Clinical trial NCT02741115: Fontan Udenafil Exercise Longitudinal Assessment Trial
Official title: Fontan Udenafil Exercise Longitudinal Assessment Trial (FUEL)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Single Ventricle Heart Disease
Keywords: Fontan
Maximal Oxygen Consumption
Vascular Function
EndoPAT
Myocardial Performance
Lead sponsor: Mezzion Pharma Co. Ltd
Sponsor class: INDUSTRY
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2016-04-18
Enrollment: 400
Sex: ALL
Minimum age (years): 12
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

Eligibility criteria: Inclusion Criteria:

1. Males and females with Fontan physiology who are 12 to less than 19 years of age at enrollment.
2. Participant consent or parental/guardian consent and participant assent
3. Participant fluency in primary language of country in which study is being conducted

Exclusion 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 trial.
8. Single lung physiology with greater than 80% flow to one lung.
9. VO2 less than 50%
10. Severe ventricular dysfunction assessed qualitatively by clinical echocardiography within six months prior to enrollment.
11. Severe valvar regurgitation, ventricular outflow obstruction, or aortic arch obstruction assessed by clinical echocardiography within six months prior to enrollment.
12. Significant renal (serum creatinine \> 2.0), hepatic (serum AST and/or ALT \> 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 six weeks prior to screening for the trial.
13. Inability to complete exercise testing at baseline screening.
14. History of PDE-5 inhibitor use within 3 months before study onset.
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 CYP3A4.
18. Current use of alpha-blockers or nitrates.
19. Ongoing or planned participation in another research protocol that would either prevent successful completion of planned study testing or invalidate its results.
20. Noncardiac medical, psychiatric, and/or social disorder that would prevent successful completion of planned study testing or would invalidate its results.
21. Cardiac care, ongoing or planned, at a non-study center that would impede study completion.
22. For females: Pregnancy at the time of screening, pregnancy 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 trial.
24. Refusal to provide written informed consent/assent.
25. In the opinion of the primary care physician, the subject is likely to be non-compliant with the study protocol.

