized by each subject’s body weight, a mean decrease was observed 
(-1.25 mL/kg/min; 95% CI: -2.1 to -0.4 mL/kg/min). 
• 
Mean decrease in VE/VCO2 at VAT of -0.66 (95% CI: -1.6 to 0.3). 
• 
Mean increase in work rate at VAT of 0.26 watts (95% CI: -5.1 to 5.6 watts). 
• 
Negligible mean decrease in MPI of -0.0 (95% CI: 0.0 to 0.0). 
 
 


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SAFETY RESULTS: 
No clinically important differences were observed in the safety profile between subjects who had 
previously received treatment with udenafil and those who were naïve to udenafil treatment prior to 
participating in this study.  
Similar percentages of subjects in the Udenafil-Udenafil and Placebo/De Novo-Udenafil groups 
reported TEAEs (77.3% and 80.3%, respectively), drug-related TEAEs (64.1% and 67.6%, 
respectively), TEAEs of Grade ≥3 (3.9% and 7.5%, respectively), serious TEAEs (10.9% and 13.9%, 
respectively), drug-related serious TEAEs (3.9% and 5.8%, respectively), and TEAEs resulting in 
temporary or permanent discontinuation of study drug (15.6% and 12.7%, respectively). 
The most common TEAEs reported included headache (35.2%), flushing (17.2%), dizziness (11.7%), 
upper respiratory tract infection (10.2%), and nausea (10.2%) in the Udenafil-Udenafil group and 
headache (40.5%), flushing (15.6%), nasopharyngitis (12.7%), and dizziness (12.7%) in the 
Placebo/De Novo-Udenafil group. Most TEAEs were mild or moderate in intensity; similar 
percentages of subjects in the Udenafil-Udenafil (5 subjects; 3.9%) and Placebo/De Novo-Udenafil 
(13 subjects; 7.5%) groups experienced a severe TEAE.  
There was no clinically important difference in the TEAE profile among males and females; the 
limited number of non-Caucasian subjects and Hispanic or Latino/Latina subjects precluded 
meaningful comparisons between race and ethnicities within treatment groups. 
No subject died during the study. At least 1 serious TEAE was reported by 14 (10.9%) subjects in the 
Udenafil-Udenafil group and 24 (13.9%) subjects in the Placebo/De Novo-Udenafil group. Among 
the serious TEAEs reported, cardiac failure was reported by 4 subjects in the Placebo/De Novo 
Udenafil group, transient ischaemic attack was reported by 2 subjects in the Placebo/De Novo 
Udenafil group and 1 subject in the Udenafil-Udenafil group, abdominal pain and appendicitis were 
reported by 2 subjects each in the Udenafil-Udenafil group, protein-losing gastroenteropathy, 
gastroenteritis, and syncope were reported by 2 subjects each in the Placebo/De Novo Udenafil group, 
and anaemia, supraventricular tachycardia, ventricular tachycardia, and vomiting were reported by 
1 subject each in the Udenafil-Udenafil and Placebo/De Novo Udenafil groups. All other serious 
TEAEs were reported by no more than a single subject in either treatment group. Hospitalization was 
reported for 14 (10.9%) subjects in the Udenafil-Udenafil group and for 24 (13.9%) subjects in the 
Placebo/De Novo Udenafil group. No transplants were reported. 
At least 1 TEAE leading to temporary or permanent discontinuation of study drug was reported by 
20 (15.6%) subjects in the Udenafil-Udenafil group and 22 (12.7%) subjects in the 
Placebo/De Novo-Udenafil group. The most common types of TEAEs that led to temporary or 
permanent discontinuation of study drug were associated with nervous system disorders including 
headache (2 Udenafil-Udenafil, 4 Placebo/De Novo-Udenafil), migraine (2 Udenafil-Udenafil, 
2 Placebo/De Novo-Udenafil), and dizziness (1 Udenafil-Udenafil, 2 Placebo/De Novo-Udenafil). 
Dizziness was the most commonly reported TEAE of special interest (11.7% Udenafil-Udenafil and 
12.7% Placebo/De Novo-Udenafil). None of the events of dizziness was serious, all were considered 
mild or moderate in intensity and most required no change in study drug. The other TEAEs of interest 
including syncope, presyncope, and hypotension occurred in <4% of subjects in either treatment 
group. 
No clinically important findings were observed in the evaluations of vital signs. 
CONCLUSION: 
Improvement in exercise capacity was observed in those who were previously naïve to udenafil 
therapy, and there was persistence of effect on exercise capacity for those who were previously 
treated with udenafil. Udenafil administered orally at 87.5 mg BID for 52 weeks was safe and well 
tolerated in this study. 
Date of the report: 25 February 2021 


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3. 
TABLE OF CONTENTS FOR THE INDIVIDUAL CLINICAL 
STUDY REPORT 
TABLE OF CONTENTS 
1. 
Title Page ................................................................................................................ 1 
2. 
Synopsis .................................................................................................................. 2 
3. 
Table of Contents for the Individual Clinical Study Report ................................... 8 
4 
List of Abbreviations and Definition of Terms ..................................................... 16 
5 
Ethics .................................................................................................................... 17 
5.1 
Independent Ethics Committee or Institutional Review Board ........................ 17 
5.2 
Ethical Conduct of the Study ............................................................................ 17 
5.3 
Subject Information and Consent ..................................................................... 17 
6 
Investigators and Study Administrative Structure ................................................ 18 
7 
Introduction ........................................................................................................... 20 
8 
Study Objectives ................................................................................................... 22 
9 
Investigational Plan .............................................................................................. 22 
9.1 
Overall Study Design and Plan Description ..................................................... 22 
9.2 
Discussion of Study Design, Including the Choice of Control Groups ............ 25 
9.3 
Selection of Study Population .......................................................................... 25 
9.3.1 
Inclusion Criteria .......................................................................................... 25 
9.3.2 
Exclusion Criteria ......................................................................................... 26 
9.3.3 
Removal of Subjects from Therapy or Assessment ...................................... 27 
9.3.3.1 
Discontinuation of Study Drug ................................................................. 27 
9.3.3.2 
Subject Withdrawal from the Trial ............................................................ 28 
9.4 
Treatments ........................................................................................................ 29 
9.4.1 
Treatments Administered .............................................................................. 29 
9.4.2 
Identity of Investigational Product(s) ........................................................... 29 
9.4.2.1 
Study Drug ................................................................................................ 29 
9.4.2.2 
Labelling ................................................................................................... 30 
9.4.2.3 
Accountability ........................................................................................... 30 
9.4.3 
Method of Assigning Subjects to Treatment Groups .................................... 30 
9.4.4 
Selection of Doses in the Study .................................................................... 31 
9.4.5 
Selection and Timing of Dose for Each Subject ........................................... 31 
9.4.6 
Blinding ........................................................................................................ 31 


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9.4.7 
Prior and Concomitant Therapy ................................................................... 31 
9.4.8 
Treatment Compliance.................................................................................. 33 
9.5 
Efficacy and Safety Variables ........................................................................... 33 
9.5.1 
Efficacy and Safety Measurements Assessed and Flow Chart ..................... 33 
9.5.1.1 
Efficacy Assessments ................................................................................ 35 
9.5.1.2 
Safety Assessments ................................................................................... 37 
9.5.2 
Appropriateness of Measurements ............................................................... 40 
9.5.3 
Primary Efficacy Variable ............................................................................. 42 
9.5.4 
Drug Concentration Measurements .............................................................. 42 
9.6 
Data Quality Assurance .................................................................................... 43 
9.7 
Statistical Methods Planned in the Protocol and Determination of Sample Size
 .......................................................................................................................... 44 
9.7.1 
Statistical and Analytical Plans .................................................................... 44 
9.7.1.1 
Analysis Populations ................................................................................. 44 
9.7.1.2 
Accountability and Protocol Deviations ................................................... 45 
9.7.1.3 
Demographic and Baseline Characteristics .............................................. 45 
9.7.1.4 
Efficacy Analyses...................................................................................... 45 
9.7.1.5 
Safety Evaluations .................................................................................... 48 
9.7.2 
Determination of Sample Size ...................................................................... 51 
9.8 
Changes in the Conduct of the Study or Planned Analyses .............................. 51 
9.8.1 
Changes in the Conduct of the Study ........................................................... 51 
9.8.2 
Changes to Planned Analyses ....................................................................... 52 
9.8.2.1 
Changes Between Protocol Finalization and Final Statistical Analysis Plan
 .................................................................................................................. 52 
9.8.2.2 
Changes Between Finalization of Statistical Analysis Plan and Blind 
Break ......................................................................................................... 53 
9.8.2.3 
Changes After Blind Break ....................................................................... 53 
9.8.2.4 
Changes to Address Refusal to File Letter ................................................ 54 
10 
Study Subjects ...................................................................................................... 54 
10.1 
Disposition of Subjects ..................................................................................... 54 
10.2 
Protocol Deviations .......................................................................................... 57 
11 
Efficacy Evaluation............................................................................................... 57 
11.1 
Datasets Analyzed ............................................................................................ 57 
11.2 
Demographic and other Baseline Characteristics ............................................. 58 
11.3 
Measurements of Treatment Compliance ......................................................... 65 
11.4 
Efficacy Results and Tabulations of Individual Subject Data .......................... 65 


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11.4.1 
Analysis of Efficacy ..................................................................................... 65 
11.4.1.1 
Overview of Results for VO2 at VAT and Maximal VO2 .......................... 65 
11.4.1.2 
Protocol-specified Primary Efficacy Endpoint ......................................... 67 
11.4.1.3 
VO2 at Ventilatory Anaerobic Threshold .................................................. 70 
11.4.1.4 
Secondary Efficacy Endpoints .................................................................. 74 
11.4.2 
Statistical/Analytical Issues .......................................................................... 82 
11.4.2.1 
Adjustments for Covariates ...................................................................... 82 
11.4.2.2 
Handling of Dropouts or Missing Data ..................................................... 82 
11.4.2.3 
Interim Analyses and Data Monitoring ..................................................... 83 
11.4.2.4 
Multicenter Studies ................................................................................... 84 
11.4.2.5 
Multiple Comparison/Multiplicity ............................................................ 84 
11.4.2.6 
Use of an "Efficacy Subset" of Subjects ................................................... 84 
11.4.2.7 
Active-Control Studies Intended to Show Equivalence ........................... 84 
11.4.2.8 
Examination of Subgroups ........................................................................ 85 
11.4.3 
Tabulation of Individual Response Data ...................................................... 90 
11.4.4 
Drug Dose, Drug Concentration, and Relationships to Response ................ 90 
11.4.5 
Drug-Drug and Drug-Disease Interactions ................................................... 90 
11.4.6 
By-Subject Displays ..................................................................................... 90 
11.4.7 
Efficacy Conclusions .................................................................................... 90 
12 
Safety Evaluation .................................................................................................. 93 
12.1 
Extent of Exposure ........................................................................................... 93 
12.2 
Adverse Events (AEs) ...................................................................................... 94 
12.2.1 
Brief Summary of Adverse Events ............................................................... 94 
12.2.2 
Display of Adverse Events ........................................................................... 95 
12.2.2.1 
Treatment-emergent Adverse Events by Intensity .................................... 96 
12.2.2.2 
Treatment-emergent Adverse Events Related to Study Drug ................... 97 
12.2.3 
Analysis of Adverse Events .......................................................................... 99 
12.2.4 
Listing of Adverse Events by Subject ........................................................ 107 
12.3 
Deaths, other Serious Adverse Events, and Other Significant Adverse Events
 ........................................................................................................................ 107 
12.3.1 
Listing of Deaths, Other Serious Adverse Events and Other Significant 
Adverse Events ........................................................................................... 107 
12.3.1.1 
Deaths ..................................................................................................... 107 
12.3.1.2 
Other Serious Adverse Events ................................................................ 107 
12.3.1.3 
Other Significant Adverse Events ........................................................... 113 
12.3.2 
Narratives of Deaths, Other Serious Adverse Events and Certain Other 
Significant Adverse Events ......................................................................... 118 


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12.3.3 
Analysis and Discussion of Deaths, Other Serious Adverse Events and Other 
Significant Adverse Events ......................................................................... 119 
12.4 
Clinical Laboratory Evaluation ...................................................................... 120 
12.4.1 
Listing of Individual Laboratory Measurements by Subject and Each 
Abnormal Laboratory Value ....................................................................... 120 
12.4.2 
Evaluation of Each Laboratory Parameter.................................................. 120 
12.4.2.1 
Laboratory Values Over Time ................................................................. 120 
12.4.2.2 
Individual Subject Changes .................................................................... 121 
12.4.2.3 
Individual Clinically Significant Abnormalities ..................................... 121 
12.5 
Vital Signs, Physical Findings and other Observations Related to Safety ..... 122 
12.6 
Safety Conclusions ......................................................................................... 125 
13 
Discussion and Overall Conclusions .................................................................. 126 
14 
Tables, Figures and Graphs Referred to but not Included in the Text ................ 128 
14.1 
Demographic Data .......................................................................................... 128 
14.2 
Efficacy Data .................................................................................................. 128 
14.3 
Safety Data ..................................................................................................... 139 
14.3.1 
Displays of Adverse Events ........................................................................ 139 
14.3.2 
Listings of Deaths, Other Serious and Significant Adverse Events ........... 141 
14.3.3 
Narratives of Deaths, other Serious and Certain other Significant Adverse 
Events ......................................................................................................... 143 
14.3.4 
Abnormal Laboratory Value and Medication Listings (Each Subject) ....... 143 
15 
Reference List ..................................................................................................... 144 
 


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LIST OF TABLES 
Table 1: 
Table of Study Responsibilities ....................................................................... 19 
Table 2: 
Study Assessments and Procedures ................................................................. 34 
Table 3: 
Schedule of Procedures – Visit 1 (Before and After First Dose in the Clinic) 35 
Table 4: 
Subject Enrollment by Site .............................................................................. 55 
Table 5: 
Subject Disposition .......................................................................................... 56 
Table 6: 
Major Protocol Deviations ............................................................................... 57 
Table 7: 
Analysis Populations ........................................................................................ 58 
Table 8: 
Demographic and Baseline Characteristics (Safety Population) ..................... 59 
Table 9: 
Abnormalities in Medical and Surgical Histories (Safety Population) ............ 60 
Table 10: 
Prior Medications Used by ≥5% of Subjects in Either Treatment Group (Safety 
Population) ....................................................................................................... 62 
Table 11: 
Concomitant Medications Used by ≥5% of Subjects in Either Treatment 
Group (Safety Population) ............................................................................... 64 
Table 12: 
Overview of Analyses of Change Between Week 26 and Baseline Visits for 
Maximal VO2 and VO2 at VAT ........................................................................ 66 
Table 13: 
Protocol-specified Primary Efficacy Analysis: Change in Maximal VO2 
Between Week 26 and Baseline Visits Using Last Observation Carried 
Forward (ITT Population) ................................................................................ 67 
Table 14: 
Change in the Natural Logarithm of Maximal VO2 Between Week 26 and 
Baseline Visits Using Last Observation Carried Forward (ITT Population) ... 69 
Table 15: 
Change in VO2 at VAT Between Week 26 and Baseline Visits Using Last 
Observation Carried Forward (ITT Population) .............................................. 71 
Table 16: 
Change in the Natural Logarithm of VO2 at VAT Between Week 26 and 
Baseline Visits Using Last Observation Carried Forward (ITT Population) ... 73 
Table 17: 
Difference in Secondary Exercise Endpoints Measured at Ventilatory 
Anaerobic Threshold Between Week 26 and Baseline Visits Using Last 
Observation Carried Forward (ITT Population) .............................................. 75 
Table 18: 
Change in Secondary Efficacy Endpoints Measured at Peak Exercise Between 
Week 26 and Baseline Visits Using Last Observation Carried Forward (ITT 
Population) ....................................................................................................... 77 


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Table 19: 
Change in Myocardial Performance Index Between Week 26 and Baseline 
Visits (ITT Population) .................................................................................... 79 
Table 20: 
Change in Endothelial Function and Brain Natriuretic Peptide Between Week 
26 and Baseline Visits (ITT Population) .......................................................... 80 
Table 21: 
Difference in Pediatric Quality of Life Inventory Endpoints Between Week 26 
and Baseline Visits (ITT Population) ............................................................... 81 
Table 22: 
Difference in Pediatric Cardiac Quality of Life Inventory Endpoints Between 
Week 26 and Baseline Visits (ITT Population) ................................................ 82 
Table 23: 
Extent of Exposure and Compliance with Study Drug (Safety Population) .... 94 
Table 24: 
Overall Summary of Treatment-emergent Adverse Events (Safety Population)
.......................................................................................................................... 95 
Table 25: 
Most Common (≥5% of All Subjects) Treatment-emergent Adverse Events 
(Safety Population) .......................................................................................... 96 
Table 26: 
Most Common (≥2% of All Subjects) Treatment-emergent Adverse Events 
Related to Study Drug (Safety Population) ..................................................... 98 
Table 27: 
Most Common (≥5% of All Subjects) Treatment-emergent Adverse Events by 
Gender (Safety Population) ............................................................................ 102 
Table 28: 
Most Common (≥5% of All Subjects) Treatment-emergent Adverse Events by 
Race Category (Safety Population) ................................................................ 103 
Table 29: 
Most Common (≥5% of All Subjects) Treatment-emergent Adverse Events by 
Ethnicity Category (Safety Population) ......................................................... 104 
Table 30: 
Most Common (≥5% of All Subjects) Treatment-emergent Adverse Events by 
Baseline Age Tertile (Safety Population) ....................................................... 105 
Table 31: 
Most Common (≥5% of All Subjects) Treatment-emergent Adverse Events by 
Baseline Weight Tertile (Safety Population) .................................................. 106 
Table 32: 
Serious Treatment-emergent Adverse Events Reported for ≥2 Subjects (Safety 
Population) ..................................................................................................... 108 
Table 33: 
Listing of Serious Treatment-emergent Adverse Events................................ 111 
Table 34: 
Treatment-emergent Adverse Events Leading to Temporary or Permanent 
Discontinuation of Study Drug That Were Reported for ≥2 Subjects (Safety 
Population) ..................................................................................................... 113 
Table 35: 
Listing of Treatment-emergent Adverse Events Resulting in Permanent 
Discontinuation of Study Drug ...................................................................... 115 


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Table 36: 
Listing of Treatment-emergent Adverse Events Resulting in Interruption of 
Study Drug ..................................................................................................... 116 
Table 37: 
Number (Percent) of Subjects Reporting Treatment-emergent Adverse Events 
of Special Interest (Safety Population) .......................................................... 118 
Table 38: 
Number (Percent) of Subjects Reporting at Least 1 Serious 
Treatment-emergent Adverse Event by Age and Weight Tertiles (Safety 
Population) ..................................................................................................... 119 
Table 39: 
Changes in Safety Laboratory Values from Baseline to Week 26 (Safety 
Population) ..................................................................................................... 120 
Table 40: 
Shifts from Within Normal Limits at Baseline to Above Upper Limit of 
Normal at Postbaseline (Safety Population) .................................................. 121 
Table 41: 
Changes in Blood Pressure and Heart Rate from Baseline to Week 2, Week 13, 
and Week 26 (Safety Population) ................................................................... 123 
Table 42: 
Potentially Clinically Significant Vital Sign Changes on Day 1 (Safety 
Population) ..................................................................................................... 124 
 


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LIST OF FIGURES 
Figure 1: 
Study Design .................................................................................................... 24 
Figure 2: 
Treatment Group Difference in Mean Maximal VO2 (mL/min) With 95% 
Confidence Interval for Change Between Week 26 and Baseline Visits in 
Subpopulations Using Last Observation Carried Forward (ITT Population) .. 86 
Figure 3: 
Treatment Group Difference in Mean Maximal VO2 (mL/kg/min) With 95% 
Confidence Interval for Change Between Week 26 and Baseline Visits in 
Subpopulations Using Last Observation Carried Forward (ITT Population) .. 87 
Figure 4: 
Treatment Group Difference in Mean VO2 (mL/min) at VAT With 95% 
Confidence Interval for Change Between Week 26 and Baseline Visits in 
Subpopulations Using Last Observation Carried Forward (ITT Population) .. 88 
Figure 5: 
Treatment Group Difference in Mean VO2 (mL/kg/min) at VAT With 95% 
Confidence Interval for Change Between Week 26 and Baseline Visits in 
Subpopulations Using Last Observation Carried Forward (ITT Population) .. 89 
 


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4 
List of Abbreviations and Definition of Terms 
Abbreviation 
Definition 
AE 
adverse event 
ANCOVA 
analysis of covariance 
BID 
twice daily 
BNP 
brain natriuretic peptide 
CPET 
cardiopulmonary exercise stress test 
CVP 
central venous pressure 
CYP 
cytochrome P450 
DCC 
data coordinating center 
DSMB 
Data and Safety Monitoring Board 
eCRF 
electronic case report form 
FUEL 
Fontan Udenafil Exercise Longitudinal (Assessment Trial) 
ICF 
informed consent form 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
InRHI 
log transformed reactive hyperemia index (ie, the PAT index) 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities  
MPI 
myocardial performance index 
NHLBI 
National Heart, Lung, and Blood Institute 
PAT 
pulse amplitude tonometry  
PCQLI 
Pediatric Cardiac Quality of Life Inventory 
PDE-5 
phosphodiesterase type 5 (inhibitor) 
PedsQL 
Pediatric Quality of Life Inventory 
PHN 
Pediatric Heart Network 
PK 
pharmacokinetic 
PVR 
pulmonary vascular resistance 
Qp 
transpulmonary blood flow 
REB 
Research Ethics Board 
RER 
respiratory exchange ratio 
RHI 
reactive hyperemia index (ie, the PAT index) 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
TEAE 
treatment-emergent adverse event 
VAT 
ventilatory anaerobic threshold 
VE/VCO2 
ventilatory equivalents of carbon dioxide 
VO2 
minute oxygen consumption 
Note:  Abbreviations used only in a table or figure are defined with the table or figure. 


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5 
Ethics 
5.1 
Independent Ethics Committee or Institutional Review Board 
An Institutional Review Board (IRB) or Research Ethics Board (REB) reviewed and 
approved the protocol and the informed consent form (ICF)/assent forms for each of the 
investigational sites prior to the first dose administration. The first informed consent was 
signed on 27 July 2016, and the last Week 26 visit was conducted on 27 December 2018.  
A copy of the final protocol (Protocol PHN-Udenafil-02, dated 31 August 2017) is provided 
in Appendix 16.1.1 and a sample electronic case report form (eCRF) is provided in 
Appendix 16.1.2. The name, address, and chairperson of each IRB/REB, and dates of 
IRB/REB approval for the protocol and ICF/assent forms are provided in Appendix 16.1.3.  
5.2 
Ethical Conduct of the Study 
This study was conducted in accordance with the International Council for Harmonisation, 
Harmonised Tripartite Guideline for Good Clinical Practice, 1997; the United States Title 21 
Code of Federal Regulations Parts 50, 56, and 312; and the ethical principles that have their 
origin in the Declaration of Helsinki. 
5.3 
Subject Information and Consent 
Subjects were approached for participation, either in person or by telephone, by study 
coordinators or Investigators, who obtained assent and/or consent following standard 
Pediatric Heart Network (PHN) procedures. The specific consent/assent procedures were in 
compliance with the requirements of each site’s IRB/REB. Prior to the performance of any 
study-related procedures, the subject or subject’s parent/legal guardian signed and dated an 
ICF. Subjects younger than 18 years of age (or as required by state law) signed an assent 
form. The consent process involved separate consent forms and signatures indicating consent 
for participation in the udenafil study and consent to submit a blood sample to the genetic 
biorepository. Sample ICF and assent forms are provided in Appendix 16.1.3. 
Each subject was assigned a subject identification number. All interview and clinical research 
data were stripped of identifiers and labeled with the subject identification number. The 
enrollment log with participant identifiers was maintained at each site in a secured, locked 
location available only to the study staff. Samples for DNA were stripped of the subject 
identification number at the laboratory and assigned distinct specimen numbers without other 
identifying information.  


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6 
Investigators and Study Administrative Structure 
The study was conducted at 30 study centers in North America and the Republic of Korea. 
Only Investigators qualified by training and experience were selected as appropriate experts 
to investigate the study drug. At each study site, the Principal Investigator at that site was 
responsible for study activities. A list of Investigators and their curricula vitae are provided in 
Appendix 16.1.4. Roles and qualifications of other staff whose participation materially 
affected the conduct of the study, including the author(s) of the clinical study report and the 
responsible biostatistician(s), are also listed in Appendix 16.1.4. The Sponsors’ approval of 
this clinical study report is located in Appendix 16.1.5. 
The study was monitored by a Data and Safety Monitoring Board (DSMB), which advised 
the Sponsor regarding the continuing safety of study subjects and potential subjects, as well 
as continuing validity and scientific merit of the trial. The details regarding frequency of 
meetings, members and the safety review criteria were outlined in a separate DSMB Charter 
(Appendix 16.1.3). The logistics of the DSMB were managed by the National Heart, Lung, 
and Blood Institute (NHLBI), which appointed the DSMB, HealthCore (previously the New 
England Research Institutes), and a blinded statistician from the biostatistics department of 
HealthCore performed the analyses. No major recommendations regarding study conduct 
were made based on the reviews of the safety data. 
A tabular display of study responsibilities is presented in Table 1. 


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Table 1: 
Table of Study Responsibilities 
Sponsor: 
Mezzion Pharma Co. Ltd in Partnership with the Pediatric 
Heart Network (PHN) 
Mezzion Pharma Co. Ltd 
7F, Seokcheon Building 
570, Samseong-ro 
Gangnam-gu 
Seoul, South Korea 06163 
Sponsor Representatives: 
James Yeager, RPh, PhD 
Study Medical Monitor: 
Brian Feingold, MD, MS, FAHA 
University of Pittsburgh School of Medicine 
Coordinating Principal Investigators: 
David Goldberg, MD 
Stephen Paridon, MD 
Children’s Hospital of Philadelphia 
Contract Research Organization (monitoring, data 
management, and statistical, and pharmacokinetic 
analysis): 
HealthCore (previously New England Research Institutes) 
480 Pleasant Street 
Watertown, MA 02472 
Contract Research Organization (statistical analysis 
and narrative writing as of 09 August 2019)  
DZS Clinical Services 
1661 U.S. 22 West  
Bound Brook, NJ 08805 
Electronic Data Capture: 
HealthCore (see above) 
Interactive Web Response System: 
HealthCore (see above) 
Data and Safety Monitoring Board Managing 
Organization: 
Data and Safety Monitoring Board for the Pediatric Heart 
Network, administered by the National Heart, Lung, and 
Blood Institute 
Clinical Drug Supply and Distribution: 
Fisher Clinical Services, Inc 
699 N. Wheeling Road 
Mount Prospect, IL 60056 
Central Laboratories: 
MMGL Molecular Genetics Laboratory,  
University of Michigan, Room 3725, Med Sci II, 1150 
West Medical Center Drive, SPC 5629  
Ann Arbor, MI 48109-5629 
Pharmacokinetic Laboratory: 
Nuvisan Pharma Services, Nuvisan GmbH 
Wegenerstraße 13 
89231 Neu-Ulm Germany 
Echocardiogram Core Laboratory: 
Boston Children’s Hospital Corporation 
300 Longwood Avenue 
Boston, MA 02115 
Vascular Core Laboratory: 
Cincinnati Children’s Hospital Medical Center 
3333 Burnet Avenue., MLC 7002 
Cincinnati, OH 45229 
Biomarker Analysis Laboratory: 
Cincinnati Children’s Hospital Medical Center  
3333 Burnet Avenue, MLC 7002 
Cincinnati, OH 45229 
MMGL Molecular Genetics Laboratory 
University of Michigan, Room 3725, Med Sci II, 1150 
West Medical Center Drive, SPC 5629  
Ann Arbor, MI 48109-5629 
Medical Writing: 
WebbWrites, LLC 
1904 Front Street, Building 600 
Durham, NC 27705 


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7 
Introduction 
The overall aim of the Fontan Udenafil Exercise Longitudinal Assessment (FUEL) trial was 
to evaluate the efficacy and safety of udenafil as a therapeutic option for those born with 
single ventricle heart disease who have undergone Fontan palliation. This study was 
conducted in coordination with the PHN, a consortium of congenital heart centers under the 
leadership of the NHLBI. At present, medical therapy for these patients is extrapolated from 
experience with adult-onset systolic heart failure, a condition distinct from the heart failure 
state associated with the Fontan circulation. The development of a medication specific to the 
physiology following Fontan palliation would represent a major therapeutic advancement in 
the field, as there are currently no approved pharmacotherapies for this unique cohort of 
patients. 
The Fontan operation is a palliative procedure for children born with a rare group of 
congenital heart defects characterized by a single functional ventricle (Fontan 1971; 
Kreutzer 1973). This operation, which creates a total cavopulmonary connection, separates 
the systemic and pulmonary circulations, and reduces the hypoxemia and ventricular volume 
overload characteristic of single ventricle heart disease. After the Fontan, the single cardiac 
ventricle is surgically assigned to pump blood only to the systemic circulation. Flow through 
the pulmonary circulation, now without the assistance of a pumping chamber, is dependent 
on the gradient between central venous pressure (CVP) and atrial pressure, and on the 
maintenance of low pulmonary vascular resistance (PVR). The introduction of the Fontan 
operation has significantly improved the morbidity and mortality burden of single ventricle 
heart disease through childhood, but has also created a unique population with a substantial 
need for ongoing cardiac care and intervention, and a limited life expectancy. Although the 
Fontan operation is initially well tolerated, the unique characteristics of the total 
cavopulmonary connection lead to progressive cardiovascular dysfunction over time. 
Exercise performance is a key metric of cardiovascular health for a variety of congenital and 
acquired forms of heart disease. For those who have undergone Fontan palliation, this 
relationship may hold particular importance (Diller 2005; Diller 2010; Fernandes 2011; 
Cunningham 2017). The decline in exercise capacity that typically occurs in the second and 
third decade after the Fontan is associated with an increase in the need for heart failure 
medications, an increase in the need for hospitalization, and an increase in the prevalence of 
both heart transplantation and mortality. The limitations in exercise capacity in the Fontan 
circulation are related to the absence of a sub-pulmonary ventricle. Without a pumping 
chamber to help deliver blood through the lungs and back to the heart, the ability to increase 
cardiac output is dependent on low PVR and an elevation in CVP. In a 2-ventricle circulation, 


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an increase in right-heart pressure to nearly 50 mmHg is key to reaching the increase in 
cardiac output of 4-fold or greater seen at peak exercise (Stickland 2006; Argiento 2010). In a 
single ventricle circulation, however, CVP cannot reach a pressure near that which can be 
achieved by a typical right ventricle. In this setting, the ability to augment cardiac output is 
limited and the role of PVR during exercise is magnified (Goldberg 2013; Navaratnam 2016; 
Egbe 2017). By minimizing PVR, one can decongest the venous system at baseline and allow 
for an improvement in the ability to increase flow through the pulmonary vasculature during 
exercise (Gewillig 2010; Goldstein 2010; La Gerche 2010). 
Udenafil is a selective, long-acting phosphodiesterase type 5 (PDE-5) inhibitor that has 
unique characteristics within the class and has demonstrated effectiveness as a pulmonary 
vasodilator in the treatment of patients with pulmonary hypertension (Chang SA 2019; 
Chang H-J 2019). Given the need for a medication specific to those with a total 
cavopulmonary connection, Mezzion Pharma Co. Ltd, in partnership with the PHN, has 
developed udenafil as a potential therapeutic option for those who have undergone the Fontan 
procedure. At present, udenafil is the only pharmacotherapy to have undergone 
pharmacokinetic (PK) analysis through a Phase 1/2 dose-finding study in this population. 
This study demonstrated that a dose of 87.5 mg twice daily (BID) provided the highest 
maximal plasma concentration with an acceptable drug tolerability and a clinical 
improvement in ventricular performance. 
After completion of the Phase 1/2 study, Mezzion Pharma Co. Ltd continued its partnership 
with the PHN to create and execute the FUEL study. This 400-patient, double-blind, 
placebo-controlled trial is the largest medication trial ever undertaken for those with any form 
of congenital heart disease and was conducted to determine the safety and efficacy of daily 
oral therapy with udenafil in adolescents with single ventricle heart disease who had 
undergone Fontan palliation. The primary aim was to determine the effect of udenafil on 
exercise performance over a 26-week treatment period. Safety was evaluated throughout the 
26-week period and for up to an additional 3 months. Mezzion Pharma Co. Ltd and the PHN 
are also conducting an open-label extension trial to continue to evaluate the tolerability and 
safety of udenafil over an additional 3-year time period. 


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8 
Study Objectives 
The primary objective of the study was to evaluate the effect of 26 weeks of treatment with 
udenafil (87.5 mg, BID) on exercise capacity in adolescents with Fontan physiology. 
The secondary objectives of this study of adolescents with Fontan physiology were to: 
• Determine the effect of 26 weeks of treatment with udenafil on echocardiographic 
indices of systolic and diastolic ventricular performance. 
• Determine the effect of 26 weeks of treatment with udenafil on endothelial function. 
• Evaluate the effect of 26 weeks of treatment with udenafil on serum brain natriuretic 
peptide (BNP) level, a biomarker of heart failure. 
• Evaluate the safety of udenafil when given over a 26-week time period. 
• Determine if 26 weeks’ treatment with udenafil alters functional health status. 
• Establish a collection of genetic material to identify genetic determinants of exercise 
capacity and response to udenafil and for unspecified future studies. 
• Determine the prevalence and severity of complications, including protein-losing 
enteropathy, plastic bronchitis, hospitalizations, cardiac transplantation and death in 
adolescents who received udenafil. 
• Explore the impact of udenafil on atrial and ventricular premature beats and 
arrhythmia burden.  
9 
Investigational Plan 
9.1 
Overall Study Design and Plan Description 
This was a Phase 3 randomized, placebo-controlled, double-blind, 26-week, multicenter 
study of the effects of udenafil versus placebo in adolescents with Fontan physiology. The 
target sample size was 400 adolescents (200 per treatment group).  
At PHN sites, potential subjects were identified through a screening chart review. Subjects 
who met initial study eligibility criteria, were receiving primary cardiac care at the PHN site, 
and were geographically local to the PHN site were approached regarding participation. In 


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addition, auxiliary sites in the United States and Korea were recruited at the beginning of the 
study to augment the number of potential subjects. 
Subjects who agreed to participate had baseline testing performed to determine eligibility 
with inclusion/exclusion criteria. Subjects performed an exercise test to maximal effort to be 
eligible for randomization and study drug initiation. A subject who was unable to achieve a 
maximal effort (respiratory exchange ratio [RER] ≥1.10) on exercise testing but who 
otherwise qualified for inclusion, was offered the opportunity to repeat the test within 
2 weeks of time of consent. Subjects with maximal minute oxygen consumption (VO2) <50% 
of predicted for age and gender, based on their most recent prior clinical exercise test, were 
excluded from the study. 
Eligible subjects were stratified by ventricular morphology (single left vs single right or 
mixed) and randomly assigned by a web-based system at the data coordinating center (DCC) 
to 1 of 2 treatment groups: orally administered udenafil (87.5 mg BID) or matching placebo 
BID. The first dose of randomized study drug was administered at the clinic (Visit 1, 
baseline).  
Approximately 2 hours (± 30 minutes) post dosing, resting heart rate and blood pressure were 
measured, and the subject performed a self-limited 6-minute walk. A repeat heart rate and 
blood pressure were measured immediately following and approximately 2 hours 
(± 30 minutes) following the 6-minute walk. Subjects who had a drop in systolic blood 
pressure >20 mmHg from the pre- to post-6-minute walk measurement, or had a drop in 
systolic blood pressure below the 5th percentile for age, were excluded from receiving any 
further study drug. Continuing subjects were dispensed their initial supply of study 
medication and instructed to take 1 tablet orally BID.  
Subjects returned to the clinic at Week 26 (study completion/early termination). In addition to 
clinic visits, study coordinators contacted each subject by telephone the day after the baseline 
visit to discuss any adverse events (AEs). Subjects were also contacted by telephone at 
Weeks 1, 2, 3, 4, 8, 13, 17, and 21 to ensure the study drug was well tolerated, to monitor 
study drug adherence, record AEs and concomitant medications, and offer pregnancy 
counseling, if needed. Subjects were encouraged to notify the study coordinator between 
scheduled contact dates with any new onset symptoms or complications.  
In-clinic study visits included assessments of safety (AEs, concomitant medication use, vital 
signs, and clinical safety laboratory evaluations), efficacy (exercise testing, echocardiogram, 
EndoPAT®, BNP, and quality of life measurements), and PK. 


