Clinical trial NCT03154476
Conditions: Cirrhosis Congenital Heart Disease
Sponsor: Mayo Clinic
Start date: 2017-07-05; Completion date: 2019-06-30
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if the medication, sildenafil (also known as Revatio), can slow or stop the progression of liver disease in patients who previously had a Fontan operation.

Detailed description:
1. All participants will undergo a baseline liver magnetic resonance elastography. The patients with liver stiffness score \>2.5 kiloPascal (KPa) \[Normal: ≤2.5 KPa\] will be enrolled in the study.
2. In addition to a baseline liver MRE, all participants will undergo cardiac MRI, transthoracic echocardiogram (TTE), FibroSure® (alpha-2 macroglobulin, haptoglobulin, gamma-glutamyltransferase, bilirubin, apolipoprotein A1, and alanine transaminase), and chemistry panel.
3. This will be a double blinded placebo control study design. All participants will be randomized 1:1 to sildenafil or placebo for a total of 12 months therapy.
4. Sildenafil will be initiated at 5 mg 3 times per day for the first week, and titrated to 10 mg 3 times per day for the second week and 20 mg 3 times per day from the 3rd week to the end of the study period. The patients will be required to check their pulse rate and blood pressure daily during the first month of drug therapy. Patient who experience hypotension (blood pressure \< 90/50 plus symptoms such as dizziness) during dose titration will be asked to remain on the previous tolerated dose. Patients who cannot tolerate 10 mg 3 times daily will be asked to withdraw from the study and will be asked to continue checking their blood pressure for three days after stopping the medication.
5. After 12 months (+/- 2 weeks) of therapy, all imaging studies (liver MRE, cardiac MRI, TTE) and blood tests (FibroSure® and chemistry panel) will be repeated. A final liver MRE and FibroSure will be performed at 18 months (+/- 2 weeks) for the participants whose 18 months follow-up still falls within the study period.
6. Adverse event and compliance monitoring: During the first month of enrollment (initiation and dose titration), adverse events will be collected by subject report and by weekly telephone interview with dedicated research personnel. For the rest of the study period, adverse events will be collected by subject report and by monthly telephone interview with dedicated research personnel. The research personnel will be responsible for sending out the monthly supply of medications and obtaining a count of the remaining number pills as a measure of compliance. All participants will be provided with a pamphlet containing all the side effects of sildenafil, and contact information of research team for reporting any adverse event of concerns about the study.

Arms: arm 1: Subjects randomized to this arm will receive sildenafil 5 mg 3 times per day for the first week, and titrated to 10 mg 3 times per day for the second week, and 20 mg 3 times per day from the third week to the end of the study period, 12 months. arm 2: Subjects will receive placebo times per day for 12 months.
Interventions: intervention 1: Sildenafil intervention 2: Placebo
Intervention descriptions: intervention 1: Sildenafil will be initiated at 5 mg 3 times per day for the first week, and titrated to 10 mg 3 times per day for the second week and 20 mg 3 times per day from the third week to the end of the study period, 12 months. intervention 2: Placebo capsules matching study drug

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Sildenafil for Fontan Associated 
Liver Disease (SiFALD) Study 
 
NCT# 03154476 
 
July 31, 2019 


Version 5.0,   07/31/2019 
1 
Sildenafil for Fontan Associated Liver Disease (SiFALD) study  
 
IRB: 16-008985 
NCT03154476 
 
Fontan associated liver disease (FALD) affect 50% of all survivor of the 
Fontan operation, about 3 decades after the initial operation. It is associated 
with significant mortality and morbidity, and currently there are no treatment 
strategies to halt progression of this disease. The purpose of this study is to 
determine the efficacy of phosphodierestate-5 inhibitor (sildenafil) in 
modifying the progression of FALD. 
 
 
 
Principal Investigator: 
Alexander Egbe, MD, MPH 
 
 
Co-investigators: 
David Driscoll, MD 
Heidi Connolly, MD 
Carole Warnes, MD 
Patrick Kamath, MD 
Sudhakar Venkatesh, MD 
 
 
 


Version 5.0,   07/31/2019 
2 
A. Rationale 
Background 
The Fontan operation is an effective surgical palliation for patients with 
complex cyanotic heart disease.1 The physiologic benefit of the Fontan 
operation is that it separates the systemic and pulmonary circulations, 
thereby eliminating cyanosis and ventricular volume overload. However, the 
absence of a subpulmonary ventricle results in an obligatory high central 
venous pressure and low cardiac output state.2, 3 These hemodynamic 
derangements result in chronic hepatic congestion and reduced blood supply 
to the liver.4, 5 The downstream effect is a spectrum of Fontan associated 
liver diseases (FALD) such as liver fibrosis, cirrhosis ad hepatocellular 
cancer.4, 6-8  
 
Clinical and Public Health Significance  
The prevalence of cirrhosis is 50% at 3 decades after their initial Fontan 
operation.6, 8 The diagnosis of cirrhosis is a strong predictor of death in this 
population because more than two-thirds of the patients with cirrhosis are 
dead within 5 years.6 Those who survive experience significant morbidities 
such as variceal bleeding, hepatic encephalopathy, liver failure and 
hepatocellular cancer. 
 