Primary outcomes:
measure: Change in Maximal VO2 From Baseline to Week 26 Using Last Observation Carried Forward (LOCF)
timeFrame: Baseline to 26 Weeks
Secondary outcomes:
measure: Change in Myocardial Performance Index (MPI) From Baseline to Week 26
timeFrame: Week 26
measure: Change in Log-transformed Reactive Hyperemia Index (InRH) From Baseline to Week 26
timeFrame: Week 26
measure: Change in Serum Brain-type Natriuretic Peptide (BNP) From Baseline to Week 26.
timeFrame: Week 26
measure: Change in VO2 at VAT
timeFrame: 26 Weeks
measure: Change in Work Rate at VAT From Baseline to Week 26 With LOCF
timeFrame: 26 Weeks
measure: Change in VE/VCO2 at VAT From Baseline to Week 26
timeFrame: 26 Weeks
measure: Change in Respiratory Rate at Maximal Exercise Effort From Baseline to Week 26 Using LOCF
timeFrame: Week 26
measure: Change in Minute Oxygen Consumption at Maximal Exercise Effort From Baseline to Week 26
timeFrame: Week 26
measure: Change in Work Rate at Maximal Exercise Effort Between Baseline and Week 26 Using LOCF
timeFrame: Week 26
measure: Change in Pediatric Quality of Life (PedsQL) Generic Core Scales - Physical Functioning Subscale (Child Reported)
timeFrame: 26 weeks
measure: Change in Pediatric Quality of Life (PedsQL) Generic Core Scales - Physical Functioning Subscale (Parent Reported)
timeFrame: 26 weeks
measure: Change in Pediatric Quality of Life (PedsQL) Generic Core Scales - Psychosocial Health Subscale (Child Reported)
timeFrame: 26 weeks
measure: Change in Pediatric Quality of Life (PedsQL) Generic Core Scales - Psychosocial Health Subscale (Parent Reported)
timeFrame: 26 weeks
measure: Change in Pediatric Quality of Life (PedsQL) Inventory - Cardiac Module Scale - Treatment II Subscale (Child-reported)
timeFrame: 26 weeks
measure: Change in Pediatric Quality of Life (PedsQL) Inventory - Cardiac Module Scale - Perceived Physical Appearance Subscale
timeFrame: 26 weeks
measure: Change in Pediatric Quality of Life (PedsQL) Inventory - Cardiac Module Scale - Treatment Anxiety Subscale
timeFrame: 26 weeks
measure: Change in Pediatric Quality of Life (PedsQL) Inventory - Cardiac Module Scale - Cognitive Problems Subscale
timeFrame: 26 weeks
measure: Change in Pediatric Quality of Life (PedsQL) Inventory - Cardiac Module Scale - Communication Problems Subscale
timeFrame: 26 weeks
measure: Change in Pediatric Cardiac Quality of Life Inventory (PCQLI) Total Score-Ages 8 to 12 (Child Reported)
timeFrame: 26 weeks
measure: Change in Pediatric Cardiac Quality of Life Inventory (PCQLI) Total Score-Ages 8 to 12 (Parent Reported)
timeFrame: 26 weeks
measure: Change in Pediatric Cardiac Quality of Life Inventory (PCQLI) Total Score-Ages 13 to 18 (Child Reported)
timeFrame: 26 weeks
measure: Change in Pediatric Cardiac Quality of Life Inventory (PCQLI) Total Score-Ages 13 to 18 (Parent Reported)
timeFrame: 26 weeks
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Children's Hospital/Children's Heart Center at Phoenix Children's Hospital
state: Arizona
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Los Angeles
country: United States
facility: Cedars/Sinai Heart Institute
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Wilmington
country: United States
facility: Nemours Cardiac Center/Alfred I. duPont Hospital for Children
state: Delaware
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Saint Petersburg
country: United States
facility: Johns Hopkins All Children's Heart Institute
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Indianapolis
country: United States
facility: Riley Hospital for Children/Herman B. Wells Center for Pediatric Research
state: Indiana
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Congenital Heart Center/C.S. Mott Children's Hospital
state: Michigan
city: Kansas City
country: United States
facility: Children's Mercy Hospital Kansas City
state: Missouri
city: Saint Louis
country: United States
facility: Washington University St. Louis/St.Louis Children's Hospital
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Children's Hospital and Medical Center
state: Nebraska
city: New York
country: United States
facility: Children's Hospital of New York
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hosptial
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Medical Hospital/Dept. of Pediatric Cardiology
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hosptial
state: Washington
city: Milwaukee
country: United States
facility: Children's Hospital of Wisconsin
state: Wisconsin
city: Edmonton
country: Canada
facility: Stollery Children's Hospital - University of Alberta
state: Alberta
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
city: Bucheon-si
country: Korea, Republic of
facility: Sejong General Hospital
state: Gyeonggi-do
city: Seoul
country: Korea, Republic of
facility: Seoul National University Children's Hospital
Study officials:
affiliation: Children's Hospital of Phildelphia
name: Steve Paridon, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Di Maria MV, Goldberg DJ, Zak V, Hu C, Lubert AM, Dragulescu A, Mackie AS, McCrary A, Weingarten A, Parthiban A, Goot B, Goldstein BH, Taylor C, Lindblade C, Petit CJ, Spurney C, Harrild DM, Urbina EM, Schuchardt E, Beom Kim G, Kyoung Yoon J, Colombo JN, Files MD, Schoessling M, Ermis P, Wong PC, Garg R, Swanson SK, Menon SC, Srivastava S, Thorsson T, Johnson TR, Krishnan US, Paridon SM, Frommelt PC; Pediatric Heart Network. Impact of Udenafil on Echocardiographic Indices of Single Ventricle Size and Function in FUEL Study Participants. Circ Cardiovasc Imaging. 2022 Nov;15(11):e013676. doi: 10.1161/CIRCIMAGING.121.013676. Epub 2022 Nov 15.
citation: Goldberg DJ, Zak V, Goldstein BH, Schumacher KR, Rhodes J, Penny DJ, Petit CJ, Ginde S, Menon SC, Kim SH, Kim GB, Nowlen TT, DiMaria MV, Frischhertz BP, Wagner JB, McHugh KE, McCrindle BW, Shillingford AJ, Sabati AA, Yetman AT, John AS, Richmond ME, Files MD, Payne RM, Mackie AS, Davis CK, Shahanavaz S, Hill KD, Garg R, Jacobs JP, Hamstra MS, Woyciechowski S, Rathge KA, McBride MG, Frommelt PC, Russell MW, Urbina EM, Yeager JL, Pemberton VL, Stylianou MP, Pearson GD, Paridon SM; Pediatric Heart Network Investigators. Results of the FUEL Trial. Circulation. 2020 Feb 25;141(8):641-651. doi: 10.1161/CIRCULATIONAHA.119.044352. Epub 2019 Nov 17.
citation: Goldberg DJ, Zak V, Goldstein BH, McCrindle BW, Menon SC, Schumacher KR, Payne RM, Rhodes J, McHugh KE, Penny DJ, Trachtenberg F, Hamstra MS, Richmond ME, Frommelt PC, Files MD, Yeager JL, Pemberton VL, Stylianou MP, Pearson GD, Paridon SM; Pediatric Heart Network Investigators. Design and rationale of the Fontan Udenafil Exercise Longitudinal (FUEL) trial. Am Heart J. 2018 Jul;201:1-8. doi: 10.1016/j.ahj.2018.03.015. Epub 2018 Apr 3.