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The duration of study drug dosing was 26 weeks. When an individual subject completed the 
study, the subject’s primary cardiologist was notified, and the study drug was stopped. All 
subjects were invited to participate in an open-label, 12-month safety extension study of 
udenafil. Any subject declining participation in the extension study was to be followed for 
90 days at Weeks 30, 34, and 39 for any additional AEs. 
Subjects were given the opportunity to participate in the heart rhythm-monitoring subset of 
FUEL until a total of 25% of all randomized subjects had been included. Heart rhythm 
monitoring included a 7-day baseline monitor and a 3-day steady state monitor, as described 
in Section 9.5.1.2.6. 
The study design is displayed in Figure 1. The overall schedule of assessments is provided in 
Table 2. Table 3 presents procedures performed before and after the first dose of study drug in 
the clinic at Visit 1. 
Figure 1: 
Study Design 
 
AE=adverse event; BNP=brain natriuretic peptide; BP=blood pressure; ECG=electrocardiogram; echo=echocardiogram; 
EST=exercise stress test; FUEL=Fontan Udenafil Exercise Longitudinal Assessment Trial; LV=left ventricular; 
min=minute; OLE=open-label extension; PK=pharmacokinetic; RV=right ventricular; yrs=years 
 


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9.2 
Discussion of Study Design, Including the Choice of Control 
Groups 
This was a Phase 3 randomized, placebo-controlled, double-blind, multicenter study. 
Randomized, double-blind controlled designs are standard to provide unbiased evaluations of 
study drug effects. Because there currently are no approved treatments for Fontan physiology, 
the use of a placebo control was considered ethical.  
The dosage (87.5 mg) and frequency of administration (BID) of the study drug were 
determined by results of the recently completed PHN dose-escalation study of udenafil in 
adolescents with Fontan palliation (PHN-Udenafil-01).  
Prior to randomization, eligible subjects were stratified by ventricular morphology (single left 
vs single right or mixed). The rationale for ventricular stratification was based on the results 
of previous PHN cross-sectional studies that demonstrated a weak but significant difference 
in certain resting echocardiographic and exercise results based on morphology (Paridon 2008; 
Anderson 2008). In addition, preliminary data on PDE-5 inhibitors suggested a difference in 
exercise performance based on morphology (Goldberg 2011).  
9.3 
Selection of Study Population 
The target sample size was 400 male and female subjects with Fontan physiology who 
fulfilled all the eligibility criteria. A chart review was performed by the PHN core sites to 
determine potential subject availability. Potential subjects were identified as meeting study 
eligibility criteria, receiving primary cardiac care at the PHN site, and being geographically 
local to the PHN site.  
9.3.1 
Inclusion Criteria 
Only subjects who met all of the following criteria were included: 
1. Males and females with Fontan physiology who were 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.  


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9.3.2 
Exclusion Criteria 
Subjects were excluded if they met any of the following criteria: 
1. Weight <40 kg. 
2. Height <132 cm. 
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 
3 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 mmHg between the regions proximal 
and distal to the obstruction as measured by either catheterization or 
echocardiography, obtained prior to screening for the study. 
8. Single lung physiology with greater than 80% flow to one lung. 
9. Maximal VO2 less than 50% of predicted for age and gender at enrollment. 
10. Severe ventricular dysfunction assessed qualitatively by clinical echocardiography 
within 6 months prior to enrollment. 
11. Severe valvar regurgitation, ventricular outflow obstruction, or aortic arch obstruction 
assessed by clinical echocardiography within 6 months prior to enrollment. 
12. Significant renal (serum creatinine >2.0 mg/dL), hepatic (serum aspartate 
aminotransferase and/or alanine aminotransferase >3 times upper limit of normal), 
gastrointestinal or biliary disorders that could impair absorption, metabolism or 
excretion of orally administered medications, based on laboratory assessment 6 weeks 
prior to screening for the study. 
13. Inability to complete exercise testing at baseline screening. 
14. History of PDE-5 inhibitor use within 3 months before study onset. 


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15. History of any other medication for treatment of pulmonary hypertension within 
3 months before study onset. 
16. Known intolerance to oral udenafil. 
17. Frequent use of medications or other substances that inhibit or induce cytochrome 
P450 (CYP)3A4. 
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 planned before study 
completion, or refusal to use an acceptable method of contraception for study duration 
if sexually active. 
23. Unable to abstain or limit intake of grapefruit juice during the duration of the study. 
24. Refusal to provide written informed consent/assent. 
25. In the opinion of the primary care physician, the subject was likely to be 
noncompliant with the study protocol. 
26. History of clinically significant thromboembolic event, as adjudicated by study 
Investigators that may have put the subject at increased risk of a subsequent event 
while participating in the study. 
9.3.3 
Removal of Subjects from Therapy or Assessment 
9.3.3.1 
Discontinuation of Study Drug 
Study drug could have been discontinued temporarily or permanently, but subjects were to 
remain in the study and complete all study data collection and follow-up measures, including 


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exercise performance testing. Study drug could have been discontinued for the following 
reasons: 
• An adverse experience, including failure to tolerate study medication that, in the 
judgment of the Investigator or primary physician, required drug discontinuation. 
• Voluntary discontinuation of study drug by the subject. 
• Meeting withdrawal criteria following the 6-minute walk (see Section 9.1). 
Per the Manual of Operations, the study drug was interrupted if the subjects needed to 
temporarily or permanently discontinue current anti-platelet or anticoagulant therapy. If the 
interruption was temporary, subjects were eligible to restart study drug with the resumption 
of anti-platelet or anticoagulant therapy. 
Study drug was to be permanently discontinued for pregnancy, anaphylactic reaction, serious 
side effects including persistent hypotension, visual changes, or priapism that did not respond 
to temporary discontinuation of the study drug, and if deemed necessary by the study 
Investigator or primary physician, either due to side effects or due to need for open-label drug 
administration of a PDE-5 inhibitor. 
When possible, the subject was to 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 was to be recorded. 
9.3.3.2 
Subject Withdrawal from the Trial 
End-of-study testing was obtained whenever possible on subjects who withdrew early. The 
reason for withdrawal was to be documented for all subjects withdrawn from the study. A 
subject could have been withdrawn from study participation for the following reasons: 
• Subject (or legal guardian) declined 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 was in the subject’s best 
interest. 


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If the subject refused to continue with the study visits, every attempt was made to continue 
contact by telephone, written communication, or record review to determine if outcome 
events (death, hospitalizations and major complications) had occurred, unless the subject 
specifically refused such follow-up. If the withdrawing subject was 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 have submitted a written refusal. 
9.4 
Treatments 
9.4.1 
Treatments Administered 
Subjects were randomized to receive either oral udenafil (87.5 mg BID) or matching placebo 
BID for 26 weeks. 
9.4.2 
Identity of Investigational Product(s) 
9.4.2.1 
Study Drug 
A description of study drug is provided below. 
Dosage form description 
Pale-orange, oval-shaped, film-coated tablets of 87.5 mg udenafil or 
matching placebo (0 mg drug). 
Tablet inactive ingredients: lactose monohydrate, corn starch, low 
substituted hydroxypropyl cellulose, hydroxypropyl cellulose, talc, 
magnesium stearate, colloidal silicon dioxide, hydroxypropyl 
methylcellulose, titanium dioxide, FD&C Yellow No. 6 Aluminum Lake, 
and iron oxide red. 
Package description 
One plastic bottle of 60 tablets per bottle.  
Manufacturer 
Dr. Reddy’s Laboratories Ltd., FTO-3, Bachupally, Hyderabad, India. 
Dosage per time unit 
One tablet orally twice a day. 
Storage 
Udenafil tablets were to be stored at 20°C to 25°C (68°F to 77°F); 
excursions were permitted to 15°C to 30°C (59°F to 86°F).  
The study drug must have been protected from unauthorized access (eg, in a 
locked storage facility). Any unused, partially used, or empty bottles of 
study drug were destroyed at the site at the time of the site’s close-out visit. 
Destruction of the study drug was properly documented on forms provided 
by the Sponsor or designee. 
Batch number 
UDBT15-10 (udenafil); P1MT15-09 (placebo to match udenafil) 
 
Subjects receiving each batch of study drug are identified in Appendix 16.1.6. 


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9.4.2.2 
Labelling 
The labels of the investigational product contained the following information: 
• Name and address of the Sponsor 
• Product name 
• Mode of administration 
• Protocol identification and name 
• Subject number 
• Quantity and bottle number 
• Storage conditions 
• “Caution: New Drug – Limited by Federal Law to Investigational Use” 
 
The composition, pharmaceutical quality, batch number, and expiration date of the 
investigational (test) product were traceable via the bottle number. 
9.4.2.3 
Accountability 
The Site Principal Investigator had overall responsibility for the use of the study drug. The 
Site Principal Investigator or designee confirmed receipt of the study drug by signature and 
date, and returned a duplicate copy of receipt to the Sponsor or designee.  
Under no circumstances was the Investigator to allow the investigational drugs to be used 
other than as directed by the protocol. Qualified study personnel used the specified 
randomization system to assign subjects to treatment and maintained accurate study 
drug-dispensing records regarding the date and amount dispensed to each subject. Reasons 
for digression from the expected dispensing regimen were to be recorded. The study drug 
inventory record was available for inspection by representatives of the Sponsor and was 
subject to regional regulatory authority inspection at any time. At the conclusion of the study, 
the Site Principal Investigator provided a copy of this record to the Sponsor. 
9.4.3 
Method of Assigning Subjects to Treatment Groups 
Randomization assignments were generated by a web-based system at the DCC, after 
confirmation of study eligibility. Eligible subjects were stratified by ventricular morphology 
(single left vs single right or mixed) and randomly assigned to udenafil or placebo.  
The randomization codes and treatment assignments by subject number are provided in 
Appendix 16.1.7.  


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9.4.4 
Selection of Doses in the Study 
The dosage and frequency of administration of the study drug were determined by the 
Phase 1/2 dose-escalation study of udenafil in adolescents with Fontan palliation completed 
by the PHN (PHN-Udenafil-01). Statistically significant improvement in exercise capacity or 
vascular function could not be determined in this very small study. However, oral 
administration of 175 mg/day udenafil (87.5 mg BID) for 5 days improved ventricular 
performance as measured by blood pool myocardial performance index (MPI). Thus, subjects 
in the current study took udenafil 87.5 mg BID or matching placebo BID.  
9.4.5 
Selection and Timing of Dose for Each Subject 
Subjects were instructed to take the study drug twice a day. To minimize any potential diurnal 
and/or PK effect, the time of administration of the study drug at baseline and Week 26 was to 
match.  
9.4.6 
Blinding 
The study drug and the placebo were identical in appearance to assure blinding of study drug. 
The randomization assignment was seen only by the statistician at the DCC and was not 
available to the family/subject, study coordinator, investigators, or personnel administering 
study procedures. The exercise testing laboratories and echocardiogram core laboratory were 
blinded to group assignment and study visit. All remained blinded as to treatment group 
assignment until after all study data were analyzed. 
In rare life-threatening or emergency situations, when the identity of the study drug must 
have been known to the Investigator in order to provide appropriate medical treatment or if 
required to assure safety of study participants, an emergency code break could have been 
requested from the site research pharmacist after full discussion with the PHN Center 
Primary Investigator. If the code break for a subject was required, the DCC must have been 
informed within 1 working day of the event. The reason for breaking the code must have 
been documented in an appropriate eCRF, along with the date and the initials of the person 
who broke the code. 
9.4.7 
Prior and Concomitant Therapy 
Subjects were to be treated with other medications at the discretion of their physicians. 
Management could have been symptomatic treatment (eg, hypotension from overdose or 
other cause) or observation and monitoring (eg, priapism). At study visits, current 


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medications were recorded on the study forms. If a subject began open-label use of any 
PDE-5 inhibitor at any time during the study, withdrawal from study drug was 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, ketoconazole, posaconazole, voriconazole, and nefazodone. 
• 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 were to be avoided: 
o Boceprevir 
o PDE-5 inhibitors including sildenafil 
o Telaprevir 
o Vasodilator (organic nitrates) including isosorbide dinitrate, isosorbide 
mononitrate, and nitroglycerin 
o Soluble guanylate cyclase stimulators 
• Select antihypertensives including amlodipine, angiotensin II receptor blockers, 
enalapril, and metoprolol were to be used with caution, as small decreases in blood 
pressure occurred when udenafil was co-administered with these agents.  
Grapefruit juice was to be limited or avoided throughout study participation, as it may 
increase serum levels and/or the toxicity of udenafil. In preparation for EndoPAT testing, 
subjects were required to abstain from caffeine and to have fasted for 8 hours prior to testing. 


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9.4.8 
Treatment Compliance 
Study drug adherence was assessed at each in-person study visit by comparing the expected 
versus actual consumption of study drug tablets. Return of study drug bottles coincided with 
scheduled monthly monitoring calls. During each call contact, the study coordinator 
reminded the subject to return study drug bottles to the site. The study coordinator or 
pharmacist measured and recorded the number of remaining tablets, and a study drug supply 
was dispensed as required. Self-report of study drug compliance was assessed with 
administration of the Morisky scale during each call contact. The Morisky scale is a 
questionnaire used to predict adherence to medication therapies (Morisky 1986).  
9.5 
Efficacy and Safety Variables 
9.5.1 
Efficacy and Safety Measurements Assessed and Flow Chart 
The overall schedule of assessments is provided in Table 2. Table 3 presents procedures 
performed before and after the first dose of study drug in the clinic at Visit 1. 
 


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Table 2: 
Study Assessments and Procedures 
Number and Type 
Visit 1 
Call 1 
Calls 2-6 
Call 7 
Calls 8-9 
Visit 2 
Calls 10-12 
Time point 
Screening/ 
Baseline Day 0a 
Day 1 
Weeks 1, 2, 3, 4, 8 
Week 13 
Weeks 17, 21 
Week 26 
Weeks 30, 34, 39 
Visit Windows 
 
 
± 3 days 
± 10 days 
± 3 days 
± 10 days 
± 10 days 
Type of Visit 
In person 
Call 
Call 
Call 
Call 
In person 
Call 
Informed consent/assent 
X 
 
 
 
 
 
 
Assign subject identification number  
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
X 
 
Medical history 
X 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
Prior/concomitant medications 
X 
 
X 
X 
X 
X 
 
EndoPAT® vascular assessment 
X 
 
 
 
 
X 
 
Serum/urine pregnancy test (females only) 
X 
 
 
 
 
X 
 
Clinical laboratory tests (creatinine, ALT, AST) 
X 
 
 
 
 
Xb 
 
Biomarker (BNP) sample 
X 
 
 
 
 
X 
 
Genetic repository sample (optional) 
X 
 
 
 
 
Xc 
 
Pharmacokinetic sample 
Xb 
 
 
 
 
Xb 
 
Echocardiogram 
X 
 
 
 
 
X 
 
Exercise testing 
Xd 
 
 
 
 
X 
 
Randomization 
X 
 
 
 
 
 
 
Dispense study drug 
X 
 
 
 
 
 
 
Vital signs (resting BP and HR) 
X 
 
 
 
 
X 
 
Administer first study drug dose in clinic (Table 3) 
X 
 
 
 
 
 
 
PedsQL generic/cardiac modules; PCQLI; HAES 
X 
 
 
 
 
X 
 
Perform drug accountability 
X 
 
 
 
 
X 
 
Pregnancy counseling (if applicable) 
X 
 
X 
X 
X 
X 
 
Adverse events assessment 
X 
X 
X 
X 
X 
X 
X 
Morisky Scale (MMAS) 
 
 
X 
X 
X 
 
 
Schedule/confirm next visit 
X 
X 
X 
X 
X 
X 
 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BNP=brain natriuretic peptide; BP=blood pressure; HAES=Habitual Activity Estimation Scale; HR=heart rate; 
MMAS=Morisky Medication Adherence Scale; PCQLI=Pediatric Cardiac Quality of Life Inventory; PedsQL=Pediatric Quality of Life Inventory 
a  Baseline visit could have been combined into a single day or split into 2 days as long as the duration of the time between the visits was no more than 7 days. 
b  At 2 hours post-dose. 
c  As applicable, if missed at baseline visit. 
d  If a subject failed the first exercise test at the baseline visit, he/she was not randomized. At the baseline and Week 26 visits, at the site Investigator's discretion, the exercise test 
    may have been repeated within 14 days. If a second exercise test was needed, the urine (or blood) pregnancy test must have been performed for eligibility (if applicable). 


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Table 3: 
Schedule of Procedures – Visit 1 (Before and After First Dose in the 
Clinic) 
 
Times 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 
(one 87.5 mg tablet or matching 
placebo) 
 
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 
 
9.5.1.1 
Efficacy Assessments 
9.5.1.1.1 
Exercise Testing 
Aerobic exercise performance was assessed by a cardiopulmonary exercise stress test (CPET) 
using a standard ramp cycle ergometry protocol and with the collection of expired gases 
(Paridon 2008). The ramp cycle protocol has been previously used in research studies of 
children and adults with congenital heart disease, including those with Fontan physiology 
(Anderson 2008; Paridon 2008). 
The CPET was performed at Visit 1 (baseline) and at Week 26. The protocol consisted of 
sitting quietly on the ergometer for 3 minutes followed by 3 minutes of unloaded pedaling. 
The work rate was then increased using a ramp protocol with a slope chosen to achieve the 
subjects predicted maximal work rate in 10 to 12 minutes of total cycling time. A maximal 
aerobic effort was based on the RER (minute carbon dioxide production divided by minute 
oxygen consumption) at peak exercise equal to or greater than 1.10. All exercise stress test 
data were averaged over 10- or 20-second time intervals based on the specifications of the 
sites’ metabolic carts.  
Achieving a RER of equal or greater than 1.10 has been associated with a maximal aerobic 
effort, being an indicator of the respiratory compensation for the lactic acidosis that occurs 


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with a maximal aerobic effort. Use of the RER for this purpose has been well described in 
multiple studies of exercise with the Fontan procedure (Giardini 2008; Paridon 2008; 
Fernandes 2010). To ensure a high proportion of subjects achieve a maximal effort on both 
the baseline and Week 26 exercise studies, subjects who failed to achieve a RER of 1.10 or 
higher were offered an opportunity to perform a second exercise test within 2 weeks of the 
failed test. 
Pulmonary function testing, electrocardiograms, blood pressure, pulse oximetry, and 
metabolic rates were monitored during exercise testing. The CPET protocol is described in 
Protocol Section 18.1. 
A test data review plan was implemented after all exercise testing was completed. In an effort 
to reduce measurement variability, all exercise stress test interpretations were to be reviewed 
by blinded exercise physiologists with specific expertise in the exercise protocol used in this 
study. Results from the metabolic cart containing the original exercise test record (or 
paper/electronic copy if original record was not available) at baseline and Week 26 were 
reviewed and compared to the local interpretation. Final data represent a consensus between 
the exercise physiologists and local personnel from the exercise laboratory. 
9.5.1.1.2 
Echocardiogram 
A focused echocardiogram was performed at Visit 1 (baseline/pre-treatment) and at Week 26 
to evaluate systemic ventricular volume, eccentricity, systolic and diastolic function, and 
severity of atrioventricular valve regurgitation.  
The change in the MPI from baseline to Week 26 was determined by velocities obtained from 
blood pool Doppler assessment of the inflow and outflow tract of the dominant ventricle.  
9.5.1.1.3 
Endothelial Function  
EndoPAT 2000 measurements were performed at Visit 1 (baseline) and at Week 26. 
Endothelial function was assessed via changes in EndoPAT2000®-derived measures of 
reactive hyperemia index (RHI), markers of endothelial function, and augmentation index, a 
marker of arterial stiffness.  
9.5.1.1.4 
Biomarker: Brain Natriuretic Peptide 
The serum level of BNP was assessed in blood samples collected at Visit 1 (baseline) and at 
Week 26. Measurements of BNP were performed at the central laboratory.  


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9.5.1.1.5 
Quality of Life and Functional Health Status 
Quality of life and functional status were measured with the Pediatric Quality of Life 
Inventory (PedsQL; self-report version), PedsQL Cardiac Module, and the Pediatric Cardiac 
Quality of Life Inventory (PCQLI) instruments. Domains of primary interest from the 
PedsQL were the Physical Functioning score and the Psychosocial Functioning score.  
The PedsQL is a short questionnaire, has been used in multiple studies and has normal 
values, has a cardiac-specific module, has both parent and subject versions, and spans ages 
into adulthood (Varni 2001; Varni 2005; Varni 2009). It has been used in a previous study of 
Fontan subjects (Manlhiot 2009).  
The PCQLI is a congenital heart disease-specific instrument that has shown good validity, 
has both parent and subject versions, and spans ages up to 18 years (Marino 2008; 
Marino 2010; Marino 2011). 
9.5.1.2 
Safety Assessments 
Safety was assessed by monitoring AEs, vital signs, clinical laboratory test results, and 
physical examinations. Optional heart rhythm-monitoring was performed for a subset of 
subjects. 
The Data and Safety Monitoring Plan for this study followed standard PHN monitoring 
principles. Oversight of data and safety was provided by the PHN DSMB, appointed by the 
NHLBI. 
9.5.1.2.1 
Adverse Events 
An AE was defined as any untoward (eg, unfavorable, negative, or harmful) medical 
occurrence associated with the use of a drug in humans, whether or not the event was 
considered drug related. An event could have been any unfavorable and unintended sign, 
symptom, or disease temporally associated with the use of the product. 
Adverse events were classified as to seriousness (serious, not serious), expectedness 
(expected, unexpected), and potential relationship to the study drugs (not related, possibly 
related, probably related). For AEs with a causal relationship to the study drug, follow-up by 
the Investigator was required until the event or its sequelae resolved or stabilized at a level 
acceptable to the Investigator.  


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All AEs unresolved at the time of the subject's termination from the study were to be 
followed by the Investigators until the events were resolved, the subject was lost to follow-
up, or the AE was otherwise explained or had stabilized. Any death or other serious adverse 
event (SAE) that may have been related to the study drugs and that occurred at any time after 
a subject had discontinued study drug or terminated study participation was to be reported. 
An SAE was one that: 
• Resulted in death, 
• Was life-threatening (the subject was, in the view of the Principal Investigator, in 
immediate danger of death from the event as it occurred), 
• Required inpatient hospitalization or prolongation of existing hospitalization, 
• Resulted in persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions, 
• Was a congenital anomaly/birth defect in the offspring of a participant, or 
• Was an important medical event that may have jeopardized the subject or required 
medical/surgical intervention to prevent one of the SAE outcomes. 
An unexpected AE or adverse reaction was one for which the nature or severity was not 
consistent with information in the protocol, consent form, or product brochure. An AE was 
considered expected if it was known to be associated with the study drugs and/or the disease 
state. 
Causality assessment was required to determine which events required expedited reporting.  
• Not related: the event was clearly related to other factors, such as the subject’s clinical 
state or non-study drugs or interventions. 
• Possibly related: the event followed 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 followed a reasonable temporal sequence from the time of 
drug administration and could not be reasonably explained by other factors such as 
the subject’s clinical state or non-study drugs or interventions. 


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The severity of AEs was categorized using the Common Terminology Criteria for Adverse 
Events Version 4.0 grades:  
• 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. 
• 3 (severe): severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care activities of daily living. 
• 4 (life-threatening): life-threatening consequences; urgent intervention indicated. 
• 5 (death): death related to AE.  
Study Investigators reported all AEs, regardless of expectedness and relationship to study 
drug, to the DCC. The DSMB and NHLBI were assisted by an independent medical monitor 
in reviewing SAEs in PHN studies. The PHN medical monitor was the NHLBI’s designee for 
determining causality and expectedness of all SAEs.  
Serious AEs, including important medical events, were to be reported within 24 hours of first 
knowledge of the event; non-serious AEs were to be reported within 7 calendar days of first 
knowledge of the event. In addition, the site Investigator or designee was responsible for 
reporting all SAEs to the local IRB/REB in accordance with local policies and procedures. 
9.5.1.2.2 
Clinical Laboratory Tests 
Blood samples were collected on the day of baseline testing and at Week 26 and consisted of 
serum creatinine, alanine aminotransferase, aspartate aminotransferase, and in females, serum 
or urine pregnancy test.  
An optional blood sample was acquired from each subject once during the trial, preferably at 
study enrollment, to explore the genetic and pharmacogenetic determinants of exercise 
capacity, response to udenafil and other outcomes in Fontan patients. If blood collection was 
not possible, saliva was collected when feasible. The sample may be used for future studies. 


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9.5.1.2.3 
Prior and Concomitant Medications 
Prior and concomitant medications were collected at baseline. Concomitant medications were 
collected at visits from Week 1 through Week 26. 
9.5.1.2.4 
Physical Examinations 
A limited physical examination was performed at baseline and Week 26.  
9.5.1.2.5 
Vital Signs 
Vital signs (resting blood pressure and heart rate) were assessed at less than 1 hour prior to 
the first dose of study drug, 2 hours ± 30 minutes after the first dose of study drug, 
immediately after self-limited 6-minute walk, 4 hours ± 30 minutes after the first dose of 
study drug, and at Week 26.  
9.5.1.2.6 
Heart Rhythm Monitoring 
For those subjects who opted to participate, heart rhythm monitoring included a 7-day 
baseline monitor and a 3-day steady-state monitor. The planned procedures for heart rhythm 
monitoring are described in Protocol PHN-Udenafil-02 (FUEL) Section 6.3.5. The number of 
subjects choosing to participate was too low for analysis of heart rhythm.  
9.5.2 
Appropriateness of Measurements 
Studying the effect of any intervention in the Fontan population is difficult given the absence 
of readily measured, reliable and reproducible end points. Given the difficulty with hard 
endpoints, measures of exercise capacity are frequently used and accepted as surrogate 
endpoints for the purpose of measuring change over time or response to therapeutic 
intervention. Of the measures of aerobic exercise performance, maximal VO2 has been shown 
to be a consistent and sensitive marker of deteriorating function, onset of symptoms of heart 
failure, and increasing risk for sudden death across a broad range of diagnostic categories of 
heart disease.  
In studies of young adults with variable types of congenital heart disease, a maximal VO2 of 
approximately 50% of predicted for age and gender appears to be the threshold value for 
increased risk of heart failure and death (Diller 2005; Canter 2007; Giardini 2007; 
Diller 2010). For those with a Fontan circulation, the PHN Fontan Cross-Sectional Study 
demonstrated a population maximal VO2 of 66% of predicted normative values at the onset of 
adolescence while Giardini and colleagues have shown a predicted rate of decline of up to 


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2.6% per year. Taken together, these data suggest that the population would fall below the 
50% threshold early in the third decade of life. An intervention capable of improving the 
baseline or slowing the slope of decline would therefore have important functional 
ramifications for long-term outcomes.  
While a good measure across heterogeneous forms of heart disease, the use of maximal VO2 
as a therapeutic endpoint does have challenges unique to the Fontan circulation. Due to the 
intrinsic limitations of pulmonary vasodilatory reserve, the Fontan circulation’s ability to 
maintain adequate preload to the systemic ventricle at higher levels of exercise is limited and 
can only be accomplished by prohibitively high CVPs. Under these circumstances, the ability 
to perform sub-maximal aerobic activity may be better preserved than maximal VO2. The 
data from the PHN Fontan Cross-Sectional Study as well as additional studies support this 
notion (Paridon 2008; d'Udekem 2009; Goldstein 2010). Using Paridon 2008 as an example, 
VO2 at ventilatory anaerobic threshold (VAT) was significantly better preserved at 78% of 
predicted compared to a maximal VO2 at 66% of predicted.  
The VO2 at VAT measures the level of oxygen consumption at which one changes from 
aerobic to anaerobic activity, a clinically relevant level of exertion that is typical of what is 
encountered in routine volitional activity. For reasons discussed in detail in Section 11.4.7, 
VO2 at VAT may be more appropriate than maximal VO2 as an outcome measure for those 
with a single ventricle circulation. As is true for maximal VO2, measurements of VO2 at VAT 
also correlate with functional outcome. For this clinical study, VO2 at VAT was chosen as a 
secondary exercise measure due to the technical challenge associated with obtaining 
measurements of the endpoint. Determination of VO2 at VAT depends on each participant 
maintaining a consistent respiratory pattern over the duration of their exercise test. This is 
generally achievable by older adolescents and adults, but it may be less reliable in younger 
adolescents. However, as discussed in Section 11.4.7, our understanding of Fontan exercise 
physiology has evolved since the inception of this study and, even with the technical 
challenges, the importance of VO2 at VAT as a critical surrogate endpoint for those who have 
undergone Fontan has become apparent. 
Echocardiography is routinely and universally used to evaluate ventricular performance in 
serial follow-up of Fontan patients, a population known to have significant abnormalities in 
both ventricular systolic and diastolic function (Sano 1989; Frommelt 1991; Akagi 1993; 
Cheung 2000; Kaneko 2012). Animal studies have suggested that PDE-5 inhibitors may 
mitigate adverse remodeling in stressed myocardium, and previous single dose trials and pilot 
studies in those with a Fontan circulation have suggested an improvement in ventricular 
performance in response to treatment (Goldberg 2012; Tunks 2014; Van De Bruaene 2014; 


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Goldberg 2017; Garcia 2018). Given the importance of ventricular performance in the 
long-term health of those with all forms of heart disease, an improvement in this aspect of 
physiology would be of significant value across the population. The MPI is a measure of 
systolic and diastolic function that indexes isovolumetric relaxation and contraction times to 
the ventricular ejection time; a smaller number suggests more efficient contraction and 
relaxation. An improvement in MPI would be of benefit in this population, one with well 
documented abnormalities in systolic and diastolic function. 
Studies have demonstrated a strong correlation between endothelial function and exercise 
capacity, including recent data utilizing EndoPAT in the assessment of endothelial function 
(Goldstein 2011; Goldstein 2016). Based on the known effect of PDE-5 inhibitors and the 
known endothelial dysfunction in the Fontan population (Mahle 2003; Inai 2004; Jin 2007; 
Binotto 2008), a measure of endothelial function is a useful candidate marker for a potential 
pharmacodynamic effect. The Framingham-modified RHI and raw RHI measures served as 
secondary outcome measures of vascular function. 
Serum BNP is a useful biomarker in patients with heart failure from a variety of causes. A 
study of BNP levels in 510 patients after the Fontan procedure (median age 11.4 years) 
performed through the PHN revealed mean BNP levels of 25 ± 48 pg/mL (Atz 2011). Higher 
BNP was associated with several markers of suboptimal outcomes albeit with weak 
associations but may be a predictor of Fontan failure. In the pilot study by Goldberg, those 
with a serum BNP level >100 pg/mL had a more robust response to sildenafil 
(Goldberg 2011). Thus, BNP may be helpful in measuring a response to medical intervention. 
The quality of life and functional status questionnaires have been widely used in multiple 
studies. The safety and PK measurements utilized were standard, widely used, and generally 
recognized as reliable, accurate, and relevant to the study population and study design. 
9.5.3 
Primary Efficacy Variable 
The primary efficacy variable was the change in maximal VO2 from baseline to Week 26 
measured by cardiopulmonary exercise testing.  
Secondary efficacy variables are listed in Section 9.7.1.4.2. 
9.5.4 
Drug Concentration Measurements 
Immediately after completion of the 6-minute walk at Visit 1, approximately 2 mL of blood 
was obtained for determination of udenafil and metabolite concentrations. Another sample 


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was obtained at Week 26. Udenafil is primarily metabolized by the CYP3A4 and CYP3A5 
enzymes in the liver. Therefore, udenafil levels can be influenced by variations in CYP3A4/5 
genes that influence udenafil pharmacokinetics which, in turn, can influence the response to 
udenafil (Goldberg 2012; Shabanian 2013). The association of relevant variants with udenafil 
pharmacokinetics was to be assessed. 
9.6 
Data Quality Assurance 
The DCC had the primary responsibility for all quality control and quality assurance 
activities for the study data. The DCC also required that each study site completed certain 
quality control activities, most of which were monitored by the DCC. Documentation of 
quality-assurance procedures are provided in Appendix 16.1.10. 
The key quality control/quality assurance activities were as follows: 
• Development of a Study Manual 
• Preparation of clearly formatted and carefully constructed Data Forms with clear, up-
to-date manuals of instruction 
• Preparation of sign-off procedures for all eCRFs 
• Provision of central protocol training and certification of all site data collection staff 
with the use of standardized checklists 
• Provision of central e-Clinical Operating System (data management system) training 
and tracking of site personnel completing data entry and/or data management 
• Verification of subject eligibility 
• Provision of on-going monitoring of all protocol/data collection activities 
• Inclusion of repeat measurements, as feasible, in the course of the study 
• Provision of monitoring visits to sites as required with pre-specified goals and/or 
remote monitoring activities. 
Review of central laboratory-related reports was conducted at least monthly to identify 
overall or site-specific problems in data or specimen acquisition and reporting of results. 


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The Sponsor contracted Advanced Clinical Services to audit the top enrolling sites and audit 
certificates were issued for these sites. 
9.7 
Statistical Methods Planned in the Protocol and Determination 
of Sample Size 
9.7.1 
Statistical and Analytical Plans 
The statistical methods described below are summarized from the final Statistical Analysis 
Plan (SAP), dated 23 June 2016. Changes from the planned analyses in the protocol that were 
specified in the final SAP are described in Section 9.8.2. 
Formal hypothesis testing was performed only for the primary efficacy endpoint. All 
statistical tests were at the 0.05 alpha level, 2-tailed, unless stated otherwise. Descriptive 
statistics for categorical endpoints included the number and percent of subjects in each 
treatment group and category. Quantitative endpoints were summarized for each treatment 
group with the mean, median, standard deviation, minimum value, and maximum value. 
Individual subject data were presented in data listings that included normal reference ranges 
when appropriate. 
9.7.1.1 
Analysis Populations 
Three analysis populations were defined: 
• Intent-to-treat (ITT) population: The ITT population included all randomized subjects 
and was the primary population for efficacy analyses. Treatment assignments were 
analyzed according to the randomized treatment assignment. 
• Safety population: The Safety population included all subjects who took at least 
1 dose of randomized study drug and was the primary population for safety analyses. 
If the wrong study drug was administered (eg, subject was randomized to udenafil but 
received placebo), treatment assignment was analyzed according to the actual study 
drug received.  
• Per Protocol population: The Per Protocol population included all subjects in the 
Safety population who met all entry criteria or, if criteria were not met, were granted a 
waiver by the Sponsor. Subjects with major protocol deviations were excluded 
(including subjects who received the wrong study drug). The Per Protocol population 
was used for sensitivity analyses of the primary efficacy endpoint.  


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9.7.1.2 
Accountability and Protocol Deviations 
Screening failures (ie, subjects who were not randomized) were summarized by the number 
and percentage of failures for each primary reason. The number and percent of subjects who 
were randomized, treated with randomized study drug, prematurely discontinued, and 
completed the study were summarized by treatment group. The number and percent of 
subjects were summarized by treatment group for each reason for premature discontinuation. 
For subjects who completed the study, the number of subjects who continued into the 
extension study were summarized. 
The number and percent of enrolled subjects were summarized by study site, and the number 
of subjects included in each analysis population were summarized by treatment group. 
Major protocol deviations were identified prior to breaking the blind. Deviations could have 
included, but were not limited to, departure from inclusion/exclusion criteria, received the 
wrong study drug, failure to perform the required assessments at specified time points, and 
scheduling of visits not in accordance with specifications. 
9.7.1.3 
Demographic and Baseline Characteristics 
Demographic (eg, age, gender, race) and baseline characteristics were summarized 
descriptively for the Safety and ITT populations, for all subjects and for each treatment 
group. Medical and surgical history/physical findings were classified by system organ class 
and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA). The 
number and percentage of subjects with abnormalities in medical and surgical histories in 
each system organ class and preferred term were summarized for all subjects and by 
treatment group for the Safety population. 
9.7.1.4 
Efficacy Analyses 
9.7.1.4.1 
Primary Efficacy Endpoint 
The treatment group difference for change in aerobic exercise performance (as measured by 
VO2 at maximum exercise effort [maximal VO2]) from baseline to Week 26 was assessed 
with an analysis of covariance (ANCOVA) with fixed factors for ventricular morphology 
(single left versus single right or mixed) and treatment group with a continuous covariate of 
baseline maximal VO2. 


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Sensitivity analyses included: 
• Primary efficacy analysis performed for the Per Protocol Population. 
• ANCOVA model to assess treatment group differences in ranked changes of maximal 
VO2 for the ITT and Per Protocol Populations. 
9.7.1.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints included change from baseline to Week 26 in: 
• Exercise capacity 
o VO2 at VAT 
o Ventilatory equivalents of carbon dioxide (VE/VCO2) at VAT 
o Respiratory rate and minute ventilation at peak exercise 
o Maximal work rate 
o Work rate at VAT 
• Ventricular performance 
o MPI determined by velocities obtained from blood pool Doppler assessment 
of the inflow and outflow tract of the dominant ventricle. It is the primary 
ventricular performance endpoint of the echocardiogram. 
o Ventricular cavity size, eccentricity, and mass (based on echocardiogram) 
o Systolic function estimate using mean derivative of pressure over time during 
isovolumetric contraction and peak systolic annular velocity (S’) on tissue 
Doppler 
o Qualitative and quantitative estimate of atrioventricular valve insufficiency 
• Endothelial function: log-transformed reactive hyperemia index (lnRHI), as measured 
by pulse amplitude tonometry (PAT) testing using the EndoPAT device 
• Natural logarithm transformation of BNP 


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• Functional health status, as measured by the full scale PedsQL 
o Physical functioning score 
o Psychosocial functioning score 
o Cardiac-specific quality-of-life score 
• PCQLI score 
Each secondary efficacy endpoint was summarized descriptively by treatment group.  
Treatment group differences for endpoints associated with the PedsQL and PCQLI were to be 
assessed with Friedman’s test using ventricular morphology (single left versus single right or 
mixed) as the stratification factor. The treatment group difference for the qualitative estimate 
of atrioventricular valve insufficiency was to be assessed with a Cochran-Mantel-Haenszel 
test using ventricular morphology (single left versus single right or mixed) as the 
stratification factor.  
The remaining secondary efficacy endpoints were analyzed with the ANCOVA model with 
fixed factors for ventricular morphology (single left versus single right or mixed) and 
treatment group with a covariate for the baseline value.  
9.7.1.4.3 
Subgroup Analyses 
Treatment group differences for the primary efficacy endpoint were summarized descriptively 
for the following subpopulations based on the following baseline characteristics: 
• Gender (male, female) 
• Race (Asian, African American, Caucasian, other) 
• Ethnicity (Hispanic, non-Hispanic) 
• Ventricular morphology (single left, single right, mixed) 
• Age at Fontan surgery (<3 years vs ≥3 years) 
• Baseline serum BNP level (<median, ≥median) 
• Percent of predicted maximal VO2 at baseline (<75%, ≥75%) 


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A 95% confidence interval of the difference in treatment group means was provided within 
each subpopulation. 
9.7.1.4.4 
Missing Data 
The following imputation method was used for the primary analysis of the primary outcome:  
• Subjects who had died or dropped out of the study with unknown vital status were to 
be assigned a maximal VO2 of zero at Week 26. No subjects met this criterion. 
• Subjects who were known to be alive, but who discontinued from the study (and were 
missing maximal VO2 at Week 26) were assigned the latest value available. 
• Subjects who completed Week 26, but were physically unable to reach maximum 
effort in cardiopulmonary exercise testing after 2 attempts, were assigned their 
baseline value (ie, zero change). 
Two additional analyses to assess the impact of missing data were conducted as follows: 
• Subjects with missing maximal VO2 at Visit 4 were assigned a maximal VO2 of zero. 
• Subjects with missing maximal VO2 at Visit 4 were excluded from analysis (ie, 
observed cases analysis). 
Missing item scores for rating scales were imputed according to published methodology for 
the scale. Otherwise, missing data were not estimated for secondary efficacy endpoints. 
9.7.1.5 
Safety Evaluations 
Safety assessments were summarized for the Safety population. No formal hypothesis testing 
was performed.  
9.7.1.5.1 
Extent of Exposure 
The number of days from first to last dose was summarized descriptively for each treatment 
group. Percent compliance for the entire study was calculated as follows: 
Number tablets missed = (number returned – (2 × number of days off study)) 
Number tablets expected = 2 × number of days on study 
Percent Compliance = (1 - (number missed / number expected)) × 100. 


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A subject was considered on-study from Visit 1 until study completion or premature 
discontinuation of study drug. Percent compliance was summarized descriptively for each 
treatment group. 
9.7.1.5.2 
Adverse Events 
All AEs were classified by the MedDRA with respect to system organ class and preferred 
term. The number and proportion of subjects who experienced treatment-emergent adverse 
events (TEAEs), defined as events that began after receipt of randomized study drug, were 
summarized by treatment group for the following: 
• By system organ class and preferred term 
• By intensity (mild, moderate, or severe/life threatening/death), system organ class, 
and preferred term 
• By relationship to study drug (not related or related), system organ class, and 
preferred term 
• By weight tertile, system organ class, and preferred term 
• By age tertile, system organ class, and preferred term 
• SAEs by system organ class and preferred term 
• SAEs by relationship to study drug (not related or related), system organ class, and 
preferred term 
• SAEs by weight tertile, system organ class, and preferred term 
• SAEs by age tertile, system organ class, and preferred term 
• AEs resulting in discontinuation of study drug by system organ class and preferred 
term 
The number and percent of subjects reporting at least 1 TEAE of hypotension (eg, blood 
pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased, 
hypotension, procedural hypotension), loss of consciousness, dizziness (eg, dizziness, 
dizziness exertional, procedural dizziness), presyncope, or syncope (syncope, syncope 
vasovagal) and the number and percent of subjects reporting each of the listed preferred 


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terms were summarized by treatment group. The 2 summaries were repeated by age tertiles 
and weight tertiles. 
The number and percent of subjects reporting at least 1 TEAE of death, hospitalization for 
heart failure, or transplant and the number and percent of subjects reporting each of the listed 
preferred terms were summarized by treatment group. The 2 summaries were repeated by age 
tertiles and weight tertiles. 
9.7.1.5.3 
Clinical Laboratory Tests 
Laboratory values were converted to the project-defined unit of measurement before analysis. 
Clinical laboratory variables were presented in 2 ways. First, change from baseline to 
Week 26 (study completion) was summarized descriptively for each treatment group. The 
baseline value was defined as the last assessment on or before dosing at Visit 1. Second, the 
number and proportion of subjects with treatment-emergent abnormal laboratory values were 
tabulated and the subjects identified. Treatment-emergent abnormal laboratory tests were 
those in which the baseline value was within the laboratory normal reference range and the 
postbaseline value was abnormal (ie, met Grade III or Grade IV toxicity criteria from the 
National Cancer Institute Common Terminology Criteria). All laboratory values obtained 
after Visit 1 were included in the analysis. 
9.7.1.5.4 
Vital Signs 
Change from baseline (last vital sign value before the first dose of study drug at Visit 1) to 
each scheduled assessment was summarized descriptively by treatment group for each vital 
sign variable. Vital signs that were potentially clinically significant were identified according 
to prespecified criteria (listed in the SAP) and summarized descriptively by treatment group. 
9.7.1.5.5 
Prior and Concomitant Medications 
The Concomitant Medications World Health Organization drug dictionary was used to 
classify all medications with respect to the Anatomical-Therapeutic-Chemical classification 
and preferred drug name. Prior and concomitant drug usage was summarized by Anatomical-
Therapeutic-Chemical level 3 and preferred drug name. Medications with a start date before 
the first dose of study drug were considered prior medications. Medications with a stop date 
after the first dose of study drug or ongoing at study completion/discontinuation were 
considered concomitant medications. Therefore, medications that started before the study and 
continued into the study were counted as both prior and concomitant medications. 


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9.7.2 
Determination of Sample Size 
A sample size of 198 subjects per group would provide 90% power to detect a mean 
treatment group difference in change from baseline to Week 26 in maximal VO2 scores of 
10% (ie, an improvement of 2.8 mL/kg/min in the udenafil group compared to zero change in 
the control group, assuming a Type I error of 0.05 and standard deviation of 7.235). A 
difference of 2.8, equivalent to a 10% increase from a baseline of 28 mL/kg/min, represents 
approximately 0.4 standard deviations. 
9.8 
Changes in the Conduct of the Study or Planned Analyses 
9.8.1 
Changes in the Conduct of the Study 
The original protocol, dated 09 March 2016, was amended 3 times. A copy of the final study 
protocol (Protocol PHN-Udenafil-02, dated 31 August 2017) is provided in Appendix 16.1.1.  
Version 2 of the protocol (04 May 2016) included the following substantive modifications to 
the original protocol: 
• Added a DSMB review of all data after the first 50 subjects had completed the study. 
• Added the opportunity for subjects to enroll in a heart rhythm-monitoring subset of 
the FUEL study. 
Version 3 of the protocol (30 May 2017) included the following substantive modifications to 
Version 2 of the protocol: 
• Conversion of Visits 2 and 3 to telephone calls, removing vital sign measurements.  
Version 4 of the protocol (31 August 2017) included the following substantive modifications 
to Version 3 of the protocol: 
• Addition of inclusion criterion #4, which required potential participants to be on 
anti-platelet or anticoagulant therapy. 
• Addition of exclusion criterion #26, which excluded potential participants if they had 
a history of clinically significant thromboembolic event. 


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9.8.2 
Changes to Planned Analyses 
9.8.2.1 
Changes Between Protocol Finalization and Final Statistical 
Analysis Plan 
The SAP was finalized 23 June 2016. Key changes to statistical analyses between protocol 
finalization and the final SAP are described below. 
The protocol defined 2 non-ITT analysis populations. The SAP replaced these non-ITT 
analysis populations by defining the more traditional Per Protocol population. In addition, the 
SAP provided a definition for the Safety population. 
The protocol stated that potential differential impact of continuous age on treatment outcomes 
would be assessed and that a treatment by subpopulation interaction test would be conducted 
to identify differential treatment effects. Tests for treatment by subpopulation were not 
performed due to the low power of the tests. 
The protocol also stated that treatment group differences would be assessed within 
subpopulations if the interaction p-value was <0.10. These tests were not performed due to 
their potentially low power and bias due to lack of randomization within each subpopulation. 
Minor clarifications were made to imputations for missing values. 
Differences between the SAP and analyses presented in the clinical study report include:  
• Presentation of the following for exercise capacity: 
o Percent predicted maximal VO2 
o Heart rate at peak exercise 
• Additional specific variables related to ventricular performance were summarized in 
the statistical tables. 
• Friedman’s test using ventricular morphology (single left versus single right or mixed) 
as the stratification factor was not used to assess treatment group differences for 
endpoints associated with the PedsQL and PCQLI. Differences were assessed using 
the same ANCOVA model as the other secondary endpoints. 
• The qualitative estimate of atrioventricular valve insufficiency was not assessed.  


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• Subgroup analyses of AEs were also performed for gender, race, and ethnicity.  
• Descriptive statistics of udenafil and metabolite concentrations were provided. 
9.8.2.2 
Changes Between Finalization of Statistical Analysis Plan 
and Blind Break 
Key changes to statistical analyses between SAP finalization on 23 June 2016 and blind break 
on 19 July 2019 are described below. 
Treatment group differences for the primary efficacy endpoint were summarized descriptively 
for subjects on afterload reducing agents in the study versus subjects who were not on 
afterload reducing agents in the study. 
Analyses by visit were updated to account for protocol version 3, which replaced in-person 
Visits 2 and 3 (at Weeks 2 and 13, respectively) by telephone calls, and to remove collection 
of vital sign measurements at those time points. 
9.8.2.3 
Changes After Blind Break 
Maximal VO2 and VO2 at VAT were summarized with units of mL/min in addition to the 
protocol-specified units of mL/kg/min. This was done since unchanged VO2 in the presence 
of weight gain would cause VO2 to appear to decrease when summarized as mL/kg/min. 
Waterfall plots and cumulative distribution plots were generated for change from baseline to 
Week 26 in maximal VO2 and VO2 at VAT (mL/min and mL/mg/min). 
Percent change from baseline was calculated for maximal VO2 and VO2 at VAT as the 
geometric mean ratio of the Week 26 minus baseline logarithm transformed exercise data. 
An additional imputation method for missing data was included for exercise variables. When 
the Week 26 value was missing, the mean of non-missing Week 26 values (ignoring treatment 
group) was imputed. 
For VO2 at VAT, a linear regression model was also used to predict Week 26 VO2 at VAT 
from Week 26 maximal VO2. The predicted value from the model was used to impute VO2 at 
VAT when maximal VO2 was available; when maximal VO2 was also missing, the average 
from all subjects with non-missing values was imputed. 


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Treatment-emergent abnormal laboratory tests were not identified on the basis of Grade III or 
Grade IV toxicity criteria from the National Cancer Institute Common Terminology Criteria. 
Shifts from within normal limits at baseline to above normal limits at Week 26 were 
summarized instead. 
9.8.2.4 
Changes to Address Refusal to File Letter 
The MedDRA coding of some adverse events was revised for consistency per request by the 
Food and Drug Administration. 
The definition of TEAEs was changed from events that began after receipt of randomized 
study drug to events that began after receipt of randomized study drug and within 90 days 
after last dose of study drug. 
10 
Study Subjects 
10.1 
Disposition of Subjects 
A total of 976 subjects were screening failures. Of the 976 screening failures, 525 were 
ineligible, 407 did not provide informed consent, 21 were ineligible after informed consent, 
and 23 had no reason provided for screen failure (Table 14.1.1). Key study calendar dates for 
each subject are provided in Listing 16.2.8.5. 
Subjects were enrolled at 30 study sites (26 United States, 2 Canada, 2 South Korea). Subject 
enrollment by site is summarized in Table 4. 


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Table 4: 
Subject Enrollment by Site 
Site 
Udenafil 
(N=200) 
n (%) 
Placebo 
(N=200) 
n (%) 
Total 
(N=400) 
n (%) 
Hospital for Sick Children Toronto  
4 (2.0) 
8 (4.0) 
12 (3.0) 
Boston Children's Hospital 
12 (6.0) 
11 (5.5) 
23 (5.8) 
Columbia/CHONY 
5 (2.5) 
3 (1.5) 
8 (2.0) 
Children's Hospital of Philadelphia 
20 (10.0) 
22 (11.0) 
42 (10.5) 
Duke University Hospital 
3 (1.5) 
1 (0.5) 
4 (1.0) 
Medical University of South Carolina 
9 (4.5) 
4 (2.0) 
13 (3.3) 
University of Utah/Primary Children Medical Center 
11 (5.5) 
8 (4.0) 
19 (4.8) 
Children's Hospital of Los Angeles 
5 (2.5) 
5 (2.5) 
10 (2.5) 
Children's Hospital of Wisconsin 
15 (7.5) 
6 (3.0) 
21 (5.3) 
University of Michigan Health System, Ann Arbor 
11 (5.5) 
2 (1.0) 
13 (3.3) 
Cincinnati Children's Hospital Medical Center 
13 (6.5) 
17 (8.5) 
30 (7.5) 
Riley Children's Hospital Prairieland 
3 (1.5) 
4 (2.0) 
7 (1.8) 
Children's Hospital of Atlanta 
9 (4.5) 
12 (6.0) 
21 (5.3) 
Johns Hopkins All Children's Heart Institute 
1 (0.5) 
1 (0.5) 
2 (0.5) 
Washington University School of Medicine 
1 (0.5) 
4 (2.0) 
5 (1.3) 
Texas Children's Hospital 
13 (6.5) 
10 (5.0) 
23 (5.8) 
Alfred I. duPont Hospital for Children  
3 (1.5) 
7 (3.5) 
10 (2.5) 
Monroe Carrell Jr Children’s Hospital Vanderbilt 
5 (2.5) 
10 (5.0) 
15 (3.8) 
Seattle Children's Hospital 
2 (1.0) 
5 (2.5) 
7 (1.8) 
Cedars-Sinai Medical Center 
3 (1.5) 
1 (0.5) 
4 (1.0) 
Rady Children's Hospital, San Diego 
4 (2.0) 
2 (1.0) 
6 (1.5) 
Children's National Medical Center 
4 (2.0) 
4 (2.0) 
8 (2.0) 
Children's Mercy Hospital 
5 (2.5) 
8 (4.0) 
13 (3.3) 
Children's Hospital of Colorado Heart Institute 
8 (4.0) 
7 (3.5) 
15 (3.8) 
Phoenix Children's Hospital/Children's Heart Center 
9 (4.5) 
7 (3.5) 
16 (4.0) 
Children's Hospital & Medical Center - Omaha 
2 (1.0) 
7 (3.5) 
9 (2.3) 
Nationwide Children's Hospital 
2 (1.0) 
2 (1.0) 
4 (1.0) 
University of Alberta/Stollery Children’s Hospital 
4 (2.0) 
3 (1.5) 
7 (1.8) 
Seoul National University Children's Hospital 
5 (2.5) 
12 (6.0) 
17 (4.3) 
Sejong General Hospital 
9 (4.5) 
7 (3.5) 
16 (4.0) 
Source: Table 14.1.3 
Program: T_14_1_3.sas 
 
The percentage of subjects who discontinued study drug was low and similar between 
treatment groups (12 [6.0%] of udenafil-treated subjects, 9 [4.5%] of placebo-treated 
subjects). Six subjects (4 udenafil, 2 placebo) were prematurely discontinued from study drug 


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by physician decision and 11 subjects (6 udenafil, 5 placebo) were prematurely discontinued 
from study drug by subject (ie, participant) decision. Three udenafil-treated subjects 
discontinued study drug due to a serious TEAE and all other subjects discontinued study drug 
due to other reasons.  
The profile of study discontinuations was similar to study drug discontinuations. Subject 
disposition is summarized in Table 5. Subjects who discontinued from study are identified in 
Listing 16.2.1, and subjects who discontinued study drug are identified in Listing 16.2.1.2. 
Table 5: 
Subject Disposition 
Disposition 
Udenafil 
(N=200) 
n (%) 
Placebo 
(N=200) 
n (%) 
Total 
(N=400) 
n (%) 
Randomized and treated 
200 (100.0) 
200 (100.0) 
400 (100.0) 
Prematurely discontinued study drug 
12 (6.0) 
9 (4.5) 
21 (5.3) 
Lost to follow-up 
2 (1.0) 
2 (1.0) 
4 (1.0) 
Physician decision to permanently stop drug 
4 (2.0) 
2 (1.0) 
6 (1.5) 
Due to serious TEAE 
3 (1.5) 
0 
3 (0.8) 
Due to other reasons 
1 (0.5) 
2 (1.0) 
3 (0.8) 
Participant decision to permanently stop drug 
6 (3.0) 
5 (2.5) 
11 (2.8) 
Due to other reasons 
6 (3.0) 
5 (2.5) 
11 (2.8) 
Discontinued study 
12 (6.0) 
6 (3.0) 
18 (4.5) 
Lost to follow-up 
7 (3.5) 
4 (2.0) 
11 (2.8) 
Physician decision to discontinue study 
1 (0.5) 
0 
1 (0.3) 
Due to serious TEAE 
1 (0.5) 
0 
1 (0.3) 
Due to other reasons 
0 
0 
0 
Subject decision to discontinue study  
4 (2.0) 
2 (1.0) 
6 (1.5) 
Due to other reasons 
4 (2.0) 
2 (1.0) 
6 (1.5) 
Completed studya 
188 (94.0) 
194 (97.0) 
382 (95.5) 
Continued in extension study 
126 (63.0) 
124 (62.0) 
250 (62.5) 
TEAE=treatment-emergent adverse event 
a As defined by status change form 
Source: Table 14.1.2 
Program: T_14_1_2.sas 
 


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10.2 
Protocol Deviations 
The most frequent reasons for exclusion from the Per Protocol population included inability 
to complete exercise testing at baseline/screening (2 subjects), weight <40 kg (2 subjects), 
and any other deviations not listed under the defined categories (8 subjects).  
Major protocol deviations are summarized in Table 6. Subjects with protocol deviations are 
identified in Listing 16.2.2. 
Table 6: 
Major Protocol Deviations 
Deviation 
Udenafil 
(N=200) 
n (%) 
Placebo 
(N=200) 
n (%) 
Total 
(N=400) 
n (%) 
Assessment compliance 
1 (0.5) 
0 
1 (0.3) 
Assessment not performed per protocol 
1 (0.5) 
0 
1 (0.3) 
Inclusion/exclusion compliance 
3 (1.5) 
1 (0.5) 
4 (1.0) 
Inability to complete exercise testing at baseline/screening 
1 (0.5) 
1 (0.5) 
2 (0.5) 
Weight <40 kg 
2 (1.0) 
0 
2 (0.5) 
Other compliance 
3 (1.5) 
5 (2.5) 
8 (2.0) 
Any other deviations not listed under the defined categoriesa 
3 (1.5) 
5 (2.5) 
8 (2.0) 
Study medication compliance 
0 
1 (0.5) 
1 (0.3) 
a 
Includes 7 subjects (3 udenafil, 4 placebo) at Riley Children's Hospital, where the data could not be verified as part 
of the on-site data cleaning project because the hard drive crashed and could not be recovered. 
Source: Table 14.1.5 
Program: t_14_1_5.sas 
 
11 
Efficacy Evaluation 
11.1 
Datasets Analyzed 
No randomized subjects were excluded in the ITT and Safety populations. Approximately 
97% of subjects in each treatment group were included in the Per Protocol population. 
Subjects excluded from the Per Protocol population are identified in Listing 16.2.3. The 
number and percentage of subjects in each analysis population are summarized in Table 7. 


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Table 7: 
Analysis Populations 
Population 
Udenafil 
(N=200) 
n (%) 
Placebo 
(N=200) 
n (%) 
Total 
(N=400) 
n (%) 
Intent-to-Treat 
200 (100.0) 
200 (100.0) 
400 (100.0) 
Safety 
200 (100.0) 
200 (100.0) 
400 (100.0) 
Per Protocol 
193 (96.5) 
193 (96.5) 
386 (96.5) 
Source: Table 14.1.4 
Program: T_14_1_4.sas 
 
11.2 
Demographic and other Baseline Characteristics 
Most subjects were male (59.8%), white (81.0%), and not Hispanic or Latino (85.5%). Mean 
age at baseline was 15.5 years, with a range of 12.0 to 19.0 years. Demographic and baseline 
characteristics were similar between treatment groups. Demographic and baseline 
characteristics are summarized in Table 8. 
Demographic and baseline characteristics of the ITT population (Table 14.1.6B) were 
identical to those of the Safety population (Table 14.1.6A). Demographic characteristics are 
provided by subject in Listing 16.2.4; weight and height are provided by subject in 
Listing 16.2.6.1.1. 


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Table 8: 
Demographic and Baseline Characteristics (Safety Population) 
 
Demographic Characteristic 
Udenafil 
(N=200) 
Placebo 
(N=200) 
Total 
(N=400) 
Age (years) 
 
 
 
Mean (SD) 
15.4 (2.033) 
15.6 (1.978) 
15.5 (2.005) 
Median 
15.43 
15.40 
15.41 
Minimum, maximum 
12.1, 19.0 
12.0, 19.0 
12.0, 19.0 
Biological Gender, n (%) 
 
 
 
Female 
89 (44.5) 
72 (36.0) 
161 (40.3) 
Male 
111 (55.5) 
128 (64.0) 
239 (59.8) 
Race, n (%) 
 
 
 
White 
169 (84.5) 
155 (77.5) 
324 (81.0) 
Asian 
17 (8.5) 
21 (10.5) 
38 (9.5) 
Black or African-American 
10 (5.0) 
13 (6.5) 
23 (5.8) 
Multiple 
2 (1.0) 
2 (1.0) 
4 (1.0) 
Unknown 
2 (1.0) 
3 (1.5) 
5 (1.3) 
Not reported 
0 
6 (3.0) 
6 (1.5) 
Ethnicity, n (%) 
 
 
 
Hispanic or Latino 
31 (15.5) 
25 (12.5) 
56 (14.0) 
Not Hispanic or Latino 
168 (84.0) 
174 (87.0) 
342 (85.5) 
Unknown 
1 (0.5) 
1 (0.5) 
2 (0.5) 
Weight (kg) 
 
 
 
Mean (SD) 
57.1 (13.925) 
59.0 (13.187) 
58.1 (13.577) 
Median 
53.45 
57.00 
55.65 
Minimum, maximum 
39.6, 123.0 
40.0, 119.4 
39.6, 123.0 
Height (cm) 
 
 
 
Mean (SD) 
162.5 (10.364) 
164.7 (8.712) 
163.6 (9.624) 
Median 
162.00 
165.00 
163.00 
Minimum, maximum 
139.8, 190.1 
146.3, 190.8 
139.8, 190.8 
SD=standard deviation 
Source: Table 14.1.6A 
Program: T_14_1_6A.sas 
 


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Single ventricle anatomic diagnoses reported for ≥20% of subjects included single ventricle 
(52.0%) and hypoplastic left heart syndrome (29.5%). Fenestration was reported for 32.8% of 
subjects.  
The profile of baseline abnormalities in medical and surgical history was similar between 
treatment groups (Table 9). Abnormalities are provided by subject in Listing 16.2.7.2. 
Table 9: 
Abnormalities in Medical and Surgical Histories (Safety 
Population) 
 
Subjects with: 
Udenafil 
(N=200) 
n (%) 
Placebo 
(N=200) 
n (%) 
Total 
(N=400) 
n (%) 
At least 1 abnormality in medical or surgical history 
199 (99.5) 
199 (99.5) 
398 (99.5) 
Fenestration 
73 (36.5) 
58 (29.0) 
131 (32.8) 
Pacemaker placed 
16 (8.0) 
11 (5.5) 
27 (6.8) 
Previous history of protein losing enteropathy 
2 (1.0) 
3 (1.5) 
5 (1.3) 
Previous history of plastic bronchitis 
1 (0.5) 
1 (0.5) 
2 (0.5) 
Liver biopsy 
16 (8.0) 
20 (10.0) 
36 (9.0) 
Latex allergy 
4 (2.0) 
6 (3.0) 
10 (2.5) 
Single ventricle anatomic diagnoses 
199 (99.5) 
199 (99.5) 
398 (99.5) 
A1: Single ventriclea 
97 (48.5) 
111 (55.5) 
208 (52.0) 
A2: Hypoplastic left heart syndromeb 
64 (32.0) 
54 (27.0) 
118 (29.5) 
A3: Other functional single ventricle not fitting any 
other categoriesc 
38 (19.0) 
32 (16.0) 
70 (17.5) 
A4: Unclassifiedd 
0 
2 (1.0) 
2 (0.5) 
a Includes double inlet left ventricle, double inlet right ventricle, mitral atresia, tricuspid atresia, unbalanced 
atrioventricular canal defect, heterotaxia syndrome, and other single ventricle (mostly left, mostly right, 
indeterminate). 
b Includes aortic and mitral atresia, aortic atresia and mitral stenosis, aortic atresia and ventricular septal defect 
(well-developed mitral valve and left ventricle), aortic stenosis and mitral stenosis, aortic stenosis and mitral 
valve hypoplasia, hypoplastic aortic valve and mitral valve and left ventricle, and left ventricle, aortic stenosis 
and mitral atresia. 
c Includes pulmonary atresia with intact ventricular septum, ventricular septal defect(s), tricuspid valve anomaly, 
D-loop double outlet right ventricle with 2 ventricles, double outlet left ventricle with two ventricles, D-loop 
transposition of the great arteries with 2 ventricles, L-loop transposition of the great arteries or L-loop double 
outlet right ventricle with 2 ventricles, mitral valve anomaly, hypoplastic left ventricle with ventricular septal 
defect(s), hypoplastic right ventricle with ventricular septal defect(s). 
d Unable to classify diagnosis into A1, A2 or A3 categories. 
Source: Table 14.1.7  
Program: t_14_1_7.sas 
 


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Almost all subjects in each treatment group reported at least 1 prior medication 
(97.5% udenafil, 99.0% placebo). Common prior medications (≥20% of subjects in either 
treatment group) included acetylsalicylic acid (89.5% udenafil, 93.5% placebo), enalapril 
(27.5% udenafil, 31.0% placebo), and lisinopril (24.0% udenafil, 20.5% placebo).  
The use of prior medications was similar between treatment groups (Table 10). Prior 
medications are provided by subject in Listing 16.2.8.3. 


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Table 10: 
Prior Medications Used by ≥5% of Subjects in Either Treatment Group 
(Safety Population) 
ATC Class (Level 3)a 
Preferred Drug Name 
Udenafil 
(N=200) 
n (%) 
Placebo 
(N=200) 
n (%) 
≥1 non-study medication 
195 (97.5) 
198 (99.0) 
ACE inhibitors, plain 
107 (53.5) 
107 (53.5) 
Enalapril 
55 (27.5) 
62 (31.0) 
Lisinopril 
48 (24.0) 
41 (20.5) 
Antithrombotic agents 
189 (94.5) 
193 (96.5) 
Acetylsalicylic acid 
179 (89.5) 
187 (93.5) 
Warfarin 
14 (7.0) 
7 (3.5) 
Beta blocking agents 
16 (8.0) 
18 (9.0) 
Carvedilol 
4 (2.0) 
11 (5.5) 
Beta-lactam antibacterials, penicillins 
12 (6.0) 
13 (6.5) 
Amoxicillin 
9 (4.5) 
10 (5.0) 
Cardiac glycosides 
17 (8.5) 
11 (5.5) 
Digoxin 
17 (8.5) 
11 (5.5) 
High-ceiling diuretics 
18 (9.0) 
14 (7.0) 
Furosemide 
18 (9.0) 
13 (6.5) 
Hypnotics and sedatives 
10 (5.0) 
5 (2.5) 
Melatonin 
10 (5.0) 
5 (2.5) 
Multivitamins, combinations 
24 (12.0) 
26 (13.0) 
Multivitamins 
21 (10.5) 
24 (12.0) 
Potassium-sparing agents 
12 (6.0) 
14 (7.0) 
Spironolactone 
12 (6.0) 
14 (7.0) 
Vitamin A and D, incl. combinations of the two 
14 (7.0) 
13 (6.5) 
Colecalciferol 
13 (6.5) 
12 (6.0) 
ACE=angiotensin-converting enzyme; ATC=Anatomical-Therapeutic-Chemical; incl=including 
a 
Subjects prescribed 2 or more drugs within an ATC class are counted only once at the class level. Therefore, the sum 
of preferred drug name frequencies can exceed the class frequency. 
Source: Table 14.3.25  
Program: T_14_3_25.sas 
 
All but 1 subject in each treatment group reported at least 1 concomitant medication. 
Frequently reported concomitant medications (≥20% of subjects in either treatment group) 
included acetylsalicylic acid (92.5% udenafil, 96.0% placebo), enalapril (28.5% udenafil, 


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31.0% placebo), lisinopril (25.0% udenafil, 20.0% placebo), and paracetamol 
(20.5% udenafil, 14.0% placebo).  
The use of concomitant medications was similar between treatment groups (Table 11). 
Concomitant medications are provided by subject in Listing 16.2.8.4.1 and Listing 16.2.8.4.2. 


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Table 11: 
Concomitant Medications Used by ≥5% of Subjects in Either 
Treatment Group (Safety Population) 
ATC Class (Level 3)a 
Preferred Drug Name 
Udenafil 
(N=200) 
n (%) 
Placebo 
(N=200) 
n (%) 
≥1 non-study medication 
199 (99.5) 
199 (99.5) 
ACE inhibitors, plain 
110 (55.0) 
106 (53.0) 
Enalapril 
57 (28.5) 
62 (31.0) 
Lisinopril 
50 (25.0) 
40 (20.0) 
Adrenergics for systemic use 
16 (8.0) 
12 (6.0) 
Salbutamol 
11 (5.5) 
8 (4.0) 
Angiotensin II antagonists, plain 
11 (5.5) 
5 (2.5) 
Losartan 
10 (5.0) 
5 (2.5) 
Antihistamines for system use 
35 (17.5) 
30 (15.0) 
Loratadine 
11 (5.5) 
9 (4.5) 
Antithrombotic agents 
194 (97.0) 
197 (98.5) 
Acetylsalicylic acid 
185 (92.5) 
192 (96.0) 
Warfarin 
14 (7.0) 
8 (4.0) 
Beta blocking agents 
17 (8.5) 
23 (11.5) 
Carvedilol 
5 (2.5) 
14 (7.0) 
Beta-lactam antibacterials, penicillins 
29 (14.5) 
37 (18.5) 
Amoxicillin 
23 (11.5) 
29 (14.5) 
Cardiac glycosides 
17 (8.5) 
11 (5.5) 
Digoxin 
17 (8.5) 
11 (5.5) 
High-ceiling diuretics 
18 (9.0) 
14 (7.0) 
Furosemide 
18 (9.0) 
13 (6.5) 
Hypnotics and sedatives 
17 (8.5) 
11 (5.5) 
Melatonin 
13 (6.5) 
7 (3.5) 
Macrolides, lincosamides and streptogramins 
12 (6.0) 
10 (5.0) 
Azithromycin 
10 (5.0) 
8 (4.0) 
Multivitamins, combinations 
26 (13.0) 
29 (14.5) 
Multivitamins 
24 (12.0) 
26 (13.0) 
Other analgesics and antipyretics 
50 (25.0) 
35 (17.5) 
Paracetamol 
41 (20.5) 
28 (14.0) 
Potassium-sparing agents 
13 (6.5) 
16 (8.0) 
Spironolactone 
13 (6.5) 
16 (8.0) 
Topical products for joint and muscular pain 
41 (20.5) 
29 (14.5) 
Ibuprofen 
39 (19.5) 
26 (13.0) 
Vitamin A and D, incl. combinations of the two 
16 (8.0) 
18 (9.0) 
Colecalciferol 
15 (7.5) 
17 (8.5) 
ACE=angiotensin-converting enzyme; ATC=Anatomical-Therapeutic-Chemical; incl=including  
a 
Subjects prescribed 2 or more drugs within an ATC class are counted only once at the class level. Therefore, the sum 
of preferred drug name frequencies can exceed the class frequency. 
Source: Table 14.3.26  
Program: T_14_3_26.sas 
 


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11.3 
Measurements of Treatment Compliance 
Mean percent compliance with study drug was 89.92% in the udenafil group and 89.97% in 
the placebo group (Table 14.3.1.1). Compliance results are listed by subject in 
Listing 16.2.5.1. 
11.4 
Efficacy Results and Tabulations of Individual Subject Data 
11.4.1 
Analysis of Efficacy 
The primary aim of this study was to evaluate the effect of 26 weeks of treatment with 
udenafil on exercise capacity in adolescents with Fontan physiology, with a primary outcome 
of change in maximal VO2 from baseline to Week 26. The udenafil group had a mean 
increase from baseline to Week 26 in maximal VO2 compared to a mean decrease in the 
placebo group, and the primary analysis identified a statistical trend for the treatment 
difference (p=0.071). Importantly, all efficacy endpoints measured at VAT indicated greater 
exercise capacity in the udenafil group than the placebo group at Week 26 (p≤0.05).  
After an initial summary of the protocol-specified primary endpoint (maximal VO2), this 
summary of efficacy will focus on measures of exercise capacity at VAT. In addition, 
maximal VO2 and VO2 at VAT were summarized with units of mL/min in addition to the 
protocol-specified units of mL/kg/min. As each participant’s VO2 at Week 26 is compared to 
their baseline, the natural fluctuations in weight over 6 months would add variability and 
could be a source of bias for individual subjects and for the study population as a whole. 
11.4.1.1 
Overview of Results for VO2 at VAT and Maximal VO2 
For the protocol-specified primary endpoint, the udenafil group had a mean increase from 
baseline to Week 26 in maximal VO2 (44.40 mL/min) compared to a mean decrease in the 
placebo group (-3.65 mL/min). The least squares mean treatment group difference for change 
from baseline to Week 26 in maximal VO2 was 41.04 mL/min (p=0.071). When standardized 
by each subject’s body weight, the least squares mean treatment group difference was 
0.64 mL/kg/min (p=0.092). Results were consistent across methods of imputation for missing 
data and analysis populations (Table 12). 
For VO2 at VAT, the udenafil group had a mean increase from baseline to Week 26 in VO2 at 
VAT (29.65 mL/min) as compared to a mean decrease in the placebo group (-8.01 mL/min). 
The least squares mean treatment group difference for change from baseline to Week 26 in 
VO2 at VAT was 41.58 mL/min (p=0.023). When standardized by each subject’s body weight, 


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the least squares mean treatment group difference was 0.78 mL/kg/min (p=0.012). Results 
were consistent across methods of imputation for missing data and analysis populations 
(Table 12). 
Table 12: 
Overview of Analyses of Change Between Week 26 and Baseline 
Visits for Maximal VO2 and VO2 at VAT 
 
Mean (Standard Deviation) 
 
 
VO2 Measure (units) 
Endpoint, Population, Imputation 
Udenafil 
Placebo 
Difference  
LS Mean (SE) p-value a 
Maximal VO2 (mL/kg/min) 
Change, ITT, LOCF 
-0.23 (4.056) 
-0.89 (3.672) 
0.64 (0.377) 
0.092 
Maximal VO2 (mL/min) 
 
 
 
 
Change, ITT, LOCF 
44.40 (238.291) 
-3.65 (222.417) 
41.04 (22.709) 
0.071 
Change, ITT, OC 
46.98 (244.914) 
-3.84 (228.224) 
44.68 (23.897) 
0.062 
Change, ITT, mean of non-missingb 
60.68 (261.742) 
-1.34 (235.417) 
51.72 (24.090) 
0.032 
Change, PP, LOCF 
42.23 (238.652) 
6.17 (207.286) 
31.40 (22.363) 
0.161 
LN (change), ITT, LOCF 
0.03 (0.163) 
-0.01 (0.195) 
0.03 (0.018) 
0.070 
LN (change), ITT, OC 
0.03 (0.168) 
-0.01 (0.200) 
0.04 (0.019) 
0.061 
LN (change), ITT, mean of non-missingb 
0.04 (0.184) 
-0.01 (0.202) 
0.04 (0.019) 
0.033 
LN (change), PP, LOCF 
0.03 (0.163) 
0.00 (0.134) 
0.02 (0.015) 
0.176 
VO2 at VAT (mL/kg/min)  
Change, ITT, LOCF 
-0.07 (2.998) 
-0.68 (3.216) 
0.78 (0.308) 
0.012 
VO2 at VAT (mL/min) 
 
 
 
 
Change, ITT, LOCF 
29.65 (177.023) 
-8.01 (183.031) 
41.58 (18.224) 
0.023 
Change, ITT, OC 
32.52 (185.191) 
-8.95 (193.508) 
50.56 (20.074) 
0.012 
Change, ITT, mean of non-missingb 
42.12 (185.414) -10.81 (204.340) 58.31 (19.040) 
0.002 
Change, ITT, linear regression 
37.66 (189.688) -15.93 (204.787) 58.83 (19.403) 
0.003 
Change, PP, LOCF 
27.95 (176.397) 
-2.78 (175.846) 
38.62 (17.945) 
0.032 
LN (change), ITT, LOCF 
0.03 (0.168) 
-0.02 (0.252) 
0.05 (0.022) 
0.024 
LN (change), ITT, OC 
0.03 (0.176) 
-0.02 (0.267) 
0.06 (0.025) 
0.015 
LN (change), ITT, mean of non-missingb 
0.05 (0.180) 
-0.02 (0.266) 
0.07 (0.023) 
0.005 
LN (change), ITT, linear regression 
0.04 (0.186) 
-0.03 (0.268) 
0.07 (0.023) 
0.005 
LN (change), PP, LOCF 
0.03 (0.167) 
0.00 (0.184) 
0.04 (0.018) 
0.028 
ANCOVA=analysis of covariance; ITT=intent-to-treat; LOCF=last observation carried forward; LN=natural 
logarithm; LS=least squares; OC=observed cases; PP=per protocol; SE=standard error; VAT=ventilatory anaerobic 
threshold; VO2=minute oxygen consumption 
a P-value was assessed using ANCOVA with fixed factors for ventricular morphology (single left versus single right 
or mixed) and treatment group with a continuous covariate of baseline maximal VO2. 
b When the Week 26 value was missing, the mean of non-missing Week 26 values (ignoring treatment group) was 
imputed. 
Source: Table 14.2.1.1.1, Table 14.2.1.1.2, Table 14.2.1.1.3, Table 14.2.1.1.4, Table 14.2.1.2.1, Table 14.2.1.2.2, 
Table 14.2.1.2.3, Table 14.2.1.2.4, Table 14.2.2.1.1, Table 14.2.3.1.1, Table 14.2.3.1.2, Table 14.2.3.1.3, 
Table 14.2.3.1.4, Table 14.2.3.1.5, Table 14.2.3.2.1, Table 14.2.3.2.2, Table 14.2.3.2.3, Table 14.2.3.2.4, Table 
14.2.3.2.5, and Table 14.2.4.1.1 
Program: T_14_2_1_1_1.sas, T_14_2_1_1_2.sas, T_14_2_1_1_3.sas, T_14_2_1_1_4.sas, T_14_2_1_2_1.sas, 
T_14_2_1_2_2.sas, T_14_2_1_2_3.sas, T_14_2_1_2_4.sas, T_14_2_2_1_1.sas,T_14_2_3_1_1.sas, 
T_14_2_3_1_2.sas, T_14_2_3_1_3.sas, t_14_2_3_1_4.sas, T_14_2_3_1_5.sas, T_14_2_3_2_1.sas, 
T_14_2_3_2_2.sas, T_14_2_3_2_3.sas, T_14_2_3_2_4.sas, T_14_2_3_2_5.sas, and T_14_2_4_1_1.sas 
 


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11.4.1.2 
Protocol-specified Primary Efficacy Endpoint 
The udenafil group had a mean increase from baseline to Week 26 in maximal VO2 
(44.40 mL/min) compared to a mean decrease in the placebo group (-3.65 mL/min). The least 
squares mean treatment group difference for change from baseline to Week 26 in maximal 
VO2 was 41.04 mL/min (p=0.071). When standardized by each subject’s body weight, the 
least squares mean treatment group difference was 0.64 mL/kg/min (p=0.092). The 
protocol-specified primary analysis of change from baseline to Week 26 in maximal VO2 
(expressed as mL/min and mL/kg/min) is summarized in Table 13. 
Table 13: 
Protocol-specified Primary Efficacy Analysis: Change in Maximal 
VO2 Between Week 26 and Baseline Visits Using Last Observation 
Carried Forward (ITT Population) 
Endpoint (units) 
Statistic 
Udenafil 
(N=200) 
Placebo 
(N=200) 
Difference  
LS Mean (SE) 
p-value 
Maximal VO2 (mL/min) 
 
 
 
 
Baseline, mean (SD) 
1562.00 (437.329) 
1626.95 (413.992) 
-64.54 (42.436) 
0.129a 
Week 26, mean (SD) 
1606.40 (451.719) 
1623.30 (432.153) 
-16.50 (44.081) 
0.708a 
Change from baseline  
 
 
 
 
Mean (SD) 
44.40 (238.291) 
-3.65 (222.417) 
41.04 (22.709) 
0.071b 
Median  
30.00 
0.00  
 
 
Interquartile range 
-70.00, 170.00 
-120.00, 120.00 
 
 
Minimum, maximum  
-620.0, 950.0 
-1170.0, 720.0 
 
 
Maximal VO2 (mL/kg/min) 
 
 
 
 
Baseline, mean (SD) 
27.84 (6.877) 
28.01 (6.128) 
-0.16 (0.652) 
0.801a 
Week 26, mean (SD) 
27.61 (6.871) 
27.12 (6.628) 
0.50 (0.676) 
0.463a 
Change from baseline  
 
 
 
 
Mean (SD) 
-0.23 (4.056) 
-0.89 (3.672) 
0.64 (0.377) 
0.092b 
Median  
-0.17 
-0.85 
 
 
Interquartile range 
-2.55, 1.70 
-3.13, 1.17 
 
 
Minimum, maximum  
-12.0, 15.5 
-16.5, 13.8 
 
 
ANCOVA=analysis of covariance; ANOVA=analysis of variance; ITT=intent-to-treat; LS=least squares; SD=standard 
deviation; SE=standard error; VO2=minute oxygen consumption 
a P-value was assessed using ANOVA with fixed factors for ventricular morphology (single left versus single right or 
mixed) and treatment group. 
b P-value was assessed using ANCOVA with fixed factors for ventricular morphology (single left versus single right 
or mixed) and treatment group with a continuous covariate of baseline maximal VO2. 
Source: Table 14.2.1.1.1 and Table 14.2.2.1.1 
Program: T_14_2_1_1_1.sas and T_14_2_2_1_1.sas 
 


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Results for treatment group differences in change from baseline in maximal VO2 using units 
of mL/min were generally similar for analyses using no imputation (p=0.062, 
Table 14.2.1.1.2), imputation with the mean of non-missing values at Week 26 (p=0.032, 
Table 14.2.1.1.3), and last observation carried forward (LOCF) for Per Protocol population 
(p=0.161, Table 14.2.1.1.4). Analysis of ranked changes using LOCF (Table 14.2.1.1.5) and 
imputation with zero (Table 14.2.1.1.6) demonstrated p<0.05 for treatment differences 
(p=0.026 and p=0.045, respectively).  
Results for treatment group differences in change from baseline in maximal VO2 using units 
of mL/kg/min were generally similar for analyses using no imputation (p=0.089, 
Table 14.2.2.1.2), imputation with the mean of non-missing values at Week 26 (p=0.083, 
Table 14.2.2.1.3), LOCF for Per Protocol population (p=0.188, Table 14.2.2.1.4), ranked 
changes (p=0.069, Table 14.2.2.1.5), and imputation with zero (p=0.422, Table 14.2.2.1.6). 
Waterfall plots for change in maximal VO2 from baseline to Week 26 are presented in 
Figure 14.2.1.1.3 for units of mL/min and in Figure 14.2.1.1.4 for units of mL/kg/min. The 
cumulative distribution curve for change in maximal VO2 from baseline to Week 26 is 
presented in Figure 14.2.1.1.5 for units of mL/kg/min. For these figures, no imputation was 
performed for missing observations. 
The udenafil group had a mean increase from baseline to Week 26 in the natural logarithm of 
maximal VO2 (0.03) compared to a mean decrease in the placebo group (-0.01). The least 
squares mean treatment group difference for change from baseline to Week 26 in the natural 
logarithm of maximal VO2 was 0.03 (p=0.070). Change from baseline to Week 26 in maximal 
VO2 (displayed as natural logarithms of mL/min and mL/kg/min) is summarized in Table 14.  


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Table 14: 
Change in the Natural Logarithm of Maximal VO2 Between Week 26 
and Baseline Visits Using Last Observation Carried Forward (ITT 
Population) 
Endpoint (units) 
Statistic 
Udenafil 
(N=200) 
Placebo 
(N=200) 
Difference  
LS Mean (SE) 
p-value 
Maximal VO2 (natural logarithm of mL/min) 
Baseline, mean (SD) 
7.32 (0.280) 
7.36 (0.251) 
-0.05 (0.027) 
0.075a 
Week 26, mean (SD) 
7.34 (0.276) 
7.35 (0.301) 
-0.01 (0.029) 
0.765a 
Change from baseline  
 
 
 
 
Mean (SD) 
0.03 (0.163) 
-0.01 (0.195) 
0.03 (0.018) 
0.070b 
Median  
0.02 
0.00 
 
 
Interquartile range 
-0.04, 0.10 
-0.09, 0.07 
 
 
Minimum, maximum  
-0.5, 1.0 
-2.0, 0.4 
 
 
Maximal VO2 (natural logarithm of mL/kg/min) 
Baseline, mean (SD) 
3.30 (0.250) 
3.31 (0.221) 
-0.01 (0.024) 
0.603a 
Week 26, mean (SD) 
3.29 (0.257) 
3.27 (0.287) 
0.02 (0.027) 
0.446a 
Change from baseline  
 
 
 
 
Mean (SD) 
-0.01 (0.163) 
-0.04 (0.191) 
0.03 (0.018) 
0.072b 
Median  
-0.01 
-0.03 
 
 
Interquartile range 
-0.10, 0.07 
-0.13, 0.04 
 
 
Minimum, maximum  
-0.05, 1.0 
-2.0, 0.4 
 
 
ANCOVA=analysis of covariance; ANOVA=analysis of variance; ITT=intent-to-treat; LS=least squares; SD=standard 
deviation; SE=standard error; VO2=minute oxygen consumption 
a P-value was assessed using ANOVA with fixed factors for ventricular morphology (single left versus single right or 
mixed) and treatment group. 
b P-value was assessed using ANCOVA with fixed factors for ventricular morphology (single left versus single right 
or mixed) and treatment group with a continuous covariate of baseline maximal VO2. 
Note: Values are summarized as natural logarithm of maximal VO2.  
Source: Table 14.2.1.2.1 and Table 14.2.2.2.1 
Program: T_14_2_1_2_1.sas and T_14_2_2_2_1.sas 
 
Results for treatment group differences in change of the natural logarithm for maximal VO2 
using units of mL/min were generally similar for analyses using no imputation (p=0.061, 
Table 14.2.1.2.2), imputation with the mean of non-missing values at Week 26 (p=0.033, 
Table 14.2.1.2.3), and LOCF for Per Protocol population (p=0.176, Table 14.2.1.2.4).  
Results for treatment group differences in change of the natural logarithm for maximal VO2 
using units of mL/kg/min were generally similar for analyses using no imputation (p=0.073, 
Table 14.2.2.2.2), imputation with the mean of non-missing values at Week 26 (p=0.075, 
Table 14.2.2.2.3), and LOCF for Per Protocol population (p=0.202, Table 14.2.2.2.4). 


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Exercise results are presented by subject in Listing 16.2.6.1.1, Listing 16.2.6.1.2, 
Listing 16.2.6.1.3, Listing 16.2.6.1.4, Listing 16.2.6.1.5, and Listing 16.2.6.1.5.1. 
11.4.1.3 
VO2 at Ventilatory Anaerobic Threshold 
The udenafil group had a mean increase from baseline to Week 26 in VO2 at VAT 
(29.65 mL/min) as compared to a mean decrease in the placebo group (-8.01 mL/min). The 
least squares mean treatment group difference for change from baseline to Week 26 in VO2 at 
VAT was 41.58 mL/min (p=0.023). When standardized by each subject’s body weight, the 
least squares mean treatment group difference was 0.78 mL/kg/min (p=0.012). The analysis 
of change from baseline to Week 26 in VO2 at VAT (expressed as mL/min and mL/kg/min) is 
summarized in Table 15. 


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Table 15: 
Change in VO2 at VAT Between Week 26 and Baseline Visits Using 
Last Observation Carried Forward (ITT Population) 
 
Udenafil 
(N=200) 
Placebo 
(N=200) 
Difference  
LS Mean (SE) 
p-value 
VO2 at VAT (mL/min) 
 
 
 
 
Baseline 
n=170 
n=181 
 
 
Mean 
(SD) 
1039.41 
(300.779) 
1020.50 
(279.683) 
19.06  
(30.963) 
0.539a 
Week 26 
n=185 
n=191 
 
 
Mean 
(SD) 
1059.03 
(291.999) 
1014.45 
(277.017) 
56.72 
(30.595) 
0.065a 
Difference, Week 26 minus baseline  
n=170 
n=181 
 
 
Mean  
(SD) 
29.65 
(177.023) 
-8.01 
(183.031) 
41.58 
(18.224) 
0.023b 
Median  
20.00 
0.00 
 
 
VO2 at VAT (mL/kg/min) 
 
 
 
 
Baseline 
n=170 
n=181 
 
 
Mean (SD) 
18.35 (4.633) 
17.71 (4.304) 
0.64 (0.478) 
0.181a 
Week 26 
n=185 
n=191 
 
 
Mean (SD) 
18.20 (4.509) 
16.99 (4.130) 
1.25 (0.465) 
0.008a 
Difference, Week 26 minus baseline  
n=170 
n=181 
 
 
Mean (SD) 
-0.07 (2.998) 
-0.68 (3.216) 
0.78 (0.308) 
0.012b 
Median  
0.00 
-0.25 
 
 
ANCOVA=analysis of covariance; ANOVA=analysis of variance; ITT=intent-to-treat; LS=least squares; SD=standard 
deviation; SE=standard error; VAT=ventilatory anaerobic threshold; VO2=minute oxygen consumption 
a P-value was assessed using ANOVA with fixed factors for ventricular morphology (single left versus single right or 
mixed) and treatment group. 
b P-value was assessed using ANCOVA with fixed factors for ventricular morphology (single left versus single right 
or mixed) and treatment group with a continuous covariate of baseline maximal VO2. 
Source: Table 14.2.3.1.1 and Table 14.2.4.1.1 
Program: T_14_2_3_1_1.sas and T_14_2_4_1_1.sas 
 
Results for treatment group differences in change from baseline in VO2 at VAT using units of 
mL/min were generally similar for analyses using no imputation (p=0.012, Table 14.2.3.1.2), 
imputation with the mean of non-missing values at Week 26 (p=0.002, Table 14.2.3.1.3), 
imputation using linear regression (p=0.003, Table 14.2.3.1.4), LOCF for Per Protocol 
population (p=0.032, Table 14.2.3.1.5), and ranked changes (p=0.075, Table 14.2.3.1.6). 
Results for treatment group differences in change from baseline in VO2 at VAT using units of 
mL/kg/min were generally similar for analyses using no imputation (p=0.009, 


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Table 14.2.4.1.2), imputation with the mean of non-missing values at Week 26 (p=0.007, 
Table 14.2.4.1.3), imputation using linear regression (p=0.003, Table 14.2.4.1.4), LOCF for 
Per Protocol population (p=0.019, Table 14.2.4.1.5), and ranked changes (p=0.152, 
Table 14.2.4.1.6). 
Waterfall plots for change in VO2 at VAT from baseline to Week 26 are presented in 
Figure 14.2.2.1.3 for units of mL/min and in Figure 14.2.2.1.4 for units of mL/kg/min. The 
cumulative distribution curve for change in VO2 at VAT from baseline to Week 26 is 
presented in Figure 14.2.2.1.5 for units of mL/kg/min. For these figures, no imputation was 
performed for missing observations. 
When change in the natural logarithm of VO2 at VAT was based on units of mL/min, the 
udenafil group had a mean increase from baseline to Week 26 in VO2 at VAT (0.03) compared 
to a mean decrease in the placebo group (-0.02). The least squares mean treatment group 
difference for change from baseline to Week 26 in the natural logarithm of VO2 at VAT was 
0.05 (p=0.024). Change from baseline to Week 26 in VO2 at VAT (displayed as natural 
logarithms of mL/min and mL/kg/min) is summarized in Table 16.  


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Table 16: 
Change in the Natural Logarithm of VO2 at VAT Between Week 26 
and Baseline Visits Using Last Observation Carried Forward (ITT 
Population) 
 
Udenafil 
(N=200) 
Placebo 
(N=200) 
Difference  
LS Mean (SE) 
p-value 
VO2 at VAT (natural logarithm of mL/min) 
Baseline 
n=170 
n=181 
 
 
Mean (SD) 
6.91 (0.280) 
6.89 (0.262) 
0.01 (0.029) 
0.629a 
Week 26 
n=185 
n=191 
 
 
Mean (SD) 
6.93 (0.267) 
6.88 (0.322) 
0.06 (0.032) 
0.054a 
Difference, Week 26 minus baseline  
n=170 
n=181 
 
 
Mean (SD) 
0.03 (0.168) 
-0.02 (0.252) 
0.05 (0.022) 
0.024b 
Median  
0.02 
0.00 
 
 
VO2 at VAT (natural logarithm of mL/kg/min) 
Baseline 
n=170 
n=181 
 
 
Mean (SD) 
2.88 (0.249) 
2.85 (0.241) 
0.03 (0.026) 
0.203a 
Week 26 
n=185 
n=191 
 
 
Mean (SD) 
2.87 (0.249) 
2.80 (0.308) 
0.08 (0.030) 
0.013a 
Difference, Week 26 minus baseline  
n=170 
n=181 
 
 
Mean (SD) 
0.00 (0.170) 
-0.05 (0.253) 
0.05 (0.023) 
0.029b 
Median  
0.00 
-0.02 
 
 
ANCOVA=analysis of covariance; ANOVA=analysis of variance; ITT=intent-to-treat; LS=least squares; SD=standard 
deviation; SE=standard error; VAT=ventilatory anaerobic threshold; VO2=minute oxygen consumption 
a P-value was assessed using ANOVA with fixed factors for ventricular morphology (single left versus single right or 
mixed) and treatment group. 
b P-value was assessed using ANCOVA with fixed factors for ventricular morphology (single left versus single right 
or mixed) and treatment group with a continuous covariate of baseline maximal VO2. 
Note: Values are summarized as natural logarithm of maximal VO2 at VAT.  
Source: Table 14.2.3.2.1 and Table 14.2.4.2.1 
Program: T_14_2_3_2_1.sas and T_14_2_4_2_1.sas 
 
Results for treatment group differences in change of the natural logarithm for VO2 at VAT 
from baseline using units of mL/min were generally similar for analyses using no imputation 
(p=0.015, Table 14.2.3.2.2), imputation with the mean of non-missing values at Week 26 
(p=0.005, Table 14.2.3.2.3), imputation with linear regression (p=0.005, Table 14.2.3.2.4), 
and LOCF for Per Protocol population (p=0.028, Table 14.2.3.2.5). 
Results for treatment group differences in change of the natural logarithm for VO2 at VAT 
from baseline using units of mL/kg/min were generally similar for analyses using no 
imputation (p=0.026, Table 14.2.4.2.2), imputation with the mean of non-missing values at 


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Week 26 (p=0.024, Table 14.2.4.2.3), imputation using linear regression (p=0.013, Table 
14.2.4.2.4), and LOCF for Per Protocol population (p=0.038, Table 14.2.4.2.5). 
11.4.1.4 
Secondary Efficacy Endpoints 
11.4.1.4.1 
Secondary Efficacy Endpoints Measured at Ventilatory 
Anaerobic Threshold 
The 2 secondary efficacy endpoints measured at VAT indicated greater exercise capacity in 
the udenafil group than the placebo group at Week 26: 
• VE/VCO2 at VAT: Greater mean decrease (improvement) for udenafil (-0.76) as 
compared to placebo (-0.05) at Week 26 (p=0.011) 
• Work rate at VAT: Greater mean increase (improvement) for udenafil (3.46 watts) as 
compared to placebo (0.31 watts) at Week 26 (p=0.029) 
Change in secondary exercise endpoints measured at VAT from baseline to Week 26 are 
summarized in Table 17. 


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Table 17: 
Difference in Secondary Exercise Endpoints Measured at Ventilatory 
Anaerobic Threshold Between Week 26 and Baseline Visits Using 
Last Observation Carried Forward (ITT Population) 
Exercise Endpoint 
Udenafil 
(N=200) 
Placebo 
(N=200) 
Difference  
LS Mean (SE) 
p-value 
VE/VCO2 at VAT 
 
 
 
 
Baseline 
n=170 
n=181 
 
 
Mean (SD) 
34.32 (4.845) 34.75 (5.157) 
-0.42 (0.536) 
0.431a 
Week 26 
n=185 
n=191 
 
 
Mean (SD) 
33.60 (4.833) 34.67 (4.872) 
-1.13 (0.509) 
0.027a 
Difference, Week 26 – baseline 
n=170 
n=181 
 
 
Mean (SD) 
-0.76 (3.564) 
-0.05 (2.967) 
-0.82 (0.321) 
0.011b 
Median 
0.00 
0.00 
 
 
Work rate at VAT (watts) 
 
 
 
 
Baseline 
n=167 
n=177 
 
 
Mean (SD) 
66.19 (26.321) 66.10 (23.446) 
0.12 (2.688) 
0.963a 
Week 26 
n=181 
n=186 
 
 
Mean (SD) 
69.20 (26.171) 66.62 (22.710) 
3.30 (2.660) 
0.215a 
Difference, Week 26 – baseline 
n=167 
n=177 
 
 
Mean (SD) 
3.46 (15.076) 0.31 (13.246) 
3.20 (1.460) 
0.029b 
Median 
1.00 
0.00 
 
 
ANCOVA=analysis of covariance; ANOVA=analysis of variance; ITT=intent-to-treat; LS=least squares; SD=standard 
deviation; SE=standard error; VAT=ventilatory anaerobic threshold; VE/VCO2=ventilatory equivalents of carbon 
dioxide; VO2=minute oxygen consumption 
a P-value was assessed using ANOVA with fixed factors for ventricular morphology (single left versus single right or 
mixed) and treatment group. 
b P-value was assessed using ANCOVA with fixed factors for ventricular morphology (single left versus single right 
or mixed) and treatment group with a continuous covariate of baseline maximal VO2. 
Source: Table 14.2.13.1.1 and Table 14.2.14.1.1 
Program: T_14_2_13_1_1.sas and T_14_2_14_1_1.sas 
 
Results for treatment group differences in change from baseline for VE/VCO2 at VAT were 
generally similar for analyses using no imputation (p=0.014, Table 14.2.13.1.2) and 
imputation with the mean of non-missing values at Week 26 (p=0.044, Table 14.2.13.1.3). 
Results for treatment group differences in percent change from baseline for VE/VCO2 at VAT 
were generally similar for analyses using LOCF (p=0.008, Table 14.2.13.2.1), no imputation 
(p=0.010, Table 14.2.13.2.2), and imputation with the mean of non-missing values at 
Week 26 (p=0.035, Table 14.2.13.2.3). 
Results for treatment group differences in change from baseline for work rate at VAT were 
generally similar for analyses using no imputation (p=0.021, Table 14.2.14.1.2) and 
imputation with the mean of non-missing values at Week 26 (p=0.011, Table 14.2.14.1.3). 
Results for treatment group differences in percent change from baseline for work rate at VAT 


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were generally similar for analyses using LOCF (p=0.053, Table 14.2.14.2.1), no imputation 
(p=0.035, Table 14.2.14.2.2), and imputation with the mean of non-missing values at 
Week 26 (p=0.030, Table 14.2.14.2.3). 
11.4.1.4.2 
Secondary Efficacy Endpoints Measured at Peak Exercise 
The treatment group difference for change from baseline to Week 26 in VE/VCO2 at peak 
exercise was statistically significant (p=0.005). A mean decrease of -1.24 was observed in the 
udenafil group as compared to a mean increase of 0.04 in the placebo group. For other 
efficacy endpoints measured at peak exercise (minute VO2, respiratory rate, minute 
ventilation, work rate, heart rate, and RER), treatment group differences for change from 
baseline to Week 26 did not achieve p≤0.05. The change in secondary efficacy endpoints 
measured at peak exercise from baseline to Week 26 is summarized in Table 18. 


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Table 18: 
Change in Secondary Efficacy Endpoints Measured at Peak Exercise 
Between Week 26 and Baseline Visits Using Last Observation Carried 
Forward (ITT Population) 
Exercise Endpoint 
Udenafil 
(N=200) 
Placebo 
(N=200) 
Difference  
LS Mean (SE) p-valuea 
Minute VO2 (L/minute) 
n=200 
n=200 
 
 
Difference, Week 26 – baseline, mean (SD) 
0.04 (0.238) 
0.00 (0.222) 
0.04 (0.023) 
0.071 
Respiratory rate (breaths/minute) 
n=199 
n=200 
 
 
Difference, Week 26 – baseline, mean (SD) 
-1.01 (10.030) -1.44 (9.928) 
0.35 (0.903) 
0.696 
Minute ventilation (L/minute) 
n=199 
n=200 
 
 
Difference, Week 26 – baseline, mean (SD) 
1.15 (13.934) -0.10 (13.748) 0.14 (1.319) 
0.915 
Work rate (watts)  
n=198 
n=199 
 
 
Difference, Week 26 – baseline, mean (SD) 
2.99 (14.334) 2.45 (13.503) 
0.19 (1.363) 
0.891 
Heart rate (beats/minute) 
n=200 
n=200 
 
 
Difference, Week 26 – baseline, mean (SD) 
-1.36 (10.773) -2.41 (12.714) 0.66 (1.140) 
0.563 
Respiratory exchange ratio  
n=200 
n=200 
 
 
Difference, Week 26 – baseline, mean (SD) 
0.02 (0.117) 
0.01 (0.073) 
0.01 (0.008) 
0.275 
VE/VCO2  
n=199 
n=200 
 
 
Difference, Week 26 – baseline, mean (SD) 
-1.24 (5.181) 
0.04 (6.092) 
-1.46 (0.519) 
0.005 
ANCOVA=analysis of covariance; ITT=intent-to-treat; LS=least squares; SD=standard deviation; SE=standard error; 
VE/VCO2=ventilatory equivalents of carbon dioxide; VO2=minute oxygen consumption 
a P-value was assessed using ANCOVA with fixed factors for ventricular morphology (single left versus single right 
or mixed) and treatment group with a continuous covariate of baseline maximal VO2. 
Source: Table 14.2.5.1.1, Table 14.2.7.1.1, Table 14.2.8.1.1, Table 14.2.9.1.1, Table 14.2.10.1.1, Table 14.2.11.1.1, 
and Table 14.2.12.1.1  
Program: T_14_2_5_1_1.sas, T_14_2_7_1_1.sas, T_14_2_8_1_1.sas, T_14_2_9_1_1.sas, T_14_2_10_1_1.sas, 
T_14_2_11_1_1.sas, and T_14_2_12_1_1.sas 
 


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Results based on LOCF, no imputation (observed cases), and imputation with the mean of 
non-missing values at Week 26 are presented for each measure at peak exercise as shown 
below. 
 
LOCF 
Observed Cases 
Week 26 Mean 
Measure at Peak Exercise 
Change 
% Change 
Change 
% Change 
Change 
% Change 
Minute VO2  
14.2.5.1.1 
14.2.5.2.1 
14.2.5.1.2 
14.2.5.2.2 
14.2.5.1.3 
14.2.5.2.3 
Respiratory rate 
14.2.7.1.1 
14.2.7.2.1 
14.2.7.1.2 
14.2.7.2.2 
14.2.7.1.3 
14.2.7.2.3 
Minute ventilation 
14.2.8.1.1 
14.2.8.2.1 
14.2.8.1.2 
14.2.8.2.2 
14.2.8.1.3 
14.2.8.2.3 
Work rate 
14.2.9.1.1 
14.2.9.2.1 
14.2.9.1.2 
14.2.9.2.2 
14.2.9.1.3 
14.2.9.2.3 
Heart rate 
14.2.10.1.1 14.2.10.2.1 14.2.10.1.2 14.2.10.2.2 14.2.10.1.3 14.2.10.2.3 
Respiratory exchange ratio 
14.2.11.1.1 14.2.11.2.1 14.2.11.1.2 14.2.11.2.2 14.2.11.1.3 14.2.11.2.3 
VE/VCO2 
14.2.12.1.1 14.2.12.2.1 14.2.12.1.2 14.2.12.2.2 14.2.12.1.3 14.2.12.2.3 
LOCF=last observation carried forward; VE/VCO2=ventilatory equivalents of carbon dioxide; VO2=minute oxygen 
consumption 
 
11.4.1.4.3 
Other Secondary Efficacy Endpoints 
A decrease in MPI (improvement in function) from baseline to Week 26 was observed in the 
udenafil group (-0.02) as compared to an increase in the placebo group (0.01). The least 
squares mean treatment difference for change in MPI from baseline to Week 26 was -0.03 
(p=0.024). Change in MPI from baseline to Week 26 is summarized in Table 19. 
Treatment group differences for the remaining ECHO endpoints did not achieve p≤0.05 
(Table 14.2.15.1, Table 14.2.15.2, Table 14.2.15.3, Table 14.2.15.4, Table 14.2.15.5, 
Table 14.2.15.6, Table 14.2.15.7, Table 14.2.15.8, Table 14.2.15.9, Table 14.2.15.10, and 
Table 14.2.15.11). Results for individual subjects are presented in Listing 16.2.6.2.1, 
Listing 16.2.6.2.2.1, and Listing 16.2.6.2.2.2. 


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Table 19: 
Change in Myocardial Performance Index Between Week 26 and 
Baseline Visits (ITT Population) 
 
Udenafil 
(N=200) 
Placebo 
(N=200) 
Difference  
LS Mean (SE) p-value 
Baseline  
n=150 
n=155 
 
 
Mean (SD) 
0.45 (0.172) 
0.45 (0.154) 
-0.00 (0.018) 
0.925a 
Week 26 
n=146 
n=147 
 
 
Mean (SD) 
0.42 (0.147) 
0.46 (0.177) 
-0.04 (0.019) 
0.022a 
Difference, Week 26 – baseline 
n=122 
n=127 
 
 
Mean (SD) 
-0.02 (0.112) 
0.01 (0.132) 
-0.03 (0.014) 
0.024b 
Median 
-0.01 
0.01 
 
 
ANCOVA=analysis of covariance; ANOVA=analysis of variance; ITT=intent-to-treat; LS=least squares; SD=standard 
deviation; SE=standard error 
a P-value was assessed using ANOVA with fixed factors for ventricular morphology (single left versus single right or 
mixed) and treatment group. 
b P-value was assessed using ANCOVA with fixed factors for ventricular morphology (single left versus single right 
or mixed) and treatment group with a continuous covariate of baseline maximal minute oxygen consumption. 
Note: No imputation was performed. 
Source: Table 14.2.15 
Program: T_14_2_15.sas 
 
The increase in log-transformed reactive hyperemia index from baseline to Week 26 was 
larger in the udenafil group (0.06) than in the placebo group (0.04). The least squares mean 
treatment difference for change in log-transformed reactive hyperemia index from baseline to 
Week 26 was 0.02 (p=0.410).  
The increase in log-transformed BNP from baseline to Week 26 was larger in the udenafil 
group (0.08 pg/mL) than in the placebo group (0.03 pg/mL). The least squares mean 
treatment difference for change in log-transformed BNP from baseline to Week 26 was 
0.13 pg/mL (p=0.169). 
The change in log-transformed reactive hyperemia index and BNP from baseline to Week 26 
is summarized in Table 20. Results for individual subjects are presented in Listing 16.2.6.2.3 
for BNP and in Listing 16.2.6.2.4 for log-transformed reactive hyperemia index. 


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Table 20: 
Change in Endothelial Function and Brain Natriuretic Peptide 
Between Week 26 and Baseline Visits (ITT Population) 
Endpoint 
Udenafil 
(N=200) 
Placebo 
(N=200) 
Difference  
LS Mean (SE) p-valuea 
Log-transformed reactive hyperemia index 
n=175 
n=184 
 
 
Difference, Week 26 – baseline, mean (SD) 
0.06 (0.301) 0.04 (0.364) 
0.02 (0.029) 
0.410 
Log-transformed brain natriuretic peptide (pg/mL) 
n=187 
n=191 
 
 
Difference, Week 26 – baseline, mean (SD) 
0.08 (0.905) 0.03 (1.137) 
0.13 (0.094) 
0.169 
ANCOVA=analysis of covariance; ITT=intent-to-treat; LS=least squares; SD=standard deviation; SE=standard error 
a P-value was assessed using ANCOVA with fixed factors for ventricular morphology (single left versus single right 
or mixed) and treatment group with a continuous covariate of baseline maximal minute oxygen consumption. 
Note: Brain natriuretic peptide values reported by the laboratory as <2.0 were imputed as 1.0. 
Source: Table 14.2.16 and Table 14.2.17 
Program: T_14_2_16.sas and T_14_2_17.sas 
 
Change in PedsQL child-reported and parent-reported scale scores from baseline to Week 26 
were generally small; no treatment group difference achieved p≤0.05 (Table 21). Results for 
individual subjects are presented in Listing 16.2.6.3.1, Listing 16.2.6.3.2, Listing 16.2.6.3.3, 
and Listing 16.2.6.3.4. 


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Table 21: 
Difference in Pediatric Quality of Life Inventory Endpoints Between 
Week 26 and Baseline Visits (ITT Population) 
 
Udenafil 
(N=200) 
Placebo 
(N=200) 
LS Mean 
Difference 
(SE) 
p-valuea 
PedsQL Generic Core Scales 
 
 
 
 
Physical functioning (child-reported) 
n=186 
n=193 
 
 
Difference, Week 26 – baseline, mean (SD)  
2.08 (12.006) 1.53 (11.823) 
0.44 (1.100) 
0.691 
Physical functioning (parent-reported) 
n=181 
n=181 
 
 
Difference, Week 26 – baseline, mean (SD)  
2.74 (18.011) 1.94 (15.328) 
0.03 (1.544) 
0.985 
Psychosocial health summary score 
(child-reported) 
n=185 
n=193 
 
 
Difference, Week 26 – baseline, mean (SD)  
2.84 (11.356) 1.74 (10.700) 
1.14 (1.039) 
0.273 
Psychosocial health summary score 
(parent-reported) 
n=181 
n=181 
 
 
Difference, Week 26 – baseline, mean (SD) 
2.64 (13.546) 2.15 (13.737) -0.06 (1.327) 
0.966 
PedsQL Cardiac Module Scales 
Treatment II (child-reported) 
n=164 
n=173 
 
 
Difference, Week 26 – baseline, mean (SD)  
0.24 (11.655) -0.09 (9.046) -0.38 (1.011) 
0.706 
Perceived physical appearance 
n=184 
n=192 
 
 
Difference, Week 26 – baseline, mean (SD)  
2.45 (20.819) 0.78 (17.396) 
1.50 (1.707) 
0.382 
Treatment anxiety 
n=184 
n=192 
 
 
Difference, Week 26 – baseline, mean (SD)  
3.37 (19.258) 1.66 (16.477) 
1.91 (1.611) 
0.236 
Cognitive problems 
n=183 
n=192 
 
 
Difference, Week 26 – baseline, mean (SD)  
2.19 (16.826) 3.05 (17.027) -0.99 (1.622) 
0.543 
Communication problems 
n=183 
n=192 
 
 
Difference, Week 26 – baseline, mean (SD)  
1.82 (20.406) 4.36 (17.954) -1.66 (1.780) 
0.352 
ANCOVA=analysis of covariance; ITT=intent-to-treat; LS=least squares; PedsQL=Pediatric Quality of Life 
Inventory; SD=standard deviation; SE=standard error 
a P-value was assessed using ANCOVA with fixed factors for ventricular morphology (single left versus single right 
or mixed) and treatment group with a continuous covariate of baseline value. 
Source: Table 14.2.18.1, Table 14.2.18.2, Table 14.2.18.3, Table 14.2.18.4, Table 14.2.18.5, Table 14.2.18.6, 
Table 14.2.18.7, Table 14.2.18.8, and Table 14.2.18.9 
Program: 14_2_18.sas 
 
Mean treatment group differences in change from baseline to Week 26 in PCQLI 
child-reported and parent-reported total scores were generally small; no treatment group 


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difference achieved p≤0.05 (Table 22). Results for individual subjects are presented in 
Listing 16.2.6.4.1 and Listing 16.2.6.4.2. 
Table 22: 
Difference in Pediatric Cardiac Quality of Life Inventory Endpoints 
Between Week 26 and Baseline Visits (ITT Population) 
PCQLI Score 
Udenafil 
(N=200) 
Placebo 
(N=200) 
LS Mean 
Difference (SE) p-valuea 
Total score for 8-12 (child-reported) 
n=16 
n=12 
 
 
Difference, Week 26 – baseline, mean (SD)  3.26 (12.287) -2.37 (16.368) 
3.59 (5.684) 
0.533 
Total score for 8-12 (parent-reported) 
n=17 
n=11 
 
 
Difference, Week 26 – baseline, mean (SD)  -0.91 (13.399) -4.44 (6.389) 
1.84 (4.057) 
0.654 
Total score for 13-18 (child-reported) 
n=158 
n=170 
 
 
Difference, Week 26 – baseline, mean (SD)  -0.08 (11.032) 0.09 (9.626) 
-0.05 (1.069) 
0.963 
Total score for 13-18 (parent-reported) 
n=152 
n=162 
 
 
Difference, Week 26 – baseline, mean (SD) 
0.36 (11.722) -1.60 (11.179) 
1.36 (1.171) 
0.246 
ANCOVA=analysis of covariance; ITT=intent-to-treat; LS=least squares; PCQLI=Pediatric Cardiac Quality of Life 
Inventory; SD=standard deviation; SE=standard error 
a P-value was assessed using ANCOVA with fixed factors for ventricular morphology (single left versus single right 
or mixed) and treatment group with a continuous covariate of baseline value. 
Source: Table 14.2.19.1, Table 14.2.19.2, Table 14.2.19.3, and Table 14.2.19.4 
Program: 14_2_19.sas 
 
11.4.2 
Statistical/Analytical Issues 
11.4.2.1 
Adjustments for Covariates 
The primary efficacy endpoint (aerobic exercise performance) and some of the secondary 
efficacy endpoints were analyzed with an ANCOVA model with fixed factors for ventricular 
morphology and treatment groups with a covariate of the relevant baseline value. 
11.4.2.2 
Handling of Dropouts or Missing Data 
The following imputation method was used for the primary analysis of the primary outcome:  
• Subjects who died or dropped out of the study with unknown vital status were to be 
assigned a maximal VO2 of zero at Week 26. No subject met this criterion. 
• Subjects who were known to be alive, but who discontinued from the study (and were 
missing maximal VO2 at Week 26) were assigned the latest value available. 


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• Subjects who completed Week 26 but were physically unable to reach maximum 
effort in cardiopulmonary exercise testing after 2 attempts, were assigned their 
baseline value (ie, zero change). 
Two additional sensitivity analyses to assess the impact of missing data were conducted as 
follows: 
• Subjects with missing maximal VO2 at Week 26 were assigned a maximal VO2 of 
zero.  
• Subjects with missing maximal VO2 at Week 26 were excluded from analysis (ie, 
observed cases analysis). 
An additional imputation method for missing data was included for exercise variables. When 
the Week 26 value was missing, the mean of non-missing Week 26 values (ignoring treatment 
group) was imputed. 
For VO2 at VAT, a linear regression model was used to predict Week 26 VO2 at VAT from 
Week 26 maximal VO2. The predicted value from the model was used to impute VO2 at VAT 
when maximal VO2 was available; when maximal VO2 was also missing, the average from 
all subjects with non-missing values was imputed. 
Missing item scores for rating scales were imputed according to published methodology for 
the scale. Otherwise, missing data were not estimated for secondary efficacy endpoints. 
11.4.2.3 
Interim Analyses and Data Monitoring 
The PHN DSMB convened at least twice per year to review safety data. In addition, the 
DSMB was asked to review all data after the first 50 subjects had completed the study. 
Formal stopping boundaries were not proposed for the 26-week study. However, the DSMB 
could have recommended stopping the study for other reasons, such as safety findings from 
this study and other studies or concerns about study conduct. In addition, premature 
termination of this study could have occurred due to the impact of results released from other 
studies, due to failure to enroll, or due to withdrawal of study approval by clinical site IRBs. 
In addition, the NHLBI retained the right to discontinue the study prior to the inclusion of the 
intended number of subjects but intended to exercise these rights only for valid scientific or 
administrative reasons. 


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After primary outcome data were obtained for approximately half of the originally planned 
sample size (approximately N=200 subjects), the variance of the primary outcome was 
estimated using a blinded method with lumped variance. If this estimated variance was higher 
than the one used for the sample size calculations, then the sample size would have been 
recalculated and increased correspondingly. Otherwise, the sample size would not change, 
and the study would proceed as planned. This approach was based on blinded re-estimation 
of nuisance parameters and did not lead to inflation of type I error. It was consistent with the 
regulatory guidance for industry in adaptive design of clinical studies.  
The estimated variance at the interim analysis did not require an increase in sample size. 
11.4.2.4 
Multicenter Studies 
The study was conducted at 30 sites. Change in maximal VO2 is summarized by site in 
Table 14.2.1.2.5 using units of mL/min and in Table 14.2.2.2.5 using units of mL/kg/min. 
Change in VO2 at VAT is summarized by site in Table 14.2.3.2.6 using units of mL/min and 
in Table 14.2.4.2.6 using units of mL/kg/min. 
11.4.2.5 
Multiple Comparison/Multiplicity 
Formal hypothesis testing was performed only for the primary efficacy endpoint. No 
adjustment for multiple comparisons was made for secondary efficacy endpoints. 
11.4.2.6 
Use of an "Efficacy Subset" of Subjects 
The primary efficacy analysis was performed with the ITT population, which included all 
randomized subjects and was the primary population for efficacy analyses. Sensitivity 
analyses were performed for the Per Protocol population (Table 14.2.1.1.4, Table 14.2.1.2.4, 
Table 14.2.2.1.4, and Table 14.2.2.2.4), which included all treated subjects who met all entry 
criteria or, if criteria were not met, were granted a waiver by the Sponsor; subjects with major 
protocol deviations were excluded. 
11.4.2.7 
Active-Control Studies Intended to Show Equivalence 
An active control was not used in this study. 


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11.4.2.8 
Examination of Subgroups 
The treatment group difference (udenafil minus placebo) for change in maximal VO2 from 
baseline to Week 26 was positive for most subgroups (Figure 2). Positive differences indicate 
greater mean improvement from baseline for udenafil than for placebo. 
Treatment group differences are also presented in mL/min without imputation by gender 
(Table 14.2.1.1.2.1), race (Table 14.2.1.1.2.2), ethnicity (Table 14.2.1.1.2.3), ventricular 
morphology (Table 14.2.1.1.2.4), age at Fontan surgery (Table 14.2.1.1.2.5), baseline serum 
BNP (Table 14.2.1.1.2.6), percent predicted maximal VO2 at baseline (Table 14.2.1.1.2.7), 
and use of afterload reducing agents (Table 14.2.1.1.2.8).  


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Figure 2: 
Treatment Group Difference in Mean Maximal VO2 (mL/min) 
With 95% Confidence Interval for Change Between Week 26 and 
Baseline Visits in Subpopulations Using Last Observation Carried 
Forward (ITT Population) 
 
%p=percent predicted; BNP=brain natriuretic peptide; ITT=intent-to-treat; VO2=minute oxygen consumption; yrs=years 
Note: No imputation was performed. 
Source: Figure 14.2.1.1.6 
Program: f_forestplot 
The treatment group difference (udenafil minus placebo) for change in maximal VO2 
(mL/kg/min) from baseline to Week 26 was positive for most subgroups (Figure 3). Positive 
differences indicate less mean deterioration from baseline for udenafil than for placebo. 
Treatment group differences are also presented in mL/kg/min without imputation by gender 
(Table 14.2.2.1.2.1), race (Table 14.2.2.1.2.2), ethnicity (Table 14.2.2.1.2.3), ventricular 
morphology (Table 14.2.2.1.2.4), age at Fontan surgery (Table 14.2.2.1.2.5), baseline serum 


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BNP (Table 14.2.2.1.2.6), percent predicted maximal VO2 at baseline (Table 14.2.2.1.2.7), 
and use of afterload reducing agents (Table 14.2.2.1.2.8). 
Figure 3: 
Treatment Group Difference in Mean Maximal VO2 (mL/kg/min) 
With 95% Confidence Interval for Change Between Week 26 and 
Baseline Visits in Subpopulations Using Last Observation Carried 
Forward (ITT Population) 
 
%p=percent predicted; BNP=brain natriuretic peptide; ITT=intent-to-treat; VO2=minute oxygen consumption; yrs=years 
Note: No imputation was performed. 
Source: Figure 14.2.1.1.7 
Program: f_forestplot 
 
The treatment group difference (udenafil minus placebo) for change in VO2 at VAT (mL/min) 
from baseline to Week 26 was positive for all subgroups (Figure 4). Positive differences 
indicate greater mean improvement from baseline for udenafil than for placebo. 


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Treatment group differences are also presented in mL/min without imputation by gender 
(Table 14.2.3.1.2.1), race (Table 14.2.3.1.2.2), ethnicity (Table 14.2.3.1.2.3), ventricular 
morphology (Table 14.2.3.1.2.4), age at Fontan surgery (Table 14.2.3.1.2.5), baseline serum 
BNP (Table 14.2.3.1.2.6), percent of predicted maximal VO2 at baseline (Table 14.2.3.1.2.7), 
and use of afterload reducing agents (Table 14.2.3.1.2.8).  
Figure 4: 
Treatment Group Difference in Mean VO2 (mL/min) at VAT With 
95% Confidence Interval for Change Between Week 26 and 
Baseline Visits in Subpopulations Using Last Observation Carried 
Forward (ITT Population) 
 
%p=percent predicted; BNP=brain natriuretic peptide; ITT=intent-to-treat; VAT=ventilatory anaerobic threshold; 
VO2=minute oxygen consumption; yrs=years 
Note: No imputation was performed. Subjects with unknown race and ethnicity were excluded from the respective analysis. 
Source: Figure 14.2.2.1.6 
Program: f_forestplot 
 


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The treatment group difference (udenafil minus placebo) for change in VO2 at VAT 
(mL/kg/min) from baseline to Week 26 was positive for all subgroups (Figure 5). Positive 
differences indicate less mean deterioration from baseline for udenafil than for placebo. 
Figure 5: 
Treatment Group Difference in Mean VO2 (mL/kg/min) at VAT 
With 95% Confidence Interval for Change Between Week 26 and 
Baseline Visits in Subpopulations Using Last Observation Carried 
Forward (ITT Population) 
 
%p=percent predicted; BNP=brain natriuretic peptide; ITT=intent-to-treat; VAT=ventilatory anaerobic threshold; 
VO2=minute oxygen consumption; yrs=years 
Note: No imputation was performed. Subjects with unknown race and ethnicity were excluded from the respective analysis. 
Source: Figure 14.2.2.1.7 
Program: f_forestplot 
 


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11.4.3 
Tabulation of Individual Response Data 
Tabulations of individual response data are found in Appendix 16.2. 
11.4.4 
Drug Dose, Drug Concentration, and Relationships to 
Response 
Drug dose and drug concentration relationships to response were not assessed. 
11.4.5 
Drug-Drug and Drug-Disease Interactions 
Drug-drug and drug-disease interactions were not assessed. 
11.4.6 
By-Subject Displays 
There were no by-subject displays of individual response to study drug except as provided in 
the data listings (Appendix 16.2). 
11.4.7 
Efficacy Conclusions 
Key Efficacy Findings 
The primary aim of this study was to evaluate the effect of 26 weeks of treatment with 
udenafil on exercise capacity in adolescents with Fontan physiology. The protocol-specified 
primary exercise outcome was change in maximal VO2 and secondary exercise outcomes 
included change in VO2 at VAT, change in ventilatory efficiency at VAT, and work rate at 
VAT. All exercise measures demonstrated a favorable outcome for udenafil relative to 
placebo. 
For maximal VO2, the udenafil group had a mean increase from baseline to Week 26 
compared to a mean decrease in the placebo group (44.40 mL/min versus -3.65 mL/min; 
p=0.071). When standardized by each subject’s body weight, the least squares mean 
treatment group difference was 0.64 mL/kg/min (p=0.092).  


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The following secondary efficacy endpoints measured at VAT also indicated greater exercise 
capacity in the udenafil group than the placebo group at Week 26: 
• VO2 at VAT: Mean increase (improvement) for udenafil as compared to a mean 
decrease in the placebo group (29.65 mL/min versus -8.01 mL/min; p=0.023). When 
standardized by each subject’s body weight, the least squares mean treatment group 
difference was 0.78 mL/kg/min (p=0.012). 
• VE/VCO2 at VAT: Greater mean decrease (improvement) for udenafil as compared to 
placebo (-0.76 versus -0.05; p=0.011). 
• Work rate at VAT: Greater mean increase (improvement) for udenafil as compared to 
placebo (3.46 watts versus 0.31 watts; p=0.029). 
An additional efficacy aim evaluated the effect of 26 weeks of treatment with udenafil on the 
performance of a single ventricle. The primary measure of ventricular performance was 
change in MPI, which indicated improvement with udenafil versus placebo (-0.02 vs 0.01; 
p=0.024).  
Relative Utility of Maximal VO2 Versus VO2 at VAT 
The protocol-specified primary endpoint of maximal VO2 measures overall aerobic capacity 
and has been shown to be useful as a predictor of cardiac death and hospitalization for heart 
failure, both in congenital and acquired heart disease. Given the relative ease of obtaining this 
measure and its utility as a surrogate outcome, maximal VO2 has been chosen as an endpoint 
in multiple observational studies and clinical trials. In view of the above, and to be consistent 
with generally accepted understanding in the pediatric cardiology community, maximal VO2 
was chosen as the primary endpoint for the FUEL trial. An alternative exercise measure, VO2 
at VAT, was also considered during the initial study design, but was designated as a secondary 
endpoint for 2 reasons: 1) There were more limited relevant data from prior studies to allow 
for a robust power calculation, and 2) VO2 at VAT is more difficult to measure precisely, 
which could lead to data loss and impact statistical power in this rare pediatric disease. The 
concern about data loss was confirmed in the FUEL trial in which 21% of participants did not 
have paired data VO2 at VAT (Table 14.2.3.1.2) versus 5% for maximal VO2 
(Table 14.2.1.1.2). 
Despite its utility in most forms of heart disease, recent publications suggest that maximal 
VO2 may not be an ideal efficacy measure for interventions in Fontan physiology, particularly 
for therapies that would improve exercise performance by modification of the PVR. During 


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exercise, there is a substantial increase in metabolic demand for oxygen delivery and, 
therefore, cardiac output. In the absence of a sub-pulmonary pump, preload is maintained by 
the pressure gradient across the pulmonary vascular bed; the difference between CVP and 
atrial pressure. As exercise intensity increases, CVP must rise to allow for increased 
transpulmonary blood flow (Qp). Udenafil may modulate this relationship by lowering PVR 
and therefore allowing for a lower CVP for any given amount of Qp. However, as exercise 
intensity increases, modification of PVR alone may not be sufficient to allow for the needed 
increase in cardiac output. Even with optimal pulmonary vasodilation, an increase in CVP is 
required to provide adequate Qp to keep up with metabolic demand. At the highest levels of 
exertion, one begins to exceed the physiologic limit of maximal CVP. This physiologic limit, 
or ceiling, is that point at which exercise is limited by an inability to raise CVP any further. 
In a person with a structurally normal heart, there is no physiologic ceiling during exercise 
related to venous pressure. CVP, which starts at 5 to 7 mmHg, is unchanged during exercise 
as pulmonary blood flow is driven by the sub-pulmonary right ventricle. In a person who has 
undergone Fontan palliation and does not have a sub-pulmonary ventricle, CVP starts out 
much higher (12 to 15 mmHg) and then increases dramatically with exercise. This high 
pressure cannot be sustained beyond the physiologic ceiling and results in limited ability to 
maintain ventricular preload and increase cardiac output at higher levels of aerobic exertion. 
Thus, while pulmonary vasodilators may improve exercise capacity at moderate levels of 
activity, there is a physiologic limit to their ability to impact performance at levels of exertion 
approaching the physiologic ceiling. Studies published since the inception of the FUEL trial 
highlight these unique physiological limitations in the Fontan circulation and point away 
from the selection of maximal VO2 as an endpoint for this specific type of congenital heart 
disease (Goldberg 2021; Navaratnam 2016).  
As a consequence of the physiologic limitations associated with Fontan palliation, therapies 
designed to improve aerobic capacity by decreasing PVR will have their greatest impact at 
lower levels of aerobic activity and thus lower levels of CVP. VO2 at VAT is a measure of 
submaximal exercise that represents the physiologic point at which the metabolic demands of 
the exercising muscles begin to outstrip the ability of the cardiovascular system to deliver 
adequate amounts of oxygen to meet those demands. While VO2 at VAT is more technically 
difficult to measure than peak VO2, it has the same association with important morbidities 
and mortality as maximal VO2 (Gitt 2002; Malhotra 2016; Tsai 2018). Given the unique 
features of the Fontan circulation, VO2 at VAT, despite the challenges associated with data 
acquisition, is more robust as a surrogate endpoint for this population than maximal VO2. 
Given the lack of understanding in the field of this unique physiology at the time of 
conception of the FUEL trial, the power analysis for maximal VO2 was predicated on the 


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impact of alterations in PVR on exercise capacity for those with other forms of heart disease. 
Although udenafil may have some effect on maximal VO2, this effect is blunted by the 
physiologic ceiling of CVP. The expanded understanding of Fontan physiology in recent 
years has taught that the assumptions informing the selection of maximal VO2 as the primary 
endpoint were inaccurate, and that VO2 at VAT is a more useful endpoint for this unique 
cohort of patients. 
Overall Efficacy Conclusions 
In summary, treatment with udenafil for 26 weeks resulted in improvements in exercise 
capacity, as well as an improvement in the performance of the single ventricle. Although the 
primary endpoint did not reach statistical significance, new knowledge of the limits of the 
Fontan circulation explains why this endpoint is an imperfect choice for this circulation. Even 
with the limitations associated with maximal VO2, this endpoint showed a clear trend toward 
improvement that, coupled with the improvement at the anaerobic threshold, speaks to the 
efficacy of udenafil to improve exercise capacity in this population. Based on the superior 
exercise capacity and ventricular performance for udenafil as compared to placebo at 
Week 26, this study achieved its primary clinical objective for a population with no 
pharmacotherapeutic options.  
12 
Safety Evaluation 
12.1 
Extent of Exposure 
The mean number of days from first to last dose was 179.8 days in the udenafil group and 
182.7 days in the placebo group (Table 23). Mean percent compliance with study drug was 
89.92% in the udenafil group and 89.97% in the placebo group. Compliance results are listed 
by subject in Listing 16.2.5.1. 


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Table 23: 
Extent of Exposure and Compliance with Study Drug (Safety 
Population) 
 
Udenafil 
(N=200) 
Placebo 
(N=200) 
Total 
(N=400) 
Number of days from first to last dose 
(N=200) 
(N=200) 
(N=400) 
Mean (SD) 
179.8 (32.23) 
182.7 (26.78) 
181.3 (29.63) 
Median 
183.0 
183.0 
183.0 
Minimum, maximum  
5, 344 
8, 280 
5, 344 
Percent compliance (%) 
(N=174) 
(N=185) 
(N=359) 
Mean (SD) 
89.92 (10.283) 
89.97 (10.342) 
89.94 (10.299) 
Median 
92.89 
93.20 
93.09 
Minimum, maximum  
48.5, 100.0 
39.6, 100.0 
39.6, 100.0 
SD=standard deviation 
Source: Table 14.3.1.1 
Program: t_14_3_1_1.sas 
 
The mean (standard deviation) udenafil concentration was 174.99 (112.00) ng/mL at 
2 hours ± 30 minutes after dosing on Day 1 and 259.19 (166.062) at Week 26 
(Table 14.3.1.2). A summary of log-transformed udenafil concentrations is provided in 
Table 14.3.1.3. The mean (standard deviation) concentration of the DA-8164 metabolite was 
74.34 (65.471) ng/mL at 2 hours ± 30 minutes after dosing on Day 1 and 225.59 (161.602) at 
Week 26 (Table 14.3.1.4). A summary of log-transformed DA-8164 concentrations is 
provided in Table 14.3.1.5. Concentrations of udenafil and DA-8164 are listed by subject and 
study visit in Listing 16.2.5.2. 
12.2 
Adverse Events (AEs) 
12.2.1 
Brief Summary of Adverse Events 
A notably larger percentage (≥5 percentage points) of udenafil-treated than placebo-treated 
subjects reported at least 1 TEAE (79.0% versus 67.5%) and drug-related TEAE (66.0% 
versus 42.5%). The incidence of TEAEs of Grade ≥3, serious TEAEs, drug-related serious 
TEAEs, and TEAEs resulting in temporary discontinuation (identified as drug interrupted in 
listings) or permanent discontinuation of study drug was similar between treatment groups 
(Table 24). 


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Table 24: 
Overall Summary of Treatment-emergent Adverse Events (Safety 
Population) 
Subjects with ≥1: 
Udenafil 
(N=200) 
n (%) 
Placebo 
(N=200) 
n (%) 
TEAE 
158 (79.0) 
135 (67.5) 
Drug-related TEAE 
132 (66.0) 
85 (42.5) 
TEAEs of Grade ≥3 
10 (5.0) 
6 (3.0) 
Serious TEAEs 
14 (7.0) 
10 (5.0) 
Drug-related serious TEAEs 
4 (2.0) 
2 (1.0) 
TEAE that led to temporary or permanent discontinuation  
of study drug 
18 (9.0) 
13 (6.5) 
TEAE=treatment-emergent adverse event 
Source: Table 14.3.2 
Program: t_14_3_2.sas 
 
12.2.2 
Display of Adverse Events 
TEAEs reported by ≥5% of subjects in the udenafil group (Table 14.3.5) included headache 
(39.0%), flushing (14.5%), epistaxis (10.0%), nasopharyngitis (10.0%), nausea (9.5%), 
dizziness (8.5%), vomiting (7.5%), upper respiratory tract infection (7.0%), erection 
increased (6.3% of males), spontaneous penile erection (6.3% of males), influenza (5.5%), 
chest pain (5.0%), pharyngitis streptococcal (5.0%), and rash (5.0%). TEAEs reported by 
≥5% of subjects in the placebo group included headache (25.5%), chest pain (9.0%), 
dizziness (9.0%), upper respiratory tract infection (8.5%), nasopharyngitis (6.5%), flushing 
(6.0%), and fatigue (5.5%).  
A notably greater percentage (≥5 percentage points) of subjects in the udenafil group as 
compared to the placebo group reported headache (39.0% versus 25.5%), flushing (14.5% 
versus 6.0%), epistaxis (10.0% versus 3.0%), nausea (9.5% versus 4.5%), and erection 
increased (6.3% of males versus 0.8% of males) (Table 14.3.5). 
Common TEAEs (reported by ≥5% of all subjects) are summarized in Table 25.  


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Table 25: 
Most Common (≥5% of All Subjects) Treatment-emergent Adverse 
Events (Safety Population) 
System Organ Class 
Preferred Term: 
Udenafil 
(N=200) 
n (%) 
Placebo 
(N=200) 
n (%) 
Subjects with ≥1 TEAE 
158 (79.0) 
135 (67.5) 
Gastrointestinal disorders 
55 (27.5) 
33 (16.5) 
Nausea 
19 (9.5) 
9 (4.5) 
Vomiting 
15 (7.5) 
6 (3.0) 
General disorders and administration site conditions 
33 (16.5) 
39 (19.5) 
Chest pain 
10 (5.0) 
18 (9.0) 
Infections and infestations 
69 (34.5) 
60 (30.0) 
Nasopharyngitis 
20 (10.0) 
13 (6.5) 
Upper respiratory tract infection 
14 (7.0) 
17 (8.5) 
Nervous system disorders 
95 (47.5) 
65 (32.5) 
Dizziness 
17 (8.5) 
18 (9.0) 
Headache 
78 (39.0) 
51 (25.5) 
Respiratory, thoracic and mediastinal disorders 
45 (22.5) 
29 (14.5) 
Epistaxis 
20 (10.0) 
6 (3.0) 
Vascular disorders 
32 (16.0) 
14 (7.0) 
Flushing 
29 (14.5) 
12 (6.0) 
TEAE=treatment-emergent adverse event 
Source: Table 14.3.3 and Table 14.3.5 
Program: 14_3_ae_tables.sas 
 
12.2.2.1 
Treatment-emergent Adverse Events by Intensity 
Most TEAEs were mild or moderate in intensity (Table 14.3.6A and Table 14.3.6B). Severe 
TEAEs were reported for 10 (5.0%) udenafil-treated subjects and 6 (3.0%) placebo-treated 
subjects (Table 14.3.6C); no life-threatening TEAEs were reported in either treatment group 
(Listing 16.2.7.1). Dizziness was the only severe TEAE reported by >1 subject (2 placebo 
subjects). 
Four drug-related, severe TEAEs were reported in the udenafil group (Listing 16.2.7.1): 
diplegia (Subject 130008), retinal vascular occlusion (Subject 140015), anxiety 


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(Subject 210003), and palpitations (Subject 530013). Study drug was withdrawn for 
Subjects 130008 and 140015 (Table 35), and study drug was interrupted for Subject 530013 
(Table 36). Two drug-related, severe TEAEs were reported in the placebo group: dizziness 
and syncope for Subject 420006. No change was made to study drug dosing. None of the 
other severe TEAEs were considered related to study drug. 
12.2.2.2 
Treatment-emergent Adverse Events Related to Study Drug 
Drug-related TEAEs reported by ≥5% of subjects in the udenafil group (Table 14.3.7A) 
included headache (38.0%), flushing (14.5%), epistaxis (7.5%), dizziness (6.5%), nausea 
(6.5%), erection increased (6.3% of males), and spontaneous penile erection (6.3% of males). 
Drug-related TEAEs reported by ≥5% of subjects in the placebo group included headache 
(22.0%), dizziness (7.0%), and flushing (6.0%). A notably greater percentage (≥5 percentage 
points) of subjects in the udenafil group as compared to the placebo group reported 
drug-related headache (38.0% versus 22.0%), flushing (14.5% versus 6.0%), erection 
increased (6.3% of males versus 0.8% of males), spontaneous penile erection (6.3% of males 
versus 0.8% of males), and epistaxis (7.5% versus 1.5%).  
Common drug-related TEAEs (reported by ≥2% of all subjects) are summarized in Table 26. 
TEAEs considered not related to study drug by the Investigator are summarized in 
Table 14.3.7B. 


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Table 26: 
Most Common (≥2% of All Subjects) Treatment-emergent Adverse 
Events Related to Study Drug (Safety Population) 
System Organ Class 
Preferred Term: 
Udenafil 
(N=200) 
n (%) 
Placebo 
(N=200) 
n (%) 
Subjects with ≥1 TEAE related to study drug 
132 (66.0) 
85 (42.5) 
Gastrointestinal disorders 
30 (15.0) 
19 (9.5) 
Abdominal pain upper 
6 (3.0) 
6 (3.0) 
Nausea 
13 (6.5) 
7 (3.5) 
General disorders and administration site conditions 
19 (9.5) 
15 (7.5) 
Chest pain 
3 (1.5) 
6 (3.0) 
Fatigue 
5 (2.5) 
7 (3.5) 
Infections and infestations 
14 (7.0) 
7 (3.5) 
Upper respiratory tract infection 
7 (3.5) 
3 (1.5) 
Nervous system disorders 
89 (44.5) 
55 (27.5) 
Dizziness 
13 (6.5) 
14 (7.0) 
Headache 
76 (38.0) 
44 (22.0) 
Migraine 
5 (2.5) 
4 (2.0) 
Reproductive system and breast disorders 
15 (7.5) 
3 (1.5) 
Erection increaseda 
7 (6.3) 
1 (0.8) 
Spontaneous penile erectiona 
7 (6.3) 
1 (0.8) 
Respiratory, thoracic and mediastinal disorders 
27 (13.5) 
13 (6.5) 
Epistaxis 
15 (7.5) 
3 (1.5) 
Nasal congestion 
5 (2.5) 
4 (2.0) 
Vascular disorders 
31 (15.5) 
13 (6.5) 
Flushing 
29 (14.5) 
12 (6.0) 
TEAE=treatment-emergent adverse event 
a Percentage calculated based on number of male subjects in each treatment group. 
Source: Table 14.3.7A 
Program: 14_3_ae_tables.sas 
 


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12.2.3 
Analysis of Adverse Events 
In this section, the most common TEAEs (reported by ≥5% of all subjects) are summarized 
for subgroups defined by gender (female, male), race (Caucasian/White, 
non-Caucasian/White), ethnicity (Hispanic or Latino/Latina, not Hispanic or Latino/Latina), 
age (tertiles at baseline), and weight (tertiles at baseline). A notable difference between 
groups is defined as ≥5 percentage points. 
Gender 
In the udenafil group, there was a notable increase among females versus males for chest pain 
(7.9% versus 2.7%). The incidence of common TEAEs is summarized separately for females 
and males in Table 27. 
Among females (N=161), a notably greater percentage of subjects in the udenafil group 
experienced headache (40.4% udenafil, 26.4% placebo) and flushing (16.9% udenafil, 
9.7% placebo). A notably greater percentage of subjects in the placebo group experienced 
dizziness (7.9% udenafil, 13.9% placebo). 
Among males (N=239), a notably greater percentage of subjects in the udenafil group 
experienced nausea (10.8% udenafil, 2.3% placebo), vomiting (9.0% udenafil, 
3.1% placebo), nasopharyngitis (11.7% udenafil, 6.3% placebo), headache (37.8% udenafil, 
25.0% placebo), epistaxis (9.9% udenafil, 0.8% placebo), and flushing (12.6% udenafil, 
3.9% placebo). A notably greater percentage of subjects in the placebo group experienced 
chest pain (2.7% udenafil, 10.2% placebo). In addition, the incidence of erection increased 
was greater in the udenafil group (6.3% udenafil, 0.8% placebo; Table 14.3.5). 
Race 
In the udenafil group, there was a notable increase among Caucasians/Whites versus 
non-Caucasians/Whites for dizziness (9.5% versus 3.4%). There was a notable decrease 
among Caucasians/Whites versus non-Caucasians/Whites for nausea (8.3% versus 13.8%), 
nasopharyngitis (8.9% versus 17.2%), and headache (37.9% versus 44.8%). Given the 
disparity in sample sizes between the racial groups, these differences are difficult to interpret. 
The incidence of common TEAEs is summarized separately for Caucasians/Whites and 
non-Caucasians/Whites in Table 28. 
Among Caucasians/Whites (N=324), a notably greater percentage of subjects in the udenafil 
group experienced headache (37.9% udenafil, 27.1% placebo), epistaxis (9.5% udenafil, 
3.2% placebo), and flushing (14.8% udenafil, 7.1% placebo).  


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Among non-Caucasians/Whites (N=65), a notably greater percentage of subjects in the 
udenafil group experienced nausea (13.8% udenafil, 5.6% placebo), vomiting 
(10.3% udenafil, 0 placebo), nasopharyngitis (17.2% udenafil, 8.3% placebo), headache 
(44.8% udenafil, 16.7% placebo), epistaxis (13.8% udenafil, 2.8% placebo), and flushing 
(13.8% udenafil, 2.8% placebo). 
Ethnicity 
In the udenafil group, there was a notable increase among Hispanic or Latino/Latina subjects 
versus subjects not Hispanic or Latino/Latina for vomiting (12.9% versus 6.5%). There was a 
notable increase among subjects not Hispanic or Latino/Latina versus Hispanic or 
Latino/Latina subjects for upper respiratory tract infection (8.3% versus 0) and flushing 
(15.5% versus 9.7%). Given the disparity in sample sizes between the ethnic groups, these 
differences are difficult to interpret. The incidence of common TEAEs is summarized 
separately for Hispanic or Latino/Latina subjects and subjects not Hispanic or Latino/Latina 
in Table 29. 
Among Hispanic or Latino/Latina subjects (N=56), a notably greater percentage of subjects 
in the udenafil group experienced nausea (12.9% udenafil, 4.0% placebo), nasopharyngitis 
(9.7% udenafil, 0 placebo), headache (41.9% udenafil, 28.0% placebo) and epistaxis 
(9.7% udenafil, 0 placebo). A notably greater percentage of subjects in the placebo group 
experienced chest pain (3.2% udenafil, 24.0% placebo).  
Among subjects not Hispanic or Latino/Latina (N=342), a notably greater percentage of 
subjects in the udenafil group experienced headache (38.1% udenafil, 25.3% placebo), 
epistaxis (10.1% udenafil, 3.4% placebo), and flushing (15.5% udenafil, 5.7% placebo).  
Age at Baseline 
For age at baseline, comparisons are focused on the extremes of the age range (ie, low tertile 
versus high tertile). In the udenafil group, there was a notable increase among subjects within 
the high age tertile versus subjects in the low age tertile for nasopharyngitis (15.2% versus 
8.3%). There was a notable increase among subjects in the low age tertile versus subjects in 
the high age tertile for flushing (18.1% versus 12.1%). The incidence of common TEAEs is 
summarized separately for baseline age tertiles in Table 30. 
Within the low age tertile (N=133), a notably greater percentage of subjects in the udenafil 
group experienced dizziness (11.1% udenafil, 4.9% placebo), headache (38.9% udenafil, 


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29.5% placebo), epistaxis (12.5% udenafil, 4.9% placebo), and flushing (18.1% udenafil, 
1.6% placebo).  
Within the high age tertile (N=133), a notably greater percentage of subjects in the udenafil 
group experienced nausea (9.1% udenafil, 0 placebo), vomiting (10.6% udenafil, 
1.5% placebo), nasopharyngitis (15.2% udenafil, 0 placebo), headache (36.4% udenafil, 
25.4% placebo), and flushing (12.1% udenafil, 6.0% placebo). A notably greater percentage 
of subjects in the placebo group experienced chest pain (6.1% udenafil, 11.9% placebo) and 
upper respiratory tract infection (6.1% udenafil, 11.9% placebo). 
Among males in the high age tertile, a greater percentage of subjects in the udenafil group 
than the placebo group reported erection increased and spontaneous penile erection 
(7.9% versus 0 for each event; Table 14.3.9C). 
Weight at Baseline 
For weight at baseline, comparisons are focused on the extremes of the weight range (ie, low 
tertile versus high tertile). In the udenafil group, there was a notable increase in the low 
weight tertile versus the high weight tertile for the percentage of subjects experiencing nausea 
(9.3% versus 3.5%), headache (41.3% versus 28.1%), and flushing (16.0% versus 10.5%). 
The incidence of common TEAEs is summarized separately for baseline weight tertiles in 
Table 31.  
Within the low weight tertile (N=134), a notably greater percentage of subjects in the 
udenafil group experienced headache (41.3% udenafil, 23.7% placebo), epistaxis 
(13.3% udenafil, 3.4% placebo), and flushing (16.0% udenafil, 1.7% placebo). A notably 
greater percentage of subjects in the placebo group experienced chest pain (2.7% udenafil, 
8.5% placebo) and dizziness (6.7% udenafil, 11.9% placebo). 
Within the high weight tertile (N=134), a notably greater percentage of subjects in the 
udenafil group experienced vomiting (8.8% udenafil, 2.6% placebo). A notably greater 
percentage of subjects in the placebo group experienced chest pain (1.8% udenafil, 
7.8% placebo). 
Among male subjects, a greater percentage of subjects in the udenafil group than the placebo 
group reported erection increased and spontaneous penile erection in the low weight tertile 
(5.0% versus 0 and 10.0% versus 3.0%, respectively; Table 14.3.8A) and in the high weight 
tertile (5.6% versus 0 and 8.3% versus 0, respectively; Table 14.3.8C).  
 


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Table 27: 
Most Common (≥5% of All Subjects) Treatment-emergent Adverse Events by Gender (Safety Population) 
 
Male Subjects (N=239) 
Female Subjects (N=161) 
Preferred Term: 
Udenafil 
(N=111) 
n (%) 
Placebo 
(N=128) 
n (%) 
Total 
(N=239) 
n (%) 
Udenafil 
(N=89) 
n (%) 
Placebo 
(N=72) 
n (%) 
Total 
(N=161) 
n (%) 
Nausea 
12 (10.8) 
3 (2.3) 
15 (6.3) 
7 (7.9) 
6 (8.3) 
13 (8.1) 
Vomiting 
10 (9.0) 
4 (3.1) 
14 (5.9) 
5 (5.6) 
2 (2.8) 
7 (4.3) 
Chest pain 
3 (2.7)  
13 (10.2) 
16 (6.7) 
7 (7.9) 
5 (6.9) 
12 (7.5) 
Nasopharyngitis 
13 (11.7) 
8 (6.3) 
21 (8.8) 
7 (7.9) 
5 (6.9) 
12 (7.5) 
Upper respiratory tract infection 
7 (6.3) 
8 (6.3) 
15 (6.3) 
7 (7.9) 
9 (12.5) 
16 (9.9) 
Dizziness 
10 (9.0) 
8 (6.3) 
18 (7.5) 
7 (7.9) 
10 (13.9) 
17 (10.6) 
Headache 
42 (37.8) 
32 (25.0) 
74 (31.0) 
36 (40.4) 
19 (26.4) 
55 (34.2) 
Epistaxis 
11 (9.9) 
1 (0.8) 
12 (5.0) 
9 (10.1) 
5 (6.9) 
14 (8.7) 
Flushing 
14 (12.6) 
5 (3.9) 
19 (7.9) 
15 (16.9) 
7 (9.7) 
22 (13.7) 
Source: Table 14.3.4A and Table 14.3.4B 
Program: 14_3_ae_tables.sas 
 
 
 


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Table 28: 
Most Common (≥5% of All Subjects) Treatment-emergent Adverse Events by Race Category (Safety 
Population) 
 
Caucasian/White Subjects (N=324) 
Non-Caucasian/White Subjects (N=65) 
Preferred Term: 
Udenafil 
(N=169) 
n (%) 
Placebo 
(N=155) 
n (%) 
Total 
(N=324) 
n (%) 
Udenafil 
(N=29) 
n (%) 
Placebo 
(N=36) 
n (%) 
Total 
(N=65) 
n (%) 
Nausea 
14 (8.3) 
6 (3.9) 
20 (6.2) 
4 (13.8) 
2 (5.6) 
6 (9.2) 
Vomiting 
11 (6.5) 
4 (2.6) 
15 (4.6) 
3 (10.3) 
0 
3 (4.6) 
Chest pain 
8 (4.7) 
14 (9.0) 
22 (6.8) 
2 (6.9) 
2 (5.6) 
4 (6.2) 
Nasopharyngitis 
15 (8.9) 
10 (6.5) 
25 (7.7) 
5 (17.2) 
3 (8.3) 
8 (12.3) 
Upper respiratory tract infection 
13 (7.7) 
17 (11.0) 
30 (9.3) 
1 (3.4) 
0 
1 (1.5) 
Dizziness 
16 (9.5) 
12 (7.7) 
28 (8.6) 
1 (3.4) 
3 (8.3) 
4 (6.2) 
Headache 
64 (37.9) 
42 (27.1) 
106 (32.7) 
13 (44.8) 
6 (16.7) 
19 (29.2) 
Epistaxis 
16 (9.5) 
5 (3.2) 
21 (6.5) 
4 (13.8) 
1 (2.8) 
5 (7.7) 
Flushing 
25 (14.8) 
11 (7.1) 
36 (11.1) 
4 (13.8) 
1 (2.8) 
5 (7.7) 
Note: Summary excludes 11 subjects of unknown or not reported race. 
Source: Table 14.3.4C and Table 14.3.4D 
Program: 14_3_ae_tables.sas 
 
 
 


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Table 29: 
Most Common (≥5% of All Subjects) Treatment-emergent Adverse Events by Ethnicity Category (Safety 
Population) 
 
Hispanic or Latino/Latina Subjects 
(N=56) 
Not Hispanic or Latino/Latina Subjects 
(N=342) 
Preferred Term: 
Udenafil 
(N=31) 
n (%) 
Placebo 
(N=25) 
n (%) 
Total 
(N=56) 
n (%) 
Udenafil 
(N=168) 
n (%) 
Placebo 
(N=174) 
n (%) 
Total 
(N=342) 
n (%) 
Nausea 
4 (12.9) 
1 (4.0) 
5 (8.9) 
15 (8.9) 
8 (4.6) 
23 (6.7) 
Vomiting 
4 (12.9) 
3 (12.0) 
7 (12.5) 
11 (6.5) 
3 (1.7) 
14 (4.1) 
Chest pain 
1 (3.2) 
6 (24.0) 
7 (12.5) 
9 (5.4) 
12 (6.9) 
21 (6.1) 
Nasopharyngitis 
3 (9.7) 
0 
3 (5.4) 
17 (10.1) 
13 (7.5) 
30 (8.8) 
Upper respiratory tract infection 
0 
0 
0 
14 (8.3) 
17 (9.8) 
31 (9.1) 
Dizziness 
2 (6.5) 
2 (8.0) 
4 (7.1) 
15 (8.9) 
16 (9.2) 
31 (9.1) 
Headache 
13 (41.9) 
7 (28.0) 
20 (35.7) 
64 (38.1) 
44 (25.3) 
108 (31.6) 
Epistaxis 
3 (9.7) 
0 
3 (5.4) 
17 (10.1) 
6 (3.4) 
23 (6.7) 
Flushing 
3 (9.7) 
2 (8.0) 
5 (8.9) 
26 (15.5) 
10 (5.7) 
36 (10.5) 
Note: Summary excludes 2 subjects of unknown ethnicity. 
Source: Table 14.3.4E and Table 14.3.4F 
Program: 14_3_ae_tables.sas 
 
 
 


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Table 30: 
Most Common (≥5% of All Subjects) Treatment-emergent Adverse Events by Baseline Age Tertile (Safety 
Population) 
 
Low Age Tertile (N=133) 
Medium Age Tertile (N=134) 
High Age Tertile (N=133) 
Preferred Term: 
Udenafil 
(N=72) 
n (%) 
Placebo 
(N=61) 
n (%) 
Total 
(N=133) 
n (%) 
Udenafil 
(N=62) 
n (%) 
Placebo 
(N=72) 
n (%) 
Total 
(N=134) 
n (%) 
Udenafil 
(N=66) 
n (%) 
Placebo 
(N=67) 
n (%) 
Total 
(N=133) 
n (%) 
Nausea 
9 (12.5) 
5 (8.2) 
14 (10.5) 
4 (6.5) 
4 (5.6) 
8 (6.0) 
6 (9.1) 
0 
6 (4.5) 
Vomiting 
6 (8.3) 
3 (4.9) 
9 (6.8) 
2 (3.2) 
2 (2.8) 
4 (3.0) 
7 (10.6) 
1 (1.5) 
8 (6.0) 
Chest pain 
3 (4.2) 
2 (3.3) 
5 (3.8) 
3 (4.8) 
8 (11.1) 
11 (8.2) 
4 (6.1) 
8 (11.9) 
12 (9.0) 
Nasopharyngitis 
6 (8.3) 
7 (11.5) 
13 (9.8) 
4 (6.5) 
6 (8.3) 
10 (7.5) 
10 (15.2) 
0 
10 (7.5) 
Upper respiratory tract infection 
7 (9.7) 
6 (9.8) 
13 (9.8) 
3 (4.8) 
3 (4.2) 
6 (4.5) 
4 (6.1) 
8 (11.9) 
12 (9.0) 
Dizziness 
8 (11.1) 
3 (4.9) 
11 (8.3) 
3 (4.8) 
8 (11.1) 
11 (8.2) 
6 (9.1) 
7 (10.4) 
13 (9.8) 
Headache 
28 (38.9) 
18 (29.5) 
46 (34.6) 
26 (41.9) 
16 (22.2) 
42 (31.3) 
24 (36.4) 
17 (25.4) 
41 (30.8) 
Epistaxis 
9 (12.5) 
3 (4.9) 
12 (9.0) 
6 (9.7) 
1 (1.4) 
7 (5.2) 
5 (7.6) 
2 (3.0) 
7 (5.3) 
Flushing 
13 (18.1) 
1 (1.6) 
14 (10.5) 
8 (12.9) 
7 (9.7) 
15 (11.2) 
8 (12.1) 
4 (6.0) 
12 (9.0) 
Source: Table 14.3.9A, Table 14.3.9B, and Table 14.3.9C 
Program: 14_3_ae_tables.sas 
 
 
 


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Table 31: 
Most Common (≥5% of All Subjects) Treatment-emergent Adverse Events by Baseline Weight Tertile (Safety 
Population) 
 
Low Weight Tertile (N=134) 
Medium Weight Tertile (N=132) 
High Weight Tertile (N=134) 
Preferred Term: 
Udenafil 
(N=75) 
n (%) 
Placebo 
(N=59) 
n (%) 
Total 
(N=134) 
n (%) 
Udenafil 
(N=68) 
n (%) 
Placebo 
(N=64) 
n (%) 
Total 
(N=132) 
n (%) 
Udenafil 
(N=57) 
n (%) 
Placebo 
(N=77) 
n (%) 
Total 
(N=134) 
n (%) 
Nausea 
7 (9.3) 
4 (6.8) 
11 (8.2) 
10 (14.7) 
1 (1.6) 
11 (8.3) 
2 (3.5) 
4 (5.2) 
6 (4.5) 
Vomiting 
6 (8.0) 
2 (3.4) 
8 (6.0) 
4 (5.9) 
2 (3.1) 
6 (4.5) 
5 (8.8) 
2 (2.6) 
7 (5.2) 
Chest pain 
2 (2.7) 
5 (8.5) 
7 (5.2) 
7 (10.3) 
7 (10.9) 
14 (10.6) 
1 (1.8) 
6 (7.8) 
7 (5.2) 
Nasopharyngitis 
5 (6.7) 
5 (8.5) 
10 (7.5) 
11 (16.2) 
4 (6.3) 
15 (11.4) 
4 (7.0) 
4 (5.2) 
8 (6.0) 
Upper respiratory tract infection 
7 (9.3) 
7 (11.9) 
14 (10.4) 
3 (4.4) 
4 (6.3) 
7 (5.3) 
4 (7.0) 
6 (7.8) 
10 (7.5) 
Dizziness 
5 (6.7) 
7 (11.9) 
12 (9.0) 
6 (8.8) 
4 (6.3) 
10 (7.6) 
6 (10.5) 
7 (9.1) 
13 (9.7) 
Headache 
31 (41.3) 
14 (23.7) 
45 (33.6) 
31 (45.6) 
16 (25.0) 
47 (35.6) 
16 (28.1) 
21 (27.3) 
37 (27.6) 
Epistaxis 
10 (13.3) 
2 (3.4) 
12 (9.0) 
5 (7.4) 
0 
5 (3.8) 
5 (8.8) 
4 (5.2) 
9 (6.7) 
Flushing 
12 (16.0) 
1 (1.7) 
13 (9.7) 
11 (16.2) 
4 (6.3) 
15 (11.4) 
6 (10.5) 
7 (9.1) 
13 (9.7) 
Source: Table 14.3.8A, Table 14.3.8B, and Table 14.3.8C 
Program: 14_3_ae_tables.sas 
 


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12.2.4 
Listing of Adverse Events by Subject 
All adverse events are listed by individual subject in Listing 16.2.7.1. 
12.3 
Deaths, other Serious Adverse Events, and Other Significant 
Adverse Events 
12.3.1 
Listing of Deaths, Other Serious Adverse Events and Other 
Significant Adverse Events 
12.3.1.1 
Deaths 
No subject died during the study (Table 14.3.18).  
12.3.1.2 
Other Serious Adverse Events 
At least 1 serious TEAE was reported by 14 (7.0%) subjects in the udenafil group and 
10 (5.0%) subjects in the placebo group (Table 32). Serious TEAEs reported by at least 
2 subjects included chest pain (2 udenafil subjects), influenza (2 udenafil subjects), syncope 
(2 placebo subjects) and dyspnoea (1 udenafil subject and 1 placebo subject). All other 
serious TEAEs were reported by a single subject each. 
Hospitalization was reported for 23 subjects (14 udenafil, 9 placebo) during the study 
(Table 14.3.18). Hospitalized subjects are identified in Listing 16.2.7.3. No transplants were 
reported during the study (Table 14.3.18). Tabular summaries of transplants and 
hospitalizations by weight tertile are provided in Table 14.3.19A, Table 14.3.19B, and 
Table 14.3.19C. Tabular summaries of transplants and hospitalizations by age tertile are 
provided in Table 14.3.20A, Table 14.3.20B, and Table 14.3.20C. 


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Table 32: 
Serious Treatment-emergent Adverse Events Reported for ≥2 Subjects 
(Safety Population) 
System Organ Class 
Preferred Term 
Udenafil 
(N=200) 
n (%) 
Placebo 
(N=200) 
n (%) 
Subjects with ≥1 serious TEAE 
14 (7.0) 
10 (5.0) 
General disorders and administration site conditions 
2 (1.0) 
1 (0.5) 
Chest pain 
2 (1.0) 
0 
Infections and infestations 
2 (1.0) 
3 (1.5) 
Influenza 
2 (1.0) 
0 
Nervous system disorders 
2 (1.0) 
5 (2.5) 
Syncope 
0 
2 (1.0) 
Respiratory, thoracic and mediastinal disorders 
3 (1.5) 
1 (0.5) 
Dyspnoea 
1 (0.5) 
1 (0.5) 
TEAE=treatment-emergent adverse event 
Source: Table 14.3.10 
Program: 14_3_ae_tables.sas 
 
Six subjects (4 udenafil, 2 placebo) had serious TEAEs that were considered related to study 
drug (Table 14.3.11A). In the udenafil group, drug-related serious TEAEs included anxiety 
and bronchospasm reported in 1 subject and diplegia, retinal vascular occlusion, and 
palpitations reported in 1 subject each. In the placebo group, 2 subjects experienced a 
drug-related serious TEAE of syncope. Serious adverse events considered not related to study 
drug by the Investigator are summarized in Table 14.3.11B. All serious TEAEs are listed in 
Table 33. 
A short description is provided below for each drug-related serious TEAE. 
A 15-year-old male (Subject 130008) in the udenafil group experienced a serious TEAE of 
diplegia (verbatim: inability to move legs) on Day 158. The event was severe in intensity and 
considered possibly related to study drug per the Investigator. Mild asthenia was also 
reported. The subject had missed approximately 1 week of study drug when he forgot to take 
his study medication on vacation. Two days after resuming study drug, the subject did not 
feel well and complained of an upset stomach, sore throat, and feeling weak. Later that day, 
the subject was admitted to the hospital after reporting he was unable to move his legs. He 
also developed sudden onset lower extremity paresthesia, weakness of his left arm, and 
experienced an episode of urinary incontinence. No abnormalities were observed on vital 
signs or laboratory assessments. Magnetic resonance imaging of the brain, neck, thoracic and 
lumbar spine were unremarkable. No treatment was administered for the event and the 


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subject was discharged from the hospital 2 days later with no confirmed clinical diagnosis. 
The subject was discontinued from study drug due to the event. At a follow-up visit 
performed 1 day after discharge, the subject reported the event had resolved and was fully 
back to normal.  
A 14-year-old female (Subject 140015) in the udenafil group experienced a serious TEAE of 
retinal vascular occlusion (verbatim: retinal vascular occlusion) on Day 128. The event was 
severe in intensity, considered possibly related to study drug per the Investigator, and resulted 
in permanent discontinuation of study drug. The subject was hospitalized after experiencing 
vision loss in the right eye characterized as sudden onset of blurry vision and gray spots, 
progressing to complete gray within 45 minutes. Ophthalmic exam revealed right afferent 
pupillary defect (4+) and slit lamp examination showed blurred optic disc margins and 
slightly pallid temporal region without blood and massive whitening with cherry red spot. 
The retina had narrowed arterioles with mild ‘boxcarring’ with question of a small cilioretinal 
artery that did not extend to the macula. The subject was not receiving anticoagulant therapy 
at the time of the event due to past history of hemoptysis; however, evaluation for a 
hypercoagulable state showed no significant findings. Additional evaluations including 
computed tomography scan of the head, brain magnetic resonance imaging, magnetic 
resonance angiography, and duplex studies of the carotid artery and lower extremities were 
unremarkable. The subject was discharged with a diagnosis of complete occlusion of the 
central retinal artery without evidence of thromboembolism. The vision loss was permanent 
and was considered stable at the date of her final study telephone call. 
An 18-year-old female (Subject 210003) in the udenafil group experienced serious TEAEs of 
anxiety (verbatim: anxiety) and bronchospasm (verbatim: bronchospasm). The anxiety event 
began on Day 35, was severe in intensity and considered possibly related to study drug per 
the Investigator; the event was noted as resolved on Day 40. The bronchospasm event began 
on Day 86, was of moderate intensity, and considered possibly related to study drug per the 
Investigator; this event was ongoing at study completion. Salbutamol was prescribed on 
Day 86. The subject also experienced nonserious TEAEs of mild dyspnoea and mild upper 
respiratory tract infection during the study.  
A 19-year-old male (Subject 530013) in the udenafil group experienced a serious TEAE of 
palpitations (verbatim: palpitation) that began on Day 45. The event was severe in intensity 
and considered probably related to study drug per the Investigator. The subject was admitted 
to the hospital for evaluation of palpitations, following an episode of pyrexia and 
gastrointestinal symptoms. Study drug was interrupted for the event. The event was treated 


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with amiodarone for 1 day, then supportive care with furosemide, spironolactone and 
intravenous fluids was administered. The event was noted as resolved on Study Day 47.  
An 18-year-old female (Subject 420006) in the placebo group experienced a serious TEAE of 
syncope (verbatim: fainted) on Day 117. The event was severe in intensity and considered 
possibly related to study drug per the Investigator. The subject presented to the hospital 
emergency department after fainting at work and having recovered consciousness within 
several minutes. The subject had been non-compliant with study drug dosing for 4 days prior 
to the event. Vital signs showed no orthostatic changes and laboratory tests were within 
normal limits with exception of slight decreases in hemoglobin and hematocrit. 
Electrocardiogram results were similar to those observed on an electrocardiogram performed 
3 months prior. No intravenous fluids or medications were administered for treatment of the 
event and the subject was discharged, with the event noted as resolved the same day. 
A 15-year-old female (Subject 490002) in the placebo group experienced a serious TEAE of 
syncope (verbatim: syncope/vasovagal) on Day 29. The event was moderate in intensity and 
considered possibly related to study drug per the Investigator. The subject was hospitalized 
following a syncopal episode upon standing, characterized as loss of consciousness with 
concurrent cyanosis. Evaluation showed orthostatic changes in vital signs. No abnormalities 
were observed on chest x-ray or telemetry. Treatment included intravenous fluids and 
ibuprofen. The event was noted as resolved the same day. 
 


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Table 33: 
Listing of Serious Treatment-emergent Adverse Events  
Treatment/ 
Subject Number 
Gender Age (Years) Preferred Term 
Day of 
Onset 
Relationship 
to Study Drug 
Intensity 
Study Drug 
Action Taken 
Udenafil 
 
 
 
 
 
 
 
110006 
Female 
14.6 
Dyspnoea 
263 
Not related 
Severe 
None reported 
 
 
14.6 
Chest pain 
263 
Not related 
Severe 
None reported 
110008 
Male 
13.8 
Influenza 
254 
Not related 
Severe 
None reported 
120004 
Female 
16.2 
Gastrointestinal haemorrhage 
134 
Not related 
Severe 
Dose not changed 
 
 
16.2 
Protein-losing gastroenteropathy 
134 
Not related 
Severe 
Dose not changed 
 
 
16.2 
Protein-losing gastroenteropathy 
159 
Not related 
Severe 
Drug withdrawn 
130008 
Male 
15.2 
Diplegia 
158 
Possibly related 
Severe 
Drug withdrawn 
140004 
Female 
17.0 
Paralysis 
104 
Not related 
Moderate 
Drug interrupted 
140015 
Female 
14.5 
Retinal vascular occlusion 
128 
Possibly related 
Severe 
Drug withdrawn 
140031 
Female 
12.8 
Arrhythmia 
130 
Not related 
Severe 
Dose not changed 
 
 
12.8 
Respiratory failure 
144 
Not related 
Severe 
Dose not changed 
210003 
Female 
18.3 
Anxiety 
35 
Possibly related 
Severe 
Dose not changed 
 
 
18.5 
Bronchospasm 
86 
Possibly related 
Moderate 
Dose not changed 
210012 
Male 
12.8 
Intestinal obstruction 
93 
Not related 
Moderate 
Drug interrupted 
 
 
13.0 
Influenza 
159 
Not related 
Moderate 
Dose not changed 
270018 
Female 
12.9 
Menorrhagia 
79 
Not related 
Severe 
None reported 
 
 
 


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Table 33: 
Listing of Serious Treatment-emergent Adverse Events (Continued) 
Treatment/ 
Subject Number 
Gender Age (Years) Preferred Term 
Day of 
Onset 
Relationship 
to Study Drug 
Intensity 
Study Drug 
Action Taken 
Udenafil (continued) 
 
 
 
 
 
 
330003 
Male 
19.1 
Renal failure 
58 
Not related 
Severe 
Drug interrupted 
 
 
19.1 
Toxicity to various agents 
58 
Not related 
Severe 
Drug interrupted 
 
 
19.2 
Bipolar I disorder 
96 
Not related 
Severe 
Dose not changed 
480013 
Female 
18.7 
Chest pain 
148 
Not related 
Mild 
Drug interrupted  
530013 
Male 
19.1 
Palpitations 
45 
Probably related 
Severe 
Drug interrupted 
 
 
19.1 
Venous stenosis 
48 
Not related 
Severe 
Dose not changed 
540010 
Male 
18.1 
Anal haemorrhage 
103 
Not related 
Moderate 
Dose not changed 
 
 
18.1 
Constipation 
103 
Not related 
Moderate 
Dose not changed 
Placebo 
 
 
 
 
 
 
 
120017 
Female 
19.1 
Migraine 
65 
Not related 
Moderate 
Dose not changed 
140040 
Male 
13.5 
Cardiac failure 
2 
Not related 
Severe 
Dose not changed 
170012 
Male 
15.9 
Appendicitis 
185 
Not related 
Severe 
Drug interrupted 
170018 
Male 
12.2 
Transient ischaemic attack 
66 
Not related 
Moderate 
Drug interrupted 
230006 
Female 
18.9 
Fatigue 
23 
Not related 
Severe 
Dose not changed 
 
 
19.0 
Abdominal pain 
76 
Not related 
Mild 
Dose not changed 
420003 
Male 
17.0 
Dyspnoea 
133 
Not related 
Moderate 
Dose not changed 
 
 
17.0 
Dizziness 
133 
Not related 
Severe 
Dose not changed 
420006 
Female 
18.4 
Syncope 
117 
Possibly related 
Severe 
Dose not changed 
 
 
18.5 
Depression 
155 
Not related 
Severe 
Dose not changed 
480008 
Male 
18.9 
Pharyngitis 
165 
Not related 
Moderate 
Dose not changed 
490002 
Female 
15.4 
Syncope 
29 
Possibly related 
Moderate 
Dose not changed 
500001 
Male 
15.0 
Viral upper respiratory tract infection 
57 
Not related 
Moderate 
Dose not changed 
Source: Listing 16.2.7.4 
 


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12.3.1.3 
Other Significant Adverse Events 
12.3.1.3.1 
Adverse Events Leading to Discontinuation of Study 
Drug 
At least 1 TEAE leading to temporary or permanent discontinuation of study drug was 
reported by 18 (9.0%) subjects in the udenafil group and 13 (6.5%) subjects in the placebo 
group (Table 34). TEAEs leading to temporary or permanent discontinuation of study drug 
reported by at least 2 subjects included headache (3 udenafil subjects and 3 placebo subjects), 
nausea (2 udenafil subjects), vomiting (2 udenafil subjects), abdominal pain upper (2 placebo 
subjects), and gastroenteritis viral (1 udenafil subject and 1 placebo subject). All other 
TEAEs leading to temporary or permanent discontinuation of study drug were reported by a 
single subject each. 
Table 34: 
Treatment-emergent Adverse Events Leading to Temporary or 
Permanent Discontinuation of Study Drug That Were Reported for 
≥2 Subjects (Safety Population) 
System Organ Class 
Preferred Term 
Udenafil 
(N=200) 
n (%) 
Placebo 
(N=200) 
n (%) 
Subjects with ≥1 TEAE resulting in discontinuation of study drug 
18 (9.0) 
13 (6.5) 
Gastrointestinal disorders 
5 (2.5) 
4 (2.0) 
Abdominal pain upper 
0 
2 (1.0) 
Nausea 
2 (1.0) 
0 
Vomiting 
2 (1.0) 
0 
Infections and infestations 
2 (1.0) 
3 (1.5) 
Gastroenteritis viral 
1 (0.5) 
1 (0.5) 
Nervous system disorders 
6 (3.0) 
5 (2.5) 
Headache 
3 (1.5) 
3 (1.5) 
TEAE=treatment-emergent adverse event 
Source: Table 14.3.14 
Program: 14_3_ae_tables.sas 
 
Of the 18 subjects in the udenafil group, 13 subjects had ≥1 TEAE that resulted in 
interruption of study drug, 4 subjects (120004, 130008, 140015, and 170013) had ≥1 TEAE 
that resulted in permanent discontinuation of study drug, and 1 subject (160011) had 1 TEAE 
each that resulted in interruption and permanent discontinuation (Listing 16.2.7.1). Of the 
13 subjects in the placebo group, 9 subjects had ≥1 TEAE that resulted in interruption of 


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study drug and 4 subjects (270020, 310009, 390001, and 470001) had ≥1 TEAE that resulted 
in permanent discontinuation of study drug (Listing 16.2.7.1). A listing of TEAEs that 
resulted in permanent discontinuation from study drug is provided in Table 35, and a listing 
of TEAEs that resulted in interruption of study drug is provided in Table 36. 
 


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Table 35: 
Listing of Treatment-emergent Adverse Events Resulting in Permanent Discontinuation of Study Drug 
Treatment/ 
Subject Number 
Gender Age (Years) Preferred Term 
Day of 
Onset 
Relationship 
to Study Drug 
Intensity 
Serious 
Udenafil 
 
 
 
 
 
 
 
120004 
Female 
16.2 
Protein-losing gastroenteropathy 
159 
Not related 
Severe 
Yes 
130008 
Male 
15.2 
Diplegia 
158 
Possibly related 
Severe 
Yes 
 
 
15.2 
Asthenia 
158 
Possibly related 
Mild 
No 
140015 
Female 
14.5 
Retinal vascular occlusion 
128 
Possibly related 
Severe 
Yes 
160011 
Male 
13.7 
Headache 
118 
Possibly related 
Moderate 
No 
170013 
Female 
18.0 
Visual field defect 
25 
Possibly related 
Mild 
No 
Placebo 
 
 
 
 
 
 
 
270020 
Male 
13.9 
Swollen tongue 
8 
Probably related 
Moderate 
No 
 
 
13.9 
Urticaria 
8 
Probably related 
Moderate 
No 
310009 
Female 
18.9 
Headache 
31 
Probably related 
Moderate 
No 
390001 
Male 
15.8 
Eye pain 
99 
Possibly related 
Mild 
No 
470001 
Female 
12.6 
Headache 
1 
Possibly related 
Mild 
No 
Source: Listing 16.2.7.1 
 
 


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Table 36: 
Listing of Treatment-emergent Adverse Events Resulting in Interruption of Study Drug 
Treatment/ 
Subject Number 
Gender Age (Years) Preferred Term 
Day of 
Onset 
Relationship 
to Study Drug 
Intensity 
Serious 
Udenafil 
 
 
 
 
 
 
 
140004 
Female 
16.8 
Hypoaesthesia 
22 
Possibly related 
Moderate 
No 
 
 
17.0 
Paralysis 
104 
Not related 
Moderate 
Yes 
140037 
Female 
15.0 
Headache 
2 
Probably related 
Mild 
No 
160011 
Male 
13.3 
Headache 
3 
Possibly related 
Mild 
No 
180007 
Male 
14.5 
Nausea 
9 
Not related 
Mild 
No 
 
 
14.5 
Vomiting 
9 
Not related 
Mild 
No 
180008 
Female 
13.1 
Nausea 
2 
Not related 
Mild 
No 
210005 
Male 
13.8 
Gastroenteritis viral 
51 
Not related 
Mild 
No 
210012 
Male 
12.8 
Intestinal obstruction 
93 
Not related 
Moderate 
Yes 
270006 
Female 
15.5 
Headache 
1 
Possibly related 
Mild 
No 
310005 
Male 
13.2 
Vomiting 
2 
Possibly related 
Moderate 
No 
330003 
Male 
19.1 
Toxicity to various agents 
58 
Not related 
Severe 
Yes 
 
 
19.1 
Renal failure 
58 
Not related 
Severe 
Yes 
470002 
Male 
14.8 
Belligerence 
8 
Possibly related 
Mild 
No 
470010 
Male 
19.1 
Candida infection 
63 
Not related 
Mild 
No 
480013 
Female 
18.7 
Chest pain 
148 
Not related 
Mild 
Yes 
530013 
Male 
19.1 
Palpitations 
45 
Probably related 
Severe 
Yes 
 
 


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Table 36: 
Listing of Treatment-emergent Adverse Events Resulting in Interruption of Study Drug (Continued) 
Treatment/ 
Subject Number 
Gender Age (Years) Preferred Term 
Day of 
Onset 
Relationship 
to Study Drug 
Intensity 
Serious 
Placebo 
 
 
 
 
 
 
 
140001 
Female 
17.6 
Gastroenteritis viral 
155 
Not related 
Mild 
No 
140038 
Male 
13.5 
Pyrexia 
163 
Not related 
Mild 
No 
160004 
Female 
16.6 
Dizziness 
2 
Possibly related 
Mild 
No 
160005 
Female 
14.5 
Conjunctivitis 
23 
Possibly related 
Moderate 
No 
170012 
Male 
15.9 
Appendicitis 
185 
Not related 
Severe 
Yes 
170018 
Male 
12.2 
Transient ischaemic attack 
66 
Not related 
Moderate 
Yes 
210008 
Female 
13.0 
Diarrhoea 
2 
Possibly related 
Mild 
No 
310006 
Female 
14.4 
Epistaxis 
1 
Possibly related 
Mild 
No 
 
 
14.5 
Abdominal pain upper 
12 
Possibly related 
Mild 
No 
330006 
Male 
16.9 
Headache 
23 
Not related 
Mild 
No 
 
 
16.9 
Abdominal pain upper 
23 
Not related 
Mild 
No 
Source: Listing 16.2.7.1 
 
 


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12.3.1.3.2 
Adverse Events of Special Interest 
Adverse events of hypotension (eg, blood pressure decreased, blood pressure diastolic 
decreased, blood pressure systolic decreased, hypotension, procedural hypotension), loss of 
consciousness, dizziness (eg, dizziness, dizziness exertional, procedural dizziness), 
presyncope, and syncope (syncope, syncope vasovagal) were identified in the SAP for 
separate summarization. Hypotension, dizziness, and syncope have been reported with other 
PDE-5 inhibitors (Pfizer 2017); loss of consciousness can be associated with these events.  
At least 1 TEAE of special interest was reported by 18 (9.0%) subjects in the udenafil group 
and 19 (9.5%) subjects in the placebo group (Table 37). The incidence of individual TEAEs 
was similar between treatment groups. 
Table 37: 
Number (Percent) of Subjects Reporting Treatment-emergent Adverse 
Events of Special Interest (Safety Population) 
System Organ Class 
Preferred Term 
Udenafil 
(N=200) 
n (%) 
Placebo 
(N=200) 
n (%) 
Subjects with ≥1 TEAE of special interest 
18 (9.0) 
19 (9.5) 
Dizziness 
17 (8.5) 
18 (9.0) 
Loss of consciousness 
0 
1 (0.5) 
Syncope 
1 (0.5) 
3 (1.5) 
TEAE=treatment-emergent adverse event 
Source: Table 14.3.15 
Program: 14_3_ae_tables.sas 
 
The incidence of TEAEs of special interest was generally similar across age and weight 
tertiles. Tabular summaries of TEAEs of special interest by weight tertile are provided in 
Table 14.3.16A, Table 14.3.16B, and Table 14.3.16C. Tabular summaries of TEAEs of special 
interest by age tertile are provided in Table 14.3.17A, Table 14.3.17B, and Table 14.3.17C. 
12.3.2 
Narratives of Deaths, Other Serious Adverse Events and 
Certain Other Significant Adverse Events 
Individual subject narratives for serious TEAEs, TEAEs resulting in discontinuation of study 
drug, and TEAEs of special interest are provided in Section 14.3.3. 


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12.3.3 
Analysis and Discussion of Deaths, Other Serious Adverse 
Events and Other Significant Adverse Events 
No subject died during the study. At least 1 serious TEAE was reported by 14 (7.0%) subjects 
in the udenafil group and 10 (5.0%) subjects in the placebo group. No individual serious 
TEAE was reported by >2 subjects in either treatment group. Hospitalization was reported for 
23 subjects (14 udenafil, 9 placebo) during the study. No transplants were reported. 
At least 1 TEAE leading to temporary or permanent discontinuation of study drug was 
reported by 18 (9.0%) subjects in the udenafil group and 13 (6.5%) subjects in the placebo 
group. Headache was the only TEAE leading to temporary or permanent discontinuation of 
study drug reported by >2 subjects in either treatment group (3 subjects each in the udenafil 
and placebo groups). 
The percentage of subjects reporting at least 1 serious TEAE is summarized across subgroups 
defined by baseline age and weight tertiles in Table 38. No specific serious TEAE was 
reported for more than 2 subjects each in the udenafil group. Due to low number of subjects 
reporting specific serious TEAEs, summaries of individual serious TEAEs across subgroups 
are not meaningful.  
Table 38: 
Number (Percent) of Subjects Reporting at Least 1 Serious 
Treatment-emergent Adverse Event by Age and Weight Tertiles (Safety 
Population) 
Subgroup: 
Udenafil 
(N=200) 
n/N (%) 
Placebo 
(N=200) 
n/N (%) 
Age at baseline 
 
 
Low tertile 
6/72 (8.3) 
2/61 (3.3) 
Medium tertile 
2/62 (3.2) 
3/72 (4.2) 
High tertile 
6/66 (9.1) 
5/67 (7.5) 
Weight at baseline 
 
 
Low tertile 
7/75 (9.3) 
1/59 (1.7) 
Medium tertile 
3/68 (4.4) 
5/64 (7.8) 
High tertile 
4/57 (7.0) 
4/77 (5.2) 
n=number of subjects with at least 1 serious adverse event; N=number of subjects in subgroup;  
%=(n divided by N) × 100 
Source: Table 14.3.12A, Table 14.3.12B, Table 14.3.12C, Table 14.3.13A, Table 14.3.13B, and Table 14.3.13C 
Program: T_14_3_ae_tables.sas 
 


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12.4 
Clinical Laboratory Evaluation 
12.4.1 
Listing of Individual Laboratory Measurements by Subject 
and Each Abnormal Laboratory Value 
Results for alanine aminotransferase, aspartate aminotransferase, and creatinine are listed by 
subject and study visit in Listing 16.2.8.2. 
12.4.2 
Evaluation of Each Laboratory Parameter 
12.4.2.1 
Laboratory Values Over Time 
Mean changes in alanine aminotransferase, aspartate aminotransferase, and creatinine from 
baseline to Week 26 were small and similar between treatment groups (Table 39). 
Table 39: 
Changes in Safety Laboratory Values from Baseline to Week 26 (Safety 
Population) 
 
Udenafil 
(N=200) 
Placebo 
(N=200) 
LS Mean  
 
N 
Mean (SD) 
N 
Mean (SD) 
Difference (SE) 
ALT (U/L) 
 
 
 
 
 
Baselinea 
200 
35.07 (14.287) 
200 
34.88 (14.552) 
0.20 (1.444) 
Week 26 
189 
35.08 (14.282) 
192 
35.93 (14.925) 
-0.84 (1.499) 
Difference, Week 26 – baseline 
189 
-0.34 (11.104) 
192 
0.73 (10.126) 
-1.01 (1.018) 
AST (U/L) 
 
 
 
 
 
Baselinea 
200 
32.57 (12.091) 
200 
32.15 (12.050) 
0.41 (1.206) 
Week 26 
189 
32.58 (11.542) 
193 
33.06 (15.350) 
-0.48 (1.390) 
Difference, Week 26 – baseline 
189 
-0.08 (9.154) 
193 
0.75 (14.538) 
-0.70 (1.156) 
Creatinine (mg/dL) 
 
 
 
 
 
Baselinea 
200 
0.68 (0.142) 
200 
0.72 (0.141) 
-0.03 (0.014) 
Week 26 
189 
0.74 (0.162) 
192 
0.76 (0.149) 
-0.02 (0.016) 
Difference, Week 26 – baseline 
189 
0.06 (0.098) 
192 
0.04 (0.113) 
0.01 (0.011) 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; LS=least squares; SD=standard deviation; SE=standard 
error 
a Baseline value was defined as the last assessment on or before dosing at baseline visit. 
Source: Table 14.3.21 
Program: T_14_3_21.sas 
 


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12.4.2.2 
Individual Subject Changes 
The percentages of subjects with a shift in alanine aminotransferase, aspartate 
aminotransferase, or creatinine from within normal limits at baseline to above the upper limit 
of normal at postbaseline were low and similar between treatment groups (Table 40). No 
subject met criteria for Grade 3 toxicity (>5 × upper limit of normal) for alanine 
aminotransferase or aspartate aminotransferase (Listing 16.2.8.2). 
Table 40: 
Shifts from Within Normal Limits at Baseline to Above Upper Limit of 
Normal at Postbaseline (Safety Population) 
Laboratory Parameter 
Udenafil 
n/N (%) 
Placebo 
n/N (%) 
ALT 
2/189 (1.1) 
1/192 (0.5) 
AST 
5/189 (2.6) 
4/193 (2.1) 
Creatinine 
0/189 
0/192 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; n=number of subjects with at least 1 shift; N=number 
of subjects with data at baseline and postbaseline; %=(n divided by N) × 100 
Source: Table 14.3.22 
Program: T_14_3_22.sas 
 
12.4.2.3 
Individual Clinically Significant Abnormalities 
The following TEAEs were reported for changes in hepatic enzymes. 
• Alanine aminotransferase increased and aspartate aminotransferase decreased: 
1 subject in the udenafil group (Subject 390005) had values of 74 and 57 U/L, 
respectively, at baseline and values of 46 and 43 U/L, respectively, at Week 26. All 
values were within the normal reference range. 
• Alanine aminotransferase increased: 2 subjects in the placebo group. Subject 310006 
had values of 26 U/L at baseline and 38 U/L at Week 26. Subject 500001 had values 
of 56 U/L at baseline and 63 U/L at Week 26. All reported values were within the 
normal reference range for both subjects. 
No TEAEs were reported for changes in creatinine.  
 


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12.5 
Vital Signs, Physical Findings and other Observations Related 
to Safety 
Mean changes from baseline in blood pressure and heart rate were small and generally 
similar between treatment groups (Table 41). Statistically significant treatment group 
differences were observed for change in diastolic blood pressure from baseline to Week 2 and 
to Week 26, with greater decreases in the udenafil group. 


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Table 41: 
Changes in Blood Pressure and Heart Rate from Baseline to Week 2, 
Week 13, and Week 26 (Safety Population) 
 
Udenafil 
(N=200) 
Placebo 
(N=200) 
p-valuea 
Systolic blood pressure (mmHg) 
 
 
 
Baselineb 
n=200 
n=200 
 
Mean (standard deviation) 
112.32 (12.136) 
113.21 (12.887) 
0.477 
Week 2 – baselinec 
n=154 
n=155 
 
Mean (standard deviation) 
-1.34 (14.846) 
-0.64 (15.424) 
0.682 
Week 13 – baselinec 
n=131 
n=143 
 
Mean (standard deviation) 
-1.15 (13.000) 
-1.26 (13.978) 
0.948 
Week 26 – baseline 
n=189 
n=190 
 
Mean (standard deviation) 
-1.90 (12.166) 
-0.49 (11.535) 
0.246 
Diastolic blood pressure (mmHg) 
 
 
 
Baselineb 
n=200 
n=200 
 
Mean (standard deviation) 
68.39 (9.508) 
69.30 (10.142) 
0.355 
Week 2 – baselinec 
n=154 
n=154 
 
Mean (standard deviation) 
-4.34 (12.113) 
-1.46 (12.398) 
0.040 
Week 13 – baselinec 
n=131 
n=143 
 
Mean (standard deviation) 
-3.75 (11.374) 
-1.95 (12.695) 
0.220 
Week 26 – baseline 
n=189 
n=190 
 
Mean (standard deviation) 
-3.01 (9.644) 
0.05 (10.696) 
0.004 
Heart rate (bpm) 
 
 
 
Baselineb 
n=200 
n=200 
 
Mean (standard deviation) 
87.52 (15.253) 
88.12 (14.128) 
0.683 
Week 2 – baselinec 
n=154 
n=155 
 
Mean (standard deviation) 
-6.90 (13.464) 
-8.30 (14.810) 
0.385 
Week 13 – baselinec 
n=131 
n=143 
 
Mean (standard deviation) 
-6.94 (15.606) 
-7.83 (14.230) 
0.621 
Week 26 – baseline 
n=189 
n=190 
 
Mean (standard deviation) 
-1.06 (12.725) 
-1.02 (12.448) 
0.977 
a P-value was assessed using analysis of variance with fixed factor for treatment group. 
b Last pre-drug administration measurement. 
c Collection of blood pressure and heart rate at Week 2 and Week 13 was stopped in the middle of the study and 
removed from the protocol version 3.0 (31 August 2017). 
Source: Table 14.3.23 
Program: T_14_3_23.sas 
 
The percentages of subjects with potentially clinically significant vital sign values 
pre-6-minute walk and post-6-minute walk on Day 1 were small and similar between 
treatment groups. Potentially clinically significant vital sign changes on Day 1 are 


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summarized in Table 42. There were no TEAEs for blood pressure or heart rate associated 
with these changes. Vital sign results for individual subjects are presented in Listing 16.2.8.1. 
Table 42: 
Potentially Clinically Significant Vital Sign Changes on Day 1 (Safety 
Population) 
Vital Sign 
Time Point 
Udenafil 
(N=200) 
Placebo 
(N=200) 
Low systolic blood pressure, n (%) with postdose value ≤80 mmHg and decreased ≥20 mmHg from value 
before dosing 
Pre-6MWTa 
0 
0 
Post-6MWTa 
0 
0 
≥1 event at either time point 
0 
0 
High systolic blood pressure, n (%) with postdose value ≥140 mmHg and increased ≥20 mmHg from value 
before dosing 
Pre-6MWTa 
0 
0 
Post-6MWTa 
11 (5.5) 
8 (4.0) 
≥1 event at either time point 
11 (5.5) 
8 (4.0) 
Low diastolic blood pressure, n (%) with postdose value ≤50 mmHg and decreased ≥15 mmHg from value 
before dosing 
Pre-6MWTa 
2 (1.0) 
2 (1.0) 
Post-6MWTa 
2 (1.0) 
3 (1.5) 
≥1 event at either time point 
4 (2.0) 
4 (2.0) 
High diastolic blood pressure, n (%) with postdose value ≥100 mmHg and increased ≥15 mmHg from value 
before dosing 
Pre-6MWTa 
0 
1 (0.5) 
Post-6MWTa 
1 (0.5) 
0 
≥1 event at either time point 
1 (0.5) 
1 (0.5) 
Low heart rate, n (%) with postdose value ≤45 bpm and decreased ≥15 bpm from value before dosing 
Pre-6MWTa 
0 
0 
Post-6MWTa 
1 (0.5) 
0 
≥1 event at either time point 
1 (0.5) 
0 
High heart rate, n (%) with postdose value ≥130 bpm and increased ≥15 bpm from value before dosing 
Pre-6MWTa 
0 
0 
Post-6MWTa 
5 (2.5) 
4 (2.0) 
≥1 event at either time point 
5 (2.5) 
4 (2.0) 
6MWT=6-minute walk test 
a Approximately 2 hours after first drug administration. 
Source: Table 14.3.24 
Program: T_14_3_24.sas 


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12.6 
Safety Conclusions 
A notably larger percentage (≥5 percentage points) of udenafil-treated than placebo-treated 
subjects reported at least 1 TEAE (79.0% versus 67.5%) and at least 1 drug-related TEAE 
(66.0% versus 42.5%). The incidence of TEAEs of Grade ≥3, serious TEAEs, drug-related 
serious TEAEs, and TEAEs resulting in temporary or permanent discontinuation of study 
drug was similar between treatment groups. 
A notably greater percentage (≥5 percentage points) of subjects in the udenafil group as 
compared to the placebo group reported headache (39.0% versus 25.5%), flushing 
(14.5% versus 6.0%), epistaxis (10.0% versus 3.0%), nausea (9.5% versus 4.5%), and 
erection increased (6.3% of males versus 0.8% of males).  
There were no clinically important differences in the TEAE profile among subgroups defined 
by gender (female, male), race (Caucasian/White, non-Caucasian/White), ethnicity (Hispanic 
or Latino/Latina, not Hispanic or Latino/Latina), age (tertiles at baseline), and weight (tertiles 
at baseline). 
Severe TEAEs were reported for 10 (5.0%) udenafil-treated subjects and 6 (3.0%) 
placebo-treated subjects; no life-threatening TEAEs were reported in either treatment group. 
Dizziness was the only severe TEAE reported by >1 subject (2 placebo subjects). 
No subject died during the study. At least 1 serious TEAE was reported by 14 (7.0%) subjects 
in the udenafil group and 10 (5.0%) subjects in the placebo group. No individual serious 
TEAE was reported by >2 subjects in either treatment group. Hospitalization was reported for 
23 subjects (14 udenafil, 9 placebo) during the study. No transplants were reported. 
At least 1 TEAE leading to temporary or permanent discontinuation of study drug was 
reported by 18 (9.0%) subjects in the udenafil group and 13 (6.5%) subjects in the placebo 
group. Headache was the only TEAE leading to temporary or permanent discontinuation of 
study drug reported by >2 subjects in either treatment group (3 subjects each in the udenafil 
and placebo groups). 
There were no clinically important treatment group differences for clinical laboratory 
findings and vital signs. 
Overall, udenafil was safe and well tolerated in this study. 


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13 
Discussion and Overall Conclusions 
The primary aim of this study was to evaluate the effect of 26 weeks of treatment with 
udenafil on exercise capacity in adolescents with Fontan physiology. The protocol-specified 
primary exercise outcome was change in maximal VO2 and secondary exercise outcomes 
included change in VO2 at VAT, change in ventilatory efficiency at VAT, and work rate at 
VAT. All exercise measures demonstrated a favorable outcome for udenafil relative to 
placebo. 
For maximal VO2, the udenafil group had a mean increase from baseline to Week 26 
compared to a mean decrease in the placebo group (44.40 mL/min versus -3.65 mL/min; 
p=0.071). When standardized by each subject’s body weight, the least squares mean 
treatment group difference was 0.64 mL/kg/min (p=0.092).  
The following secondary efficacy endpoints measured at VAT also indicated greater exercise 
capacity in the udenafil group than the placebo group at Week 26: 
• VO2 at VAT: Mean increase (improvement) for udenafil as compared to a mean 
decrease in the placebo group (29.65 mL/min versus -8.01 mL/min; p=0.023). When 
standardized by each subject’s body weight, the least squares mean treatment group 
difference was 0.78 mL/kg/min (p=0.012). 
• VE/VCO2 at VAT: Greater mean decrease (improvement) for udenafil as compared to 
placebo (-0.76 versus -0.05; p=0.011). 
• Work rate at VAT: Greater mean increase (improvement) for udenafil as compared to 
placebo (3.46 watts versus 0.31 watts; p=0.029). 
An additional efficacy aim evaluated the effect of 26 weeks of treatment with udenafil on the 
performance of a single ventricle. The primary measure of ventricular performance was 
change in MPI, which indicated improvement with udenafil versus placebo (-0.02 versus 
0.01; p=0.024). 
Common TEAEs with a notably greater incidence (≥5 percentage points) in the udenafil 
group as compared to the placebo group included headache, flushing, epistaxis, nausea, and 
erection increased (in males). These events have been reported with other PDE-5 inhibitors 
(Pfizer 2017). 
There were no clinically important differences in the TEAE profile among subgroups defined 
by gender (female, male), race (Caucasian/White, non-Caucasian/White), ethnicity (Hispanic 


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or Latino/Latina, not Hispanic or Latino/Latina), age (tertiles at baseline), and weight (tertiles 
at baseline). 
The incidence of TEAEs of Grade ≥3, serious TEAEs, drug-related serious TEAEs, and 
TEAEs resulting in temporary or permanent discontinuation of study drug was similar 
between treatment groups. No subject died during the study. No individual serious TEAE was 
reported by >2 subjects in either treatment group. Hospitalization was reported for 
23 subjects (14 udenafil, 9 placebo) during the study.  
There were no clinically important treatment group differences for clinical laboratory 
findings and vital signs. Overall, udenafil was safe and well tolerated in this study. 
In summary, this study achieved its primary clinical objectives by demonstrating that udenafil 
administered orally at 87.5 mg BID for 26 weeks led to improved exercise capacity as 
compared to placebo in adolescents with Fontan physiology. In addition, myocardial 
performance was improved in the group treated with udenafil.  
 


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14 
Tables, Figures and Graphs Referred to but not Included in the 
Text 
14.1 
Demographic Data 
Table 14.1.1 Screening Failures (All Screened Subjects Who Were Not Randomized) 
Table 14.1.2 Subject Disposition (ITT Population) 
Table 14.1.3 Enrollment Report by Site and Treatment Arm (ITT Population) 
Table 14.1.4 Analysis Populations 
Table 14.1.5 Protocol Deviations (ITT Population) 
Table 14.1.6A Baseline Characteristics (Safety Population) 
Table 14.1.6B Baseline Characteristics (ITT Population) 
Table 14.1.7 Subjects with Baseline Abnormalities in Medical and Surgical Histories 
(Safety Population) 
 
14.2 
Efficacy Data 
Table 14.2.1.1.1 Change in Maximal VO2 (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: LOCF 
Table 14.2.1.1.2 Change in Maximal VO2 (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: None 
Table 14.2.1.1.2.1 Change in Maximal VO2 (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: None  
By Subpopulation - Biological Gender 
Table 14.2.1.1.2.2 Change in Maximal VO2 (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: None  
By Subpopulation - Race 
Table 14.2.1.1.2.3 Change in Maximal VO2 (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: None  
By Subpopulation - Ethnicity 
Table 14.2.1.1.2.4 Change in Maximal VO2 (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: None  
By Subpopulation - Ventricular Morphology 
Table 14.2.1.1.2.5 Change in Maximal VO2 (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: None  
By Subpopulation - Age at Fontan Surgery 


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Table 14.2.1.1.2.6 Change in Maximal VO2 (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: None  
By Subpopulation - Baseline Serum BNP Level 
Table 14.2.1.1.2.7 Change in Maximal VO2 (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: None  
By Subpopulation - Percent of Predicted Max VO2 at Baseline 
Table 14.2.1.1.2.8 Change in Maximal VO2 (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: None  
By Subpopulation - Afterload Reducing Agents 
Table 14.2.1.1.3 Change in Maximal VO2 (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: Mean Value 
Figure 14.2.1.1.3 Change in Maximal VO2 (mL/min) – Waterfall Plot (ITT Population) – 
Imputation: None 
Table 14.2.1.1.4 Change in Maximal VO2 (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (Per Protocol Population) - Imputation: LOCF 
Figure 14.2.1.1.4 Change in Maximal VO2 (mL/kg/min) – Waterfall Plot (ITT Population) – 
Imputation: None 
Table 14.2.1.1.5 Change in Maximal VO2 (ml/min) By Treatment Arm between Week 26 
and Baseline Visits Analyzed by Ranks (ITT Population) - Imputation: 
LOCF 
Figure 14.2.1.1.5 Improvement Maximal VO2 (mL/kg/min) – (ITT Population) – 
Imputation: None 
Table 14.2.1.1.6 Change in Maximal VO2 (ml/min) By Treatment Arm between Week 26 
and Baseline Visits Analyzed by Ranks (ITT Population) - Imputation: 
Missing VO2 at Week 26 is Imputed as Zero 
Figure 14.2.1.1.6 Change in Maximal VO2 (mL/min) – Forest Plot Treatment Group 
Difference With 95% Confidence Interval for Change Between Week 26 
and Baseline Visits in Subpopulations (ITT Population) – Imputation: 
LOCF 
Figure 14.2.1.1.7 Change in Maximal VO2 (mL/kg/min) – Forest Plot Treatment Group 
Difference With 95% Confidence Interval for Change Between Week 26 
and Baseline Visits in Subpopulations (ITT Population) – Imputation: 
LOCF 
Table 14.2.1.2.1 Percent Change in Maximal VO2 (ml/min) By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: LOCF 
Table 14.2.1.2.2 Percent Change in Maximal VO2 (ml/min) By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: None 
Table 14.2.1.2.3 Percent Change in Maximal VO2 (ml/min) By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: Mean Value 


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Table 14.2.1.2.4 Percent Change in Maximal VO2 (ml/min) By Treatment Arm between 
Week 26 and Baseline Visits (Per Protocol Population) - Imputation: 
LOCF 
Table 14.2.1.2.5 Change in Maximal VO2 (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: None By Site 
Table 14.2.2.1.1 Change in Maximal VO2 (ml/kg/min) By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: LOCF 
Table 14.2.2.1.2 Change in Maximal VO2 (ml/kg/min) By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: None 
Table 14.2.2.1.2.1 Change in Maximal VO2 (ml/kg/min) By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: None  
By Subpopulation - Biological Gender 
Table 14.2.2.1.2.2 Change in Maximal VO2 (ml/kg/min) By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: None  
By Subpopulation - Race 
Table 14.2.2.1.2.3 Change in Maximal VO2 (ml/kg/min) By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: None  
By Subpopulation - Ethnicity 
Table 14.2.2.1.2.4 Change in Maximal VO2 (ml/kg/min) By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: None  
By Subpopulation - Ventricular Morphology 
Table 14.2.2.1.2.5 Change in Maximal VO2 (ml/kg/min) By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: None  
By Subpopulation - Age at Fontan Surgery 
Table 14.2.2.1.2.6 Change in Maximal VO2 (ml/kg/min) By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: None  
By Subpopulation - Baseline Serum BNP 
Table 14.2.2.1.2.7 Change in Maximal VO2 (ml/kg/min) By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: None  
By Subpopulation - Percent of Predicted Max VO2 at Baseline 
Table 14.2.2.1.2.8 Change in Maximal VO2 (ml/kg/min) By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: None  
By Subpopulation - Afterload Reducing Agents 
Table 14.2.2.1.3 Change in Maximal VO2 (ml/kg/min) By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: Mean Value 
Figure 14.2.2.1.3 Change in VO2 at VAT (mL/min) – Waterfall Plot (ITT Population) – 
Imputation: None 
Table 14.2.2.1.4 Change in Maximal VO2 (ml/kg/min) By Treatment Arm between 
Week 26 and Baseline Visits (Per Protocol Population) - Imputation: 
LOCF 


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Figure 14.2.2.1.4 Change in VO2 at VAT (mL/kg/min) – Waterfall Plot (ITT Population) – 
Imputation: None 
Table 14.2.2.1.5 Change in Maximal VO2 (ml/kg/min) By Treatment Arm between 
Week 26 and Baseline Visits Analyzed by Ranks (ITT Population) - 
Imputation: LOCF 
Figure 14.2.2.1.5 Improvement VO2 at VAT (mL/kg/min) – (ITT Population) – Imputation: 
None 
Table 14.2.2.1.6 Change in Maximal VO2 (ml/kg/min) By Treatment Arm between 
Week 26 and Baseline Visits Analyzed by Ranks (ITT Population) - 
Imputation: Missing VO2 at Week 26 is Imputed as Zero 
Figure 14.2.2.1.6 Change in VO2 at VAT (mL/min) – Forest Plot Treatment Group 
Difference With 95% Confidence Interval for Change Between Week 26 
and Baseline Visits in Subpopulations (ITT Population) – Imputation: 
LOCF 
Figure 14.2.2.1.7 Change in VO2 at VAT (mL/kg/min) – Forest Plot Treatment Group 
Difference With 95% Confidence Interval for Change Between Week 26 
and Baseline Visits in Subpopulations (ITT Population) – Imputation: 
LOCF 
Table 14.2.2.2.1 Percent Change in Maximal VO2 (ml/kg/min) By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: LOCF 
Table 14.2.2.2.2 Percent Change in Maximal VO2 (ml/kg/min) By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: None 
Table 14.2.2.2.3 Percent Change in Maximal VO2 (ml/kg/min) By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: Mean Value 
Table 14.2.2.2.4 Percent Change in Maximal VO2 (ml/kg/min) By Treatment Arm between 
Week 26 and Baseline Visits (Per Protocol Population) - Imputation: 
LOCF 
Table 14.2.2.2.5 Change in Maximal VO2 (ml/mg/min) By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: None By Site 
Table 14.2.3.1.1 Change in VO2 at VAT (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: LOCF 
Table 14.2.3.1.2 Change in VO2 at VAT (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: None 
Table 14.2.3.1.2.1 Change in VO2 at VAT (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: None By 
Subpopulation - Biological Gender 
Table 14.2.3.1.2.2 Change in VO2 at VAT (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: None By 
Subpopulation - Race 


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Table 14.2.3.1.2.3 Change in VO2 at VAT (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: None By 
Subpopulation - Ethnicity 
Table 14.2.3.1.2.4 Change in VO2 at VAT (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: None By 
Subpopulation - Ventricular Morphology 
Table 14.2.3.1.2.5 Change in VO2 at VAT (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: None By 
Subpopulation - Age at Fontan Surgery 
Table 14.2.3.1.2.6 Change in VO2 at VAT (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: None By 
Subpopulation - Baseline Serum BNP 
Table 14.2.3.1.2.7 Change in VO2 at VAT (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: None By 
Subpopulation - Percent of Predicted Max VO2 at Baseline 
Table 14.2.3.1.2.8 Change in VO2 at VAT (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: None By 
Subpopulation - Afterload Reducing Agents 
Table 14.2.3.1.3 Change in VO2 at VAT (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: Mean Value 
Table 14.2.3.1.4 Change in VO2 at VAT (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: Linear Regression 
Model 
Table 14.2.3.1.5 Change in VO2 at VAT (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (Per Protocol Population) - Imputation: LOCF 
Table 14.2.3.1.6 Change in VO2 at VAT (ml/min) By Treatment Arm between Week 26 
and Baseline Visits Analyzed by Ranks (ITT Population) - Imputation: 
LOCF 
Table 14.2.3.2.1 Percent Change in VO2 at VAT (ml/min) By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: LOCF 
Table 14.2.3.2.2 Percent Change in VO2 at VAT (ml/min) By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: None 
Table 14.2.3.2.3 Percent Change in VO2 at VAT (ml/min) By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: Mean Value 
Table 14.2.3.2.4 Percent Change in VO2 at VAT (ml/min) By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: Linear 
Regression Model 
Table 14.2.3.2.5 Percent Change in VO2 at VAT (ml/min) By Treatment Arm between 
Week 26 and Baseline Visits (Per Protocol Population) - Imputation: 
LOCF 


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Table 14.2.3.2.6 Change in VO2 at VAT (ml/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: None By Site 
Table 14.2.4.1.1 Change in VO2 at VAT (ml/kg/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: LOCF 
Table 14.2.4.1.2 Change in VO2 at VAT (ml/kg/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: None 
Table 14.2.4.1.3 Change in VO2 at VAT (ml/kg/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: Mean Value 
Table 14.2.4.1.4 Change in VO2 at VAT (ml/kg/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: Linear Regression 
Model 
Table 14.2.4.1.5 Change in VO2 at VAT (ml/kg/min) By Treatment Arm between Week 26 
and Baseline Visits (Per Protocol Population) - Imputation: LOCF 
Table 14.2.4.1.6 Change in VO2 at VAT (ml/kg/min) By Treatment Arm between Week 26 
and Baseline Visits Analyzed by Ranks (ITT Population) - Imputation: 
LOCF 
Table 14.2.4.2.1 Percent Change in VO2 at VAT (ml/kg/min) By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: LOCF 
Table 14.2.4.2.2 Percent Change in VO2 at VAT (ml/kg/min) By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: None 
Table 14.2.4.2.3 Percent Change in VO2 at VAT (ml/kg/min) By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: Mean Value 
Table 14.2.4.2.4 Percent change in VO2 at VAT (ml/kg/min) By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: Linear 
Regression Model 
Table 14.2.4.2.5 Percent Change in VO2 at VAT (ml/kg/min) By Treatment Arm between 
Week 26 and Baseline Visits (Per Protocol Population) - Imputation: 
LOCF 
Table 14.2.4.2.6 Change in VO2 at VAT (ml/kg/min) By Treatment Arm between Week 26 
and Baseline Visits (ITT Population) - Imputation: None By Site 
Table 14.2.5.1.1 Change in Minute Oxygen Consumption (L/Min) at Maximal Exercise 
Effort By Treatment Arm Between Week 26 and Baseline Visits (ITT 
Population) - Imputation: LOCF 
Table 14.2.5.1.2 Change in Minute Oxygen Consumption (L/Min) at Maximal Exercise 
Effort By Treatment Arm Between Week 26 and Baseline Visits (ITT 
Population) - Imputation: None 
Table 14.2.5.1.3 Change in Minute Oxygen Consumption (L/Min) at Maximal Exercise 
Effort By Treatment Arm Between Week 26 and Baseline Visits (ITT 
Population) - Imputation: Mean Value 


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Table 14.2.5.2.1 Percent change in Minute Oxygen Consumption (L/Min) at Maximal 
Exercise Effort By Treatment Arm Between Week 26 and Baseline Visits 
(ITT Population) - Imputation: LOCF 
Table 14.2.5.2.2 Percent change in Minute Oxygen Consumption (L/Min) at Maximal 
Exercise Effort By Treatment Arm Between Week 26 and Baseline Visits 
(ITT Population) - Imputation: None 
Table 14.2.5.2.3 Percent change in Minute Oxygen Consumption (L/Min) at Maximal 
Exercise Effort By Treatment Arm Between Week 26 and Baseline Visits 
(ITT Population) - Imputation: Mean Value 
Table 14.2.6 
Intentionally not used 
Table 14.2.7.1.1 Change in Respiratory Rate at Maximal Exercise Effort By Treatment 
Arm Between Week 26 and Baseline Visits (ITT Population) - Imputation: 
LOCF 
Table 14.2.7.1.2 Change in Respiratory Rate at Maximal Exercise Effort By Treatment 
Arm Between Week 26 and Baseline Visits (ITT Population) - Imputation: 
None 
Table 14.2.7.1.3 Change in Respiratory Rate at Maximal Exercise Effort By Treatment 
Arm Between Week 26 and Baseline Visits (ITT Population) - Imputation: 
Mean Value 
Table 14.2.7.2.1 Percent Change in Respiratory Rate at Peak Exercise Effort By Treatment 
Arm Between Week 26 and Baseline Visits (ITT Population) - Imputation: 
LOCF 
Table 14.2.7.2.2 Percent Change in Respiratory Rate at Peak Exercise Effort By Treatment 
Arm Between Week 26 and Baseline Visits (ITT Population) - Imputation: 
None 
Table 14.2.7.2.3 Percent Change in Respiratory Rate at Peak Exercise Effort By Treatment 
Arm Between Week 26 and Baseline Visits (ITT Population) - Imputation: 
Mean Value 
Table 14.2.8.1.1 Change in Minute Ventilation (L/min) at Maximal Exercise Effort By 
Treatment Arm Between Week 26 and Baseline Visits (ITT Population) - 
Imputation: LOCF 
Table 14.2.8.1.2 Change in Minute Ventilation (L/min) at Maximal Exercise Effort By 
Treatment Group Between Week 26 and Baseline Visits (ITT Population) 
- Imputation: None 
Table 14.2.8.1.3 Change in Minute Ventilation (L/min) at Maximal Exercise Effort By 
Treatment Arm Between Week 26 and Baseline Visits (ITT Population) - 
Imputation: Mean Value 
Table 14.2.8.2.1 Percent Change in Minute Ventilation (L/min) at Maximal Exercise Effort 
By Treatment Arm Between Week 26 and Baseline Visits (ITT 
Population) - Imputation: LOCF 


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Table 14.2.8.2.2 Percent Change in Minute Ventilation (L/min) at Maximal Exercise Effort 
By Treatment Arm Between Week 26 and Baseline Visits (ITT 
Population) - Imputation: None 
Table 14.2.8.2.3 Percent Change in Minute Ventilation (L/min) at Maximal Exercise Effort 
By Treatment Arm Between Week 26 and Baseline Visits (ITT 
Population) - Imputation: Mean Value 
Table 14.2.9.1.1 Change in Work Rate (watts) at Maximal Exercise Effort By Treatment 
Arm Between Week 26 and Baseline Visits (ITT Population) - Imputation: 
LOCF 
Table 14.2.9.1.2 Change in Work Rate (watts) at Maximal Exercise Effort By Treatment 
Arm Between Week 26 and Baseline Visits (ITT Population) - Imputation: 
None 
Table 14.2.9.1.3 Change in Work Rate (watts) at Maximal Exercise Effort By Treatment 
Arm Between Week 26 and Baseline Visits (ITT Population) - Imputation: 
Mean Value 
Table 14.2.9.2.1 Change in Work Rate (watts) at Maximal Exercise Effort By Treatment 
Arm Between Week 26 and Baseline Visits (ITT Population) - Imputation: 
LOCF 
Table 14.2.9.2.2 Change in Work Rate (watts) at Maximal Exercise Effort By Treatment 
Arm Between Week 26 and Baseline Visits (ITT Population) - Imputation: 
None 
Table 14.2.9.2.3 Change in Work Rate (watts) at Maximal Exercise Effort By Treatment 
Arm Between Week 26 and Baseline Visits (ITT Population) - Imputation: 
Mean Value 
Table 14.2.10.1.1 Change in Heart Rate (beats/min) at Maximal Exercise Effort by 
Treatment Arm Between Week 26 and Baseline Visits (ITT Population) - 
Imputation: LOCF 
Table 14.2.10.1.2 Change in Heart Rate (beats/min) at Maximal Exercise Effort by 
Treatment Group Between Week 26 and Baseline Visits (ITT Population) 
- Imputation: None 
Table 14.2.10.1.3 Change in Heart Rate (beats/min) at Maximal Exercise Effort by 
Treatment Arm Between Week 26 and Baseline Visits (ITT Population) - 
Imputation: Mean Value 
Table 14.2.10.2.1 Percent Change in Heart Rate (beats/min) at Maximal Exercise Effort by 
Treatment Arm Between Week 26 and Baseline Visits (ITT Population) - 
Imputation: LOCF 
Table 14.2.10.2.2 Percent Change in Heart Rate (beats/min) at Maximal Exercise Effort by 
Treatment Arm Between Week 26 and Baseline Visits (ITT Population) - 
Imputation: None 


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Table 14.2.10.2.3 Percent Change in Heart Rate (beats/min) at Maximal Exercise Effort by 
Treatment Arm Between Week 26 and Baseline Visits (ITT Population) - 
Imputation: Mean Value 
Table 14.2.11.1.1 Change in Respiratory Exchange Ratio (RER) at Maximal Exercise Effort 
by Treatment Arm Between Week 26 and Baseline Visits (ITT Population) 
- Imputation: LOCF 
Table 14.2.11.1.2 Change in Respiratory Exchange Ratio (RER) at Maximal Exercise Effort 
by Treatment Group Between Week 26 and Baseline Visits (ITT 
Population) - Imputation: None 
Table 14.2.11.1.3 Change in Respiratory Exchange Ratio (RER) at Maximal Exercise Effort 
by Treatment Arm Between Week 26 and Baseline Visits (ITT Population) 
- Imputation: Mean Value 
Table 14.2.11.2.1 Percent Change in Respiratory Exchange Ratio (RER) at Maximal 
Exercise Effort by Treatment Arm Between Week 26 and Baseline Visits 
(ITT Population) - Imputation: LOCF 
Table 14.2.11.2.2 Percent Change in Respiratory Exchange Ratio (RER) at Maximal 
Exercise Effort by Treatment Arm Between Week 26 and Baseline Visits 
(ITT Population) - Imputation: None 
Table 14.2.11.2.3 Percent Change in Respiratory Exchange Ratio (RER) at Maximal 
Exercise Effort by Treatment Arm Between Week 26 and Baseline Visits 
(ITT Population) - Imputation: Mean Value 
Table 14.2.12.1.1 Change in Ventilatory Equivalents of Carbon Dioxide (VE/VCO2) at 
Maximal Exercise Effort By Treatment Arm between Week 26 and 
Baseline Visits (ITT Population) - Imputation: LOCF 
Table 14.2.12.1.2 Change in Ventilatory Equivalents of Carbon Dioxide (VE/VCO2) at 
Maximal Exercise Effort By Treatment Arm between Week 26 and 
Baseline Visits (ITT Population) - Imputation: None 
Table 14.2.12.1.3 Change in Ventilatory Equivalents of Carbon Dioxide (VE/VCO2) at 
Maximal Exercise Effort By Treatment Arm between Week 26 and 
Baseline Visits (ITT Population) - Imputation: Mean Value 
Table 14.2.12.2.1 Percent Change in Ventilatory Equivalents of Carbon Dioxide 
(VE/VCO2) at Maximal Exercise Effort By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: LOCF 
Table 14.2.12.2.2 Percent Change in Ventilatory Equivalents of Carbon Dioxide 
(VE/VCO2) at Maximal Exercise Effort By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: None 
Table 14.2.12.2.3 Percent Change in Ventilatory Equivalents of Carbon Dioxide 
(VE/VCO2) at Maximal Exercise Effort By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: Mean Value 


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Table 14.2.13.1.1 Change in Ventilatory Equivalents of Carbon Dioxide (VE/VCO2) at VAT 
By Treatment Arm between Week 26 and Baseline Visits (ITT Population) 
- Imputation: LOCF 
Table 14.2.13.1.2 Change in Ventilatory Equivalents of Carbon Dioxide (VE/VCO2) at VAT 
By Treatment Group between Week 26 and Baseline (ITT Population) - 
Imputation: None 
Table 14.2.13.1.3 Change in Ventilatory Equivalents of Carbon Dioxide (VE/VCO2) at VAT 
By Treatment Arm between Week 26 and Baseline Visits (ITT Population) 
- Imputation: Mean Value 
Table 14.2.13.2.1 Percent Change in Ventilatory Equivalents of Carbon Dioxide 
(VE/VCO2) at VAT By Treatment Arm between Week 26 and Baseline 
Visits (ITT Population) - Imputation: LOCF 
Table 14.2.13.2.2 Percent Change in Ventilatory Equivalents of Carbon Dioxide 
(VE/VCO2) at VAT By Treatment Arm between Week 26 and Baseline 
Visits (ITT Population) - Imputation: None 
Table 14.2.13.2.3 Percent Change in Ventilatory Equivalents of Carbon Dioxide 
(VE/VCO2) at VAT By Treatment Arm between Week 26 and Baseline 
Visits (ITT Population) - Imputation: Mean Value 
Table 14.2.14.1.1 Change in Work Rate (watts) at VAT By Treatment Arm Between 
Week 26 and Baseline Visits (ITT Population) - Imputation: LOCF 
Table 14.2.14.1.2 Change in Work Rate (watts) at VAT By Treatment Arm Between 
Week 26 and Baseline Visits (ITT Population) - Imputation: None 
Table 14.2.14.1.3 Change in Work Rate (watts) at VAT By Treatment Arm Between 
Week 26 and Baseline Visits (ITT Population) - Imputation: Mean Value 
Table 14.2.14.2.1 Percent Change in Work Rate (watts) at VAT By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: LOCF 
Table 14.2.14.2.2 Percent Change in Work Rate (watts) at VAT By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: None 
Table 14.2.14.2.3 Percent Change in Work Rate (watts) at VAT By Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) - Imputation: Mean Value 
14.2.15 
Change in Myocardial Performance Index (MPI) by Treatment Arm 
between Week 26 and Baseline Visits (ITT Population) 
14.2.15.1 
Change in End-diastolic Ventricular Volume by Modified Simpsons Rule 
(mL) (ITT Population) 
14.2.15.2 
Change in End-systolic Ventricular Volume by Modified Simpsons Rule 
(mL) by Treatment Arm between Week 26 and Baseline Visits (ITT 
Population) 
14.2.15.3 
Change in End-diastolic Ventricular Area (cm2) by Treatment Arm 
between Week 26 and Baseline Visits (ITT Population) 


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14.2.15.4 
Change in End-systolic Ventricular Area (cm2) by Treatment Arm 
between Week 26 and Baseline Visits (ITT Population) 
14.2.15.5 
Change in Mean dP/dt During Isovolumetric Contraction (mmHg/s) by 
Treatment Arm between Week 26 and Baseline Visits (ITT Population) 
14.2.15.6 
Change in Doppler Tissue Imaging (DTI) (m/s) by Treatment Arm 
between Week 26 and Baseline Visits (ITT Population) 
14.2.15.7 
Change in Ventricular Eccentricity Index by Treatment Arm between 
Week 26 and Baseline Visits (ITT Population) 
14.2.15.8 
Change in Atrioventricular Valve Regurgitation Severity by Treatment 
Arm between Week 26 and Baseline Visits (ITT Population) 
14.2.15.9 
Change in Anterior/posterior Atrioventricular Valve Vena Contracta(mm) 
by Treatment Arm between Week 26 and Baseline Visits (ITT Population) 
14.2.15.10 
Change in Transverse Atrioventricular Valve Vena Contracta(mm) by 
Treatment Arm between Week 26 and Baseline Visits (ITT Population) 
14.2.15.11 
Change in Vena Contracta Area (mm2) by Treatment Arm between Week 
26 and Baseline Visits (ITT Population) 
14.2.16 
Change in Log-Transformed Reactive Hyperemia Index (inRHI) by 
Treatment Arm between Week 26 and Baseline Visits (ITT Population) 
14.2.17 
Change in Log BNP (pg/mL) by Treatment Arm between Week 26 and 
Baseline Visits (ITT Population) 
Table 14.2.18.1 
Peds_QL Outcomes: Change in General Core Scale - Physical 
Functioning (Child Reported) by Treatment Arm Between Week 26 and 
Baseline Visits (ITT Population) 
Table 14.2.18.2 
Peds_QL Outcomes: Change in General Core Scale - Physical 
Functioning (Parent Reported) by Treatment Arm Between Week 26 and 
Baseline Visits (ITT Population) 
Table 14.2.18.3 
Peds_QL Outcomes: Change in General Core Scale - Psychosocial Health 
Summary Score (Child Reported) by Treatment Arm Between Week 26 
and Baseline Visits (ITT Population) 
Table 14.2.18.4 
Peds_QL Outcomes: Change in General Core Scale - Psychosocial Health 
Summary Score (Parent Reported) by Treatment Arm Between Week 26 
and Baseline Visits (ITT Population) 
Table 14.2.18.5 
Peds_QL Outcomes: Change in Cardiac Module Scale (Treatment II) by 
Treatment Arm Between Week 26 and Baseline Visits (ITT Population) 
Table 14.2.18.6 
Peds_QL Outcomes: Change in Cardiac Module Scale (Perceived 
Physical Appearance) by Treatment Arm Between Week 26 and Baseline 
Visits (ITT Population) 


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Table 14.2.18.7 
Peds_QL Outcomes: Change in Cardiac Module Scale (Treatment 
Anxiety) by Treatment Arm Between Week 26 and Baseline Visits (ITT 
Population) 
Table 14.2.18.8 
Peds_QL Outcomes: Change in Cardiac Module Scale (Cognitive 
Problems) by Treatment Arm Between Week 26 and Baseline Visits (ITT 
Population) 
Table 14.2.18.9 
Peds_QL Outcomes: Change in Cardiac Module Scale (Communication 
Problems) by Treatment Arm Between Week 26 and Baseline Visits (ITT 
Population) 
Table 14.2.19.1 
PCQLI Outcomes: Change in Total Score (Ages 8-12, Child Reported) by 
Treatment Arm Between Week 26 and Baseline Visits (ITT Population) 
Table 14.2.19.2 
PCQLI Outcomes: Change in Total Score (Ages 8-12, Parent Reported) 
by Treatment Arm Between Week 26 and Baseline Visits (ITT Population) 
Table 14.2.19.3 
PCQLI Outcomes: Change in Total Score (Ages 13-18, Child Reported) 
by Treatment Arm Between Week 26 and Baseline Visits (ITT Population) 
Table 14.2.19.4 
PCQLI Outcomes: Change in Total Score (Ages 13-18, Parent Reported) 
by Treatment Arm Between Week 26 and Baseline Visits (ITT Population) 
14.3 
Safety Data 
Table 14.3.1.1 Extent of Exposure Percent Compliance for Study Drug (Safety Population) 
Table 14.3.1.2 Udenafil Pharmacokinetic Results, by Visit and Treatment Arm Difference 
in Measurements (ng/ml) between Week 26 and Baseline* Udenafil (Safety 
Population) 
Table 14.3.1.3 Udenafil Pharmacokinetic Results, by Visit and Treatment Arm Difference 
in Log-Transformed Analyte Concentration (ng/ml) between Week 26 and 
Baseline Udenafil (Safety Population) 
Table 14.3.1.4 DA-8164 Pharmacokinetic Results, by Visit and Treatment Arm Difference 
in Measurements (ng/ml) between Week 26 and Baseline* DA-8164 (Safety 
Population) 
Table 14.3.1.5 DA-8164 Pharmacokinetic Results, by Visit and Treatment Arm Difference 
in Log-Transformed Analyte Concentration (ng/ml) between Week 26 and 
Baseline DA-8164 (Safety Population) 
 
14.3.1 
Displays of Adverse Events 
Table 14.3.2 
Treatment Emergent Adverse Event Reporting Profile (Safety Population) 
Table 14.3.3 
Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events Limited to Preferred Terms Reported for ≥ 5% of All Subjects 
(Safety Population) 


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Table 14.3.4A 
Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events Limited to Preferred Terms Reported for ≥ 5% of All Subjects: Male 
Subjects Only (Safety Population) 
Table 14.3.4B 
Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events Limited to Preferred Terms Reported for ≥ 5% of All Subjects: 
Female Subjects Only (Safety Population) 
Table 14.3.4C 
Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events Limited to Preferred Terms Reported for ≥ 5% of All Subjects: 
Caucasian Subjects Only (Safety Population) 
Table 14.3.4D 
Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events Limited to Preferred Terms Reported for ≥ 5% of All Subjects: 
Non-Caucasian Subjects Only (Safety Population) 
Table 14.3.4E 
Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events Limited to Preferred Terms Reported for ≥ 5% of All Subjects: 
Hispanic or Latino/Latina Subjects Only (Safety Population) 
Table 14.3.4F 
Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events Limited to Preferred Terms Reported for ≥ 5% of All Subjects: Not 
Hispanic or Latino/Latina Subjects Only (Safety Population) 
Table 14.3.5 
Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events by System Organ Class and Preferred Term (Safety Population) 
Table 14.3.6A 
Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events by Intensity, System Organ Class and Preferred Term, Mild Intensity 
(Safety Population) 
Table 14.3.6B 
Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events by Intensity, System Organ Class and Preferred Term, Moderate 
Intensity (Safety Population) 
Table 14.3.6C 
Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events by Intensity, System Organ Class and Preferred Term, Severe/Life 
Threatening/Death Intensity (Safety Population) 
Table 14.3.7A 
Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events by Relationship to Study Drug, System Organ Class and Preferred 
Term, Related to Study Drug (Safety Population) 
Table 14.3.7B 
Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events by Relationship to Study Drug, System Organ Class and Preferred 
Term, Not Related to Study Drug (Safety Population) 
Table 14.3.8A 
Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events by Weight Tertile, System Organ Class and Preferred Term, Low 
Weight Tertile (Safety Population) 


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Table 14.3.8B 
Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events by Weight Tertile, System Organ Class and Preferred Term, Medium 
Weight Tertile (Safety Population) 
Table 14.3.8C 
Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events by Weight Tertile, System Organ Class and Preferred Term, High 
Weight Tertile (Safety Population) 
Table 14.3.9A 
Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events by Age Tertile, System Organ Class and Preferred Term, Low Age 
Tertile (Safety Population) 
Table 14.3.9B 
Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events by Age Tertile, System Organ Class and Preferred Term, Medium 
Age Tertile (Safety Population) 
Table 14.3.9C 
Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events by Age Tertile, System Organ Class and Preferred Term, High Age 
Tertile (Safety Population) 
 
14.3.2 
Listings of Deaths, Other Serious and Significant Adverse 
Events 
Table 14.3.10 
Number (Percent) of Subject Reporting Treatment Emergent Serious 
Adverse Events by System Organ Class and Preferred Term (Safety 
Population) 
Table 14.3.11A Number (Percent) of Subjects Reporting Treatment Emergent Serious 
Adverse Events by Relationship to Study Drug, System Organ Class and 
Preferred Term, Related to Study Drug (Safety Population) 
Table 14.3.11B Number (Percent) of Subjects Reporting Treatment Emergent Serious 
Adverse Events by Relationship to Study Drug, System Organ Class and 
Preferred Term, Not Related to Study Drug (Safety Population) 
Table 14.3.12A Number (Percent) of Subjects Reporting Treatment Emergent Serious 
Adverse Events by Weight Tertile, System Organ Class and Preferred Term, 
Low Weight Tertile (Safety Population) 
Table 14.3.12B Number (Percent) of Subjects Reporting Treatment Emergent Serious 
Adverse Events by Weight Tertile, System Organ Class and Preferred Term, 
Medium Weight Tertile (Safety Population) 
Table 14.3.12C Number (Percent) of Subjects Reporting Treatment Emergent Serious 
Adverse Events by Weight Tertile, System Organ Class and Preferred Term, 
High Weight Tertile (Safety Population) 


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Table 14.3.13A Number (Percent) of Subjects Reporting Treatment Emergent Serious 
Adverse Events by Age Tertile, System Organ Class and Preferred Term, 
Low Age Tertile (Safety Population) 
Table 14.3.13B Number (Percent) of Subjects Reporting Treatment Emergent Serious 
Adverse Events by Age Tertile, System Organ Class and Preferred Term, 
Medium Age Tertile (Safety Population) 
Table 14.3.13C Number (Percent) of Subjects Reporting Treatment Emergent Serious 
Adverse Events by Age Tertile, System Organ Class and Preferred Term, 
High Age Tertile (Safety Population) 
Table 14.3.14 
Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events Resulting in Discontinuation of Study Drug by System Organ Class 
and Preferred Term (Safety Population) 
Table 14.3.15 
Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events with Selected Preferred Terms (Safety Population) 
Table 14.3.16A Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events with Selected Preferred Terms, Low Weight Tertile (Safety 
Population) 
Table 14.3.16B Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events with Selected Preferred Terms, Medium Weight Tertile (Safety 
Population) 
Table 14.3.16C Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events with Selected Preferred Terms, High Weight Tertile (Safety 
Population) 
Table 14.3.17A Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events with Selected Preferred Terms, Low Age Tertile (Safety Population) 
Table 14.3.17B Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events with Selected Preferred Terms, Medium Age Tertile (Safety 
Population) 
Table 14.3.17C Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events with Selected Preferred Terms, High Age Tertile (Safety Population) 
Table 14.3.18 
Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events with Death, Hospitalization or Transplant (Safety Population) 
Table 14.3.19A Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events with Death, Hospitalization or Transplant by Weight Tertile, Low 
Weight Tertile (Safety Population) 
Table 14.3.19B Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events with Death, Hospitalization or Transplant by Weight Tertile, 
Medium Weight Tertile (Safety Population) 


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       Study PHN-Udenafil-02 Clinical Study Report 
 
CONFIDENTIAL 
Page 143 of 148 
Table 14.3.19C Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events with Death, Hospitalization or Transplant by Weight Tertile, High 
Weight Tertile (Safety Population) 
Table 14.3.20A Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events with Death, Hospitalization or Transplant by Age Tertile, Low Age 
Tertile (Safety Population) 
Table 14.3.20B Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events with Death, Hospitalization or Transplant by Age Tertile, Medium 
Age Tertile (Safety Population) 
Table 14.3.20C Number (Percent) of Subjects Reporting Treatment Emergent Adverse 
Events with Death, Hospitalization or Transplant by Age Tertile, High Age 
Tertile (Safety Population) 
 
14.3.3 
Narratives of Deaths, other Serious and Certain other 
Significant Adverse Events 
 
14.3.4 
Abnormal Laboratory Value and Medication Listings (Each 
Subject) 
 
Table 14.3.21 
Clinical Laboratory Tests Change from Baseline to Week 26 (Safety 
Population) 
Table 14.3.22 
Clinical Laboratory Tests Number (Percent) of Subjects with Treatment 
Emergent Abnormal Laboratory Values (Safety Population) 
Table 14.3.23 
Descriptive Statistics for Changes in Blood Pressure and Heart Rate from 
Baseline to the Week 2, Week 13 and Week 26 Visits (Safety Population) 
Table 14.3.24 
Subjects with Potentially Clinically Significant Vital Signs Changes (Safety 
Population) 
Table 14.3.25 
Anatomical Therapeutic Chemical Classification and Preferred Drug Name 
for Prior Medications (Safety Population) 
Table 14.3.26 
Anatomical Therapeutic Chemical Classification and Preferred Drug Name 
for Concomitant Medications (Safety Population) 
 


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CONFIDENTIAL 
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15 
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double-blind, placebo-controlled, crossover trial. Circulation. 2011;123:1185-93. 
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of myocardial performance after the Fontan operation. Pediatr Cardiol. 2012;33:689-96. 
Goldberg DJ, Avitabile CM, McBride MG, Paridon SM. Exercise capacity in the Fontan 
circulation. Cardiol Young. 2013;23(6):824-30. 
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udenafil in adolescents after Fontan palliation. Am Heart J. 2017;188:42-52. 
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Goldstein BH, Connor CE, Gooding L, Rocchini AP. Relation of systemic venous return, 
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Goldstein BH, Golbus JR, Sandelin AM, et al. Usefulness of peripheral vascular function to 
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Goldstein BH, Urbina EM, Khoury PR, et al. Endothelial function and arterial stiffness relate 
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Inai K, Saita Y, Takeda S, Nakazawa M, Kimura H. Skeletal muscle hemodynamics and 
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tricuspid atresia. J Thorac Cardiovasc Surg. 1973;66:613-21. 
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SAP_001.pdf: 
 
 
Protocol No.: PHN-Udenafil-02 
CONFIDENTIAL 
 
 
1 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol No. PHN-Udenafil-02 
 
IND# 121648 
 
 
 
FONTAN UDENAFIL EXERCISE LONGITUDINAL ASSESSMENT TRIAL (FUEL) 
 
 
 
Mezzion Pharma Ltd. in partnership with Pediatric Heart Network 
 
 
Version:   
23 June 2016  
 
 
 
 


 
 
Protocol No.: PHN-Udenafil-02 
CONFIDENTIAL 
 
 
2 
 
SIGNATURES OF AGREEMENT FOR STATISTICAL ANALYSIS PLAN 
 
 
 
Name  
 
 
 
 
 
 
 
Date 
Title 
Affiliation 
 
 
 
Name  
 
 
 
 
 
 
 
Date 
Title 
Affiliation 
 
 
 
Name  
 
 
 
 
 
 
 
Date 
Title 
Affiliation 


 
 
Protocol No.: PHN-Udenafil-02 
CONFIDENTIAL 
 
 
3 
 
TABLE OF CONTENTS 
 
List of Abbreviations .......................................................................................................... 5 
1.0 Study Objectives ........................................................................................................... 6 
2.0 Overall Study Design .................................................................................................... 6 
3.0 Sample Size ................................................................................................................... 7 
4.0 Drug Regimens ............................................................................................................. 7 
5.0 Study Procedures .......................................................................................................... 7 
6.0 Statistics ........................................................................................................................ 9 
6.1 Analysis Populations ..................................................................................................9 
6.2 Accountability and Protocol Deviations ..................................................................10 
6.3 Demographic and Baseline Characteristics .............................................................10 
6.4 Efficacy Analyses ....................................................................................................10 
6.4.1 Primary Efficacy Endpoint (Aerobic Exercise Performance) ...........................10 
6.4.2 Secondary Efficacy Endpoints ..........................................................................11 
6.4.3 Missing Data .....................................................................................................12 
6.4.4 Subpopulations ..................................................................................................13 
6.4.5 Adjustments for Multiple Comparisons ............................................................13 
6.5 Safety Evaluations ...................................................................................................13 
6.5.1 Extent of Exposure ............................................................................................13 
6.5.2 Adverse Events .................................................................................................14 
6.5.3 Clinical Laboratory Tests ..................................................................................15 
6.5.4 Vital Signs .........................................................................................................16 
6.6 Prior and Concomitant Medications ........................................................................16 


 
 
Protocol No.: PHN-Udenafil-02 
CONFIDENTIAL 
 
 
4 
 
6.7 Telephone Interview ................................................................................................17 
6.8 Interim Analyses ......................................................................................................17 
7.0 Quality Control and Software ..................................................................................... 17 
8.0 Changes from the Protocol.......................................................................................... 18 
 
 
 


 
 
Protocol No.: PHN-Udenafil-02 
CONFIDENTIAL 
 
 
5 
 
List of Abbreviations 
 
ANCOVA 
analysis of covariance 
ATC 
Anatomical-Therapeutic-Chemical classification  
BNP 
brain-type natriuretic peptide 
HAES 
Habitual Activity Estimation Scale 
ICH 
International Conference on Harmonisation 
ITT 
intent-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPI 
myocardial performance index 
PAT 
pulse amplitude tonometry 
PCQLI 
Pediatric Cardiac Quality of Life Inventory 
PDE5 
phosphodiesterase type 5 
PedsQL 
Pediatric Quality of Life Inventory 
SAE 
serious adverse event 
TEAE 
treatment-emergent adverse event 
VAT 
ventilator anaerobic threshold 
VE/VCO2 
ventilatory equivalents of carbon dioxide 
VO2 
minute oxygen consumption 
 
 


 
 
Protocol No.: PHN-Udenafil-02 
CONFIDENTIAL 
 
 
6 
 
1.0 Study Objectives 
The purpose of this study will be to evaluate the clinical efficacy and safety of udenafil, an 
orally administered, potent and selective inhibitor of phosphodiesterase type 5 (PDE5), 
versus placebo for the treatment of adolescent subjects who have undergone the Fontan 
procedure 
2.0 Overall Study Design 
This study is a randomized, double-blind, 26-week, multicenter trial of udenafil (87.5 mg, 
twice daily) versus placebo on aerobic exercise performance as measured by change in 
minute oxygen consumption (VO2) at maximum exercise effort (maximal VO2) from 
baseline to six months in adolescent survivors of the Fontan procedure. 
Eligible subjects will be randomly assigned to one of two treatment groups (udenafil or 
placebo) by a web-based system at the data coordinating center. Randomization will occur 
within strata defined by ventricular morphology (single left versus single right or mixed).   
The first dose of randomized study drug will be administered at the clinic (Visit 1) and 
outpatient dosing will be used for the remainder of the 26-week study. Subjects will return 
to the clinic for assessments at 2 weeks (Visit 2), 13 weeks (Visit 3), and 26 weeks (Visit 4) 
or study completion after initiation of study drug dosing.  
Maximal VO2 will be assessed at Visits 1 and 4 (or study completion) using a braked cycle 
ergometer following a ramp protocol. Additional assessments will include ventricular 
performance as measured by echocardiogram, endothelial function assessment with 
EndoPat®, and serum brain-type natriuretic peptide (BNP) level. Quality of life will be 
assessed with the Pediatric Quality of Life Inventory (PedsQL), Pediatric Cardiac Quality 
of Life Inventory (PCQLI), and the Habitual Activity Estimation Scale (HAES). 
Blood samples for pharmacokinetic assessments of udenafil and its primary metabolite will 
be obtained after the first dose of randomized study drug and at Visit 4 (or study 
completion). Safety will be monitored by adverse event reports, resting vital signs, and 
clinical laboratory tests. 
When an individual subject completes the study, the subject’s primary cardiologist will be 
notified, and the study drug will be stopped; there will be no need to wean subjects off the 
study drug. Subjects will not be told which drug they received until all recruitment and 
follow-up is completed per-protocol. All subjects will be invited to participate in an 
open-label, 12-month safety extension trial of udenafil. 


 
 
Protocol No.: PHN-Udenafil-02 
CONFIDENTIAL 
 
 
7 
 
The blind for the study will be broken when the later of the following 2 events occur and 
all database queries have been resolved: 
 Visit 4 is completed for the last subject who enters the safety extension trial, or 
 The 90-day follow-up is completed for the last subject who does not enter the safety 
extension trial. 
3.0 Sample Size 
A sample size of 198 subjects per group will provide 90% power to detect a mean treatment 
group difference in change from baseline to Week 26 in maximal VO2 scores of 10%; that 
is, an improvement of 2.8 mL/kg/min in the udenafil group compared to zero change in the 
control group, assuming a Type I error of 0.05 and standard deviation of 7.235. A difference 
of 2.8 represents approximately 0.4 standard deviations, a difference equivalent to a 10% 
increase from an expected baseline of 28 mL/kg/min. 
4.0 Drug Regimens 
Subjects will be randomized to either oral udenafil or matching placebo. Subjects will take 
udenafil 87.5 mg or matching placebo twice a day. Duration of study drug administration 
will be six months. Study drug may be temporarily discontinued for up to 2 weeks for side 
effects. Study drug may be resumed on resolution of symptoms or side effects if considered 
safe in the judgment of the investigators and the subject’s primary physician and with 
consent of subject. 
Study drug will be permanently discontinued if deemed necessary by the study investigator 
or primary physician either due to side-effects or due to need for open-label drug 
administration of a PDE5 inhibitor. 
5.0 Study Procedures  
Study procedures will be performed as outlined in Error! Reference source not found.. 
In-clinic procedures associated with the first dose of study drug at Visit 1 are outlined in 
Table 1. 
 
 


 
 
Protocol No.: PHN-Udenafil-02 
CONFIDENTIAL 
 
 
8 
 
Table 1  Schedule of Measurements/Events 
 
Visit Number 
1 
TC1 
TC2 
2 
TC3-5 
3 
TC6-7 
4 
TC8-10 
 
Time point     
Screening/
Baseline 
Day 0 
Day 1  
Week 1 Week2 Weeks  
3, 4, 8 
Week 13 Week 
17, 21 
Week  
26 
Week 30, 
34, 39 
 
Visit Window(s) 
  
  
± 3 days ± 3 days ± 3 days ±10 days ± 3 days ±10 days ± 10 days 
 
Type of Visit(s)   
In-Person Call 
Call  
In-
Person Call   
In-
Person 
Call    
In-
Person 
Call 
Informed Consent/Assent 
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 
X 
X 
X 
X 
 
EndoPAT®  
X 
  
  
  
  
  
  
X 
 
Serum or urine pregnancy testa  
X 
  
  
X 
  
X 
  
X 
 
Clinical Laboratory tests (creatinine, 
ALT, AST) 
X 
  
  
  
  
  
  
X 
 
Biomarker (BNP) sample 
X 
  
  
  
  
  
  
X 
 
Genetic repository sample (optional) 
Xa 
  
  
  
  
  
  
Xb 
 
Echocardiogram  
X 
  
  
  
  
  
  
X 
 
Exercise test 
Xc 
  
  
  
  
  
  
Xc 
 
Randomization 
X 
  
  
  
  
  
  
  
 
Dispense Study Drug  
X 
  
  
X 
  
 X 
  
  
 
Resting BP and HR 
X 
  
  
X 
  
X 
  
X 
 
Administer first dose of study drug 
(see Additional Procedures and 
Measurements in Table 2) 
X 
  
  
  
  
  
  
  
 
Peds QL generic and cardiac 
modules; PCQLI; HAES 
X 
  
  
  
  
  
  
X 
 
Drug Accountability 
X 
  
X 
X 
X 
X 
X 
X 
 
Pregnancy counseling (if applicable) 
X 
  
X 
X 
X 
X 
X 
X 
 
Adverse events assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Xa 
Morisky Scale (MMAS)  
  
  
X 
  
X 
  
X 
  
 
Schedule/Confirm next visit 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
aas applicable  
bas applicable if missed at baseline visit 
cBaseline visit: If failed 1st exercise test, do NOT randomize; At baseline and Week 26 visits, at Site Investigator's 
discretion, exercise test may be repeated w/in 14 days -- If a second exercise test needed, you MUST perform urine (or 
blood) pregnancy test for eligibility (if applicable). 


 
 
Protocol No.: PHN-Udenafil-02 
CONFIDENTIAL 
 
 
9 
 
Table 1 Schedule of Assessments at  Visit 1 
 
Time From Administration of First Dose of Study Drug 
Procedure 
< 1 Hour  
Prior to Dose 
0 Hour 
2 Hours 
(± 30 Minutes) 
4Hours 
(± 30 Minutes) 
Resting vital signsa 
X 
 
 
Xb 
Administer first dose of study drug 
 
X 
 
 
Vital signs immediately before and 
following a 6-minute self-limited walk 
 
 
X 
 
Pharmacokinetic blood sample 
immediately after 6-minute walk 
 
 
X 
 
Record adverse events 
 
X 
X 
X 
Dispense study drug for 
home administration 
 
 
 
X 
Discharge from clinic 
 
 
 
X 
a 
Includes blood pressure and heart rate. 
b 
Before discharge from the clinic. 
 
6.0 Statistics 
All statistical tests will be at the 0.05 alpha level, 2-tailed, unless stated otherwise. 
Probabilities will be rounded to 4 decimal places before assigning statistical significance.  
Descriptive statistics for categorical endpoints will include the number and percent of 
subjects in each treatment group and category. Quantitative endpoints will be summarized 
for each treatment group with the mean, median, standard deviation, minimum value, and 
maximum value. 
Individual subject data will be presented in data listings, which will include normal 
reference ranges when appropriate. 
6.1 Analysis Populations 
Three analysis populations will be defined: 
 Intent-to-treat (ITT) Population:  The population will include all randomized 
subjects and will be the primary population for efficacy analyses. Treatment 
assignments will be analyzed according to the randomized treatment assignment.  
 Safety Population:  The population will include all subjects who take at least one 
dose of randomized study drug and will be the primary population for safety 
analyses. If the wrong study drug is administered (e.g., subject is randomized to 
undenafil but receives placebo), treatment assignments will be analyzed according 
to the actual study drug received. 
 Per Protocol Population:  The population will include all subjects in the Safety 
Population who meet all entry criteria, or if criteria were not met, were granted a 
waiver by the Sponsor. Subjects with major protocol deviations will be excluded 


 
 
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(including subjects who receive the wrong study drug). The Per Protocol 
Population will be used for sensitivity analyses of the primary efficacy endpoint.  
6.2 Accountability and Protocol Deviations 
Screening failures (i.e., subjects who were not randomized) will be summarized by the 
number and percentage of failures for each primary reason. 
The number and percent of subjects who are randomized, treated with randomized study 
drug, prematurely discontinue, and complete the study will be summarized by treatment 
group. The number and percent of subjects will be summarized by treatment group for each 
reason for premature discontinuation. For subjects who complete the study, the number of 
subjects who continue into the extension study will be summarized. 
The number and percent of enrolled subjects will be summarized by study site. 
The number of subjects included in each analysis population will be summarized by 
treatment group. 
Major protocol deviations will be identified prior to breaking the blind. Deviations may 
include, but are not limited to, departure from inclusion/exclusion criteria, received the 
wrong study drug; failure to perform the required assessments at specified time points; and 
scheduling of visits not in accordance with specifications. 
6.3 Demographic and Baseline Characteristics 
Demographic (e.g., age, sex, and race) and baseline characteristics will be summarized 
descriptively for the Safety and ITT Populations. Summaries will be provided for all 
subjects and for each treatment group. 
Medical and surgical history/physical findings will be classified by system organ class and 
preferred term using the Medical Dictionary for Regulatory Activities (MedDRA). The 
number and percentage of subjects with abnormalities in medical and surgical histories in 
each system organ class and preferred term will be summarized for all subjects and by 
treatment group for the Safety Population. 
6.4 Efficacy Analyses 
6.4.1 Pr imar y Efficacy Endpoint (Aerobic Exercise Performance) 
The treatment group difference for change in aerobic exercise performance (as measured 
by VO2 at maximum exercise effort [maximal VO2]) from baseline to Visit 4 will be 
assessed with an analysis of covariance (ANCOVA) with fixed factors for ventricular 
morphology (single left versus single right or mixed) and treatment group with a 
continuous covariate of baseline maximal VO2. 


 
 
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Sensitivity analyses will include: 
 Primary efficacy analysis performed for the Per Protocol Population 
 ANCOVA model to assess treatment group differences in ranked changes of 
maximal VO2 for the ITT and Per Protocol Populations. 
6.4.2 Secondar y Efficacy Endpoints 
Secondary efficacy endpoints include change from baseline to Visit 4 (Week 26) in: 
 Exercise capacity 
o Minute oxygen consumption at the ventilator anaerobic threshold (VAT) 
o Ventilatory equivalents of carbon dioxide (VE/VCO2) at VAT 
o Respiratory rate and minute ventilation at peak exercise 
o Maximal work rate 
o Work rate at the VAT 
 Ventricular performance 
o Myocardial performance index (MPI) determined by velocities obtained 
from blood pool Doppler assessment of the inflow and outflow tract of the 
dominant ventricle. It is the primary performance endpoint of the 
echocardiogram. 
o Ventricular cavity size, eccentricity, and mass (based on echocardiogram) 
o Systolic function estimate using mean dP/dt during isovolumetric 
contraction (dP/dtic) and peak systolic annular velocity (S’) on tissue 
Doppler 
o Qualitative and quantitative estimate of atrioventricular valve insufficiency 
 Endothelial function:  log-transformed reactive hyperemia index (lnRHI), as 
measured by pulse amplitude tonometry (PAT) testing using the EndoPAT® device 
 Natural logarithm transformation of BNP 
 Functional health status as measured by the full scale PedsQL 
o Physical functioning score 


 
 
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o Psychosocial functioning score 
o Cardiac-specific quality-of-life score 
 Pediatric Cardiac Quality of Life Inventory (PCQLI) score 
Each secondary efficacy endpoint will be summarized descriptively by treatment group.  
Treatment group differences for endpoints associated with the PedsQL and PCQLI will be 
assessed with Friedman’s test using ventricular morphology (single left versus single right 
or mixed) as the stratification factor. The treatment group difference for the qualitative 
estimate of atrioventricular valve insufficiency will be assessed with a 
Cochran-Mantel-Haenszel test using ventricular morphology (single left versus single 
right or mixed) as the stratification factor.  
The remaining secondary efficacy endpoints will be analyzed with the ANCOVA model 
with fixed factors for ventricular morphology (single left versus single right or mixed) and 
treatment group with a covariate for the baseline value.  
6.4.3 Missing Data 
The following imputation method will be used for the primary analysis of the primary 
outcome:  
 Subjects who have died or have dropped out of the study with unknown vital status 
will be assigned a maximal VO2 of zero at Visit 4. 
 Subjects who are known to be alive, but who discontinued from the study (and are 
missing maximal VO2 at Visit 4) will be assigned the latest value available (e.g., 
value from end of study visit if available, and from baseline visit otherwise). 
 Subjects who complete Visit 4, but are physically unable to reach maximum effort 
in cardiopulmonary exercise testing after two attempts, will be assigned their 
baseline value (i.e., zero change). 
Two additional analyses to assess the impact of missing data will be conducted as follows: 
 Subjects with missing maximal VO2 at Visit 4 will be assigned a maximal VO2 of 
zero 
 Subjects with missing maximal VO2 at Visit 4 will be excluded from analysis (i.e., 
observed cases analysis). 
Missing item scores for rating scales will be imputed according to published methodology 
for the scale. Otherwise, missing data will not be estimated for secondary efficacy 
endpoints. 


 
 
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6.4.4 Subpopulation s 
Treatment group differences for the primary efficacy endpoint will be summarized 
descriptively for the following subpopulations based on the following baseline 
characteristics: 
 Gender (female, male) 
 Race (Asian, African-American, Caucasian, other) 
 Ethnicity (Hispanic, non-Hispanic) 
 Ventricular morphology (single left, single right or mixed) 
 Age at Fontan surgery (< 3 years, ≥ 3 years) 
 Baseline serum BNP level (< median, ≥ median) 
 Percent of predicted maximal VO2 at baseline (< 75%, ≥ 75%) 
A 95% confidence interval of the difference in treatment group means will be provided 
within each subpopulation. 
6.4.5 Adju stments for Multiple Compar isons 
Formal hypothesis testing will be performed only for the primary efficacy endpoint. Thus, 
no adjustment for multiple comparisons will be necessary. 
6.5 Safety Evaluations 
Safety assessments will be summarized for the Safety Population. No formal hypothesis 
testing will be performed. 
6.5.1 Extent of Exposure  
The number of days from first to last dose will be summarized descriptively for each 
treatment group. Percent compliance for the entire study will be calculated as follows: 
Number tablets missed = (number returned – (2 × number of days off study)) 
Number tablets expected = 2 × number of days on study 
Percent Compliance = (1 - (number missed / number expected)) × 100. 
A subject will be considered on-study from Visit 1 until study completion or premature 
discontinuation of study drug. Percent compliance will be summarized descriptively for 
each treatment group. 


 
 
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6.5.2 Adverse Events 
The number and proportion of subjects who report treatment-emergent adverse events 
(TEAEs) will be summarized for each treatment group. A TEAE is an event that begins 
after receipt of randomized study drug. All adverse events will be classified by MedDRA 
with respect to system organ class and preferred term.  
The adverse event profile will be characterized with intensity and relationship to study drug 
(related, unrelated, unknown). Related adverse events will be defined as events considered 
possibly or probably related to treatment by the investigator. Events with unknown severity 
or relationship will be counted as unknown.  The incidence of serious adverse events will 
be summarized similarly.  
Subjects who report the same preferred term on multiple occasions will be counted once for 
the preferred term: under the highest severity when summarized by severity and under the 
closest relationship to study drug when summarized by relationship.  If a subject reports 
multiple preferred terms for a system organ class, the subject will be counted only once for 
that system organ class. 
Proportions for adverse events that are gender-specific (e.g., dysmenorrhea) will be based 
on the number of subjects from that gender. 
The number and percentage of subjects who experience TEAEs will be summarized by 
treatment group for the following: 
 By system organ class and preferred term 
 By intensity (mild, moderate, or severe/life threatening/death), system organ class, 
and preferred term 
 By relationship to study drug (not related or related), system organ class, and 
preferred term 
 By weight tertile, system organ class, and preferred term 
 By age tertile, system organ class, and preferred term 
 Serious adverse events (SAEs) by system organ class and preferred term 
 SAEs by relationship to study drug (not related or related), system organ class, and 
preferred term 
 SAEs by weight tertile, system organ class, and preferred term 
 SAEs by age tertile, system organ class, and preferred term 


 
 
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 Adverse events resulting in discontinuation of study drug by system organ class and 
preferred term 
An adverse event cluster including occurrences of hypotension (e.g., blood pressure 
decreased, blood pressure diastolic decreased, blood pressure systolic decreased, 
hypotension, procedural hypotension), loss of consciousness, dizziness (e.g., dizziness, 
dizziness exertional, procedural dizziness), presyncope, or syncope (syncope, syncope 
vasovagal) will be summarized as follows: 
 The number and percent of subjects reporting at least 1 TEAE from the above cluster 
will be summarized by treatment group.  
 The number and percent of patients reporting each of the preferred terms will also 
be summarized by treatment group.  
 The 2 summaries will also be repeated by  
o age tertiles 
o weight tertiles. 
An adverse event cluster including death, hospitalization for heart failure, and transplant 
will be summarized as follows: 
 The number and percent of subjects reporting at least 1 TEAE from the above cluster 
will be summarized by treatment group.  
 The number and percent of patients reporting each of the preferred terms will also 
be summarized by treatment group.  
 The 2 summaries will also be repeated by  
o age tertiles 
o weight tertiles. 
6.5.3 Clinical Laboratory Tests 
Laboratory values will be converted to the project-defined unit of measurement before 
analysis. 
Clinical laboratory variables will be presented in 2 ways. First, change from baseline to 
Visit 4 (study completion) will be summarized descriptively for each treatment group. The 
baseline value will be defined as the last assessment on or before dosing at Visit 1.   


 
 
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Second, the number and proportion of subjects with treatment-emergent abnormal 
laboratory values will be tabulated and the subjects identified. Treatment-emergent 
abnormal laboratory tests are those in which the baseline value is normal (within the 
laboratory normal reference range) and post-baseline value is abnormal (i.e., meets Grade 
III or Grade IV toxicity criteria from the National Cancer Institute Common Terminology 
Criteria. All laboratory values obtained after Visit 1 will be included in the analysis.   
6.5.4 Vital Signs 
Change from baseline (last value before dosing at Visit 1) to each scheduled assessment 
will be summarized descriptively by treatment group for each vital sign variable. 
Vital signs that are potentially clinically significant will be identified with the criteria in 
Table 2 and summarized descriptively by treatment group.  Baseline will be defined as the 
last vital sign value obtained before the first dose of study drug.   
Table 2 
Cr iteria for Potentially Clinically Significant V ital Signs 
Vital Sign 
Crit erion 
Definition of Potentially Clinically Significant Value  
Systolic blood 
pressure 
Low 
Value  80 mmHg and decreased  20 mmHg from value before 
dosing 
 
High 
Value  140 mmHg and increased  20 mmHg from value before 
dosing 
Diastolic blood 
pressure 
Low 
Value  50 mmHg and decreased  15 mmHg from value before 
dosing 
 
High 
Value  100 mmHg and increased  15 mmHg from value before 
dosing 
Pulse 
Low 
Value  45 bpm and decreased  15 bpm from value before dosing 
 
High 
Value  130 mmHg and increased  15 mmHg from value before 
dosing 
bpm = beats per minute 
 
6.6 Prior and Concomitant Medications 
The Concomitant Medications World Health Organization drug dictionary will be used to 
classify all medications with respect to the Anatomical-Therapeutic-Chemical 
classification (ATC system) and preferred drug name. Prior and concomitant drug usage 
will be summarized by ATC level 3 and preferred drug name. The summary will provide 


 
 
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the number and percent of subjects in each treatment group who receive at least 
1 non-study medication.  
Medications with a start date before the first dose of study drug will be considered prior 
medications. Medications with a stop date after the first dose of study drug or ongoing at 
study completion/discontinuation will be considered concomitant medications. Therefore, 
medications that start before the study and continue into the study will be counted as both 
prior and concomitant medications. 
For the Safety Population, separate summaries will be provided for prior and concomitant 
medications. 
6.7 Telephone Interview 
Patient responses to questions during the telephone interview will be summarized 
descriptively. Responses to these questions have not been validated as indicators of 
treatment compliance. 
6.8 Interim Analyses 
A Data Safety Monitoring Board will meet at least twice per year to review safety data. 
Formal stopping boundaries are not proposed for the 26-week trial. However, the Data 
Safety Monitoring Board may recommend stopping the study for other reasons, such as 
safety findings from this trial and other studies, or concerns about study conduct. 
In addition, premature termination of this study may occur due to the impact of results 
released from other studies, due to failure to enroll, or due to withdrawal of study approval 
by clinical site Institutional Review Boards. In addition, the National Heart, Lung and Blood 
Institute retains the right to discontinue the study prior to the inclusion of the intended 
number of subjects, but intends to exercise these rights only for valid scientific or 
administrative reasons. 
After primary outcome data is obtained for approximately half of the originally planned 
sample size (approximately N=200 subjects) the variance of the primary outcome will be 
estimated, using a blinded method with lumped variance. If this estimated variance is higher 
than the one used for the sample size calculations, then the sample size will be recalculated 
and increased correspondingly. Otherwise, the sample size doesn’t change and the trial 
proceeds as planned. This approach is based on blinded re-estimation of nuisance 
parameters and doesn’t lead to inflation of type I error. It is consistent with the regulatory 
guidance for industry in adaptive design of clinical trials. 
7.0 Quality Control and Software 
All data displays and analyses will adhere to the International Conference on Harmonisation 
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use 


 
 
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Harmonized Tripar tite Guideline: Structure and Content of Clinical Study Reports (ICH 
Topic E3). 
All analyses will be performed using SAS Version 9 (or later) software. The responsible 
statistical contract research organization will follow the company’s standard operating 
procedures in the creation and quality control of all tables, listings, figures and analyses. 
The Sponsor or its designee will review all tables, listings, and figures for accuracy.   
8.0 Changes from the Protocol 
Key changes to statistical analyses between protocol finalization and this Statistical 
Analysis Plan are described below. 
Analysis Populations 
The protocol defined 2 non-ITT analysis populations based on compliance with use of 
PDE5 inhibitors (udenafil or other medication) and compliance with study drug dosing, 
respectively. These populations were replaced by the more traditional Per Protocol 
Population based on major protocol deviations. 
Subpopulation Analyses 
The protocol stated that potential differential impact of continuous age on treatment 
outcomes would be assessed and that a treatment by subpopulation interaction test would 
be conducted to identify differential treatment effects. Tests for treatment by subpopulation 
will not be performed due to the low power of the tests. 
The protocol also stated that treatment group differences would be assessed within 
subpopulations if the interaction p-value were < 0.10. These tests will not be performed due 
to their potentially low power and bias due to lack of randomization within each 
subpopulation. 
Missing Values 
Minor clarifications were made.