The incidence of complex cyanotic heart disease such as single ventricle 
diagnosis is 91 per 100, 000 live births.9, 10 Based on the annual birth rate of 
4.2 million in the United States,11 more than 4 thousand babies with complex 
single ventricle diagnosis are born every year, and most of them will 
undergo Fontan operation. More than 80% of patients undergoing Fontan 


Version 5.0,   07/31/2019 
3 
operation in the current era survive to adulthood, and most of these patients 
will develop FALD.12  
 
 
Figure 1: Schematic showing the hemodynamic interaction between the 
liver and the Fontan circulation. Adapted from Poterucha et al.13 
 
B. Hypothesis 
The use of pulmonary vasodilators will promote forward flow in the Fontan 
circuit, reduce hepatic congestion and halt the progression of liver fibrosis.  
 
C. Innovation 
(i) Available data suggest that chronic hepatic congestion, inherent in the 
Fontan physiology, is the precursor of early liver fibrosis and cirrhosis in the 
Fontan population. 2, 3A recent study based on the Mayo Clinic Fontan 


Version 5.0,   07/31/2019 
4 
cohort show ed that half of the patients had liver fibrosis after 30 years from 
the time of initial Fontan.6  
(ii) This proposed study would be the first study to assess the role of 
pulmonary vasodilators in the management of FALD. 
 
D. Significance  
(i) The adult congenital heart disease program at Mayo Clinic has the largest 
and oldest cohort of Fontan patients in the United States, and this places 
Mayo Clinic in a unique position to study this problem. 
(ii) Data from this study will influence the management of FALD nationally 
and worldwide. 
 
E. Brief Synopsis of Methods  
(i) All patients enrolled in the study will undergo a baseline liver magnetic 
resonance elastography (MRE) prior to the initiation of phosphodiesterase-5 
inhibitor (sildenafil). 
(ii) A second MRE will be performed after 12 months of therapy. 
 
F. Preliminary studies to support feasibility 
(i) Several studies have shown that the use of pulmonary vasodilators in  
Fontan patients (even those with normal pulmonary vascular resistance) 
results in increased cardiac output and exercise tolerance by promoting 
forward flow in the Fontan circuit.14-16  
(ii) A recent study from the Mayo Clinic showed that liver stiffness 
measured by MRE correlates with severity of fibrosis on liver biopsy.13  
(iii) The proposed study is built on the foundation of these previous studies. 
Pulmonary vasodilators will be used to promote forward flow in the Fontan 


Version 5.0,   07/31/2019 
5 
circuit, and thereby reduce liver congestion. MRE will then be used to 
monitor treatment effect. We chose a phosphodiesterase-5 inhibitor instead 
of an endothelin receptor antagonist because the latter is associated with 
hepatotoxicity.  
 
G. Study design  
1. Inclusion criteria: All adult (age ≥ 18 years old) Fontan patients who 
have no contraindications for magnetic resonance imaging (MRI) will 
be eligible for the study. Informed consent will be obtained from 
potential participants by their primary cardiologist or dedicated study 
personnel.  
2. Exclusion criteria: Subjects with implantable pacemakers, residual 
cardiac lesions (severe ventricular dysfunction, severe atrioventricular 
valve regurgitation, Fontan baffle or conduit obstruction), viral 
hepatitis, severe renal dysfunction, a history of sildenafil use in the six 
months prior to study enrollment, ongoing sildenafil therapy, or 
patients currently taking nitrates. Based on the stipulation from the 
Food and Drug Administration regarding the approved use of 
sildenafil, we also excluded patients with hypotension at baseline (BP 
<80/50 mmHg), pulmonary veno-occlusive disease, and pulmonary 
hypertension due to sickle cell disease. Women of child-bearing 
potential with a positive pregnancy test will additionally be excluded. 
3. All participants may undergo the following baseline tests (+/- 4 
weeks) as part of standard clinical care: transthoracic echocardiogram, 
electrocardiogram, cardiopulmonary exercise test, complete blood 
count, chemistry panel, INR, alpha-fetoprotein. All these tests are 
routine clinical tests in the Mayo Clinic Adult Congenital Heart 


Version 5.0,   07/31/2019 
6 
Disease program. Baseline clinical tests performed within 6 months 
prior to enrollment will be accepted as part of the study (data will be 
utilized if results are available). Any routine standard clinical tests or 
procedures that are not completed will not be considered a deviation. 
4. Other additional baseline tests include:   
a. MRI studies: [cardiac MRI + Liver MRE + 4D phase contrast 
imaging of the abdomen] 
b. Abdominal ultrasound [full abdominal scan with Doppler of 
portal/hepatic/mesenteric vessels]  
c. Biomarkers [NT-proBNP, ST2, Galectin-3, ADMA, ceramides, 
hs-CRP, Cystatin C, electrolytes]  
d. Quality of life indices: MLHFQ: Minnesota Living with Heart 
Failure Questionnaire (for patients enrolled prior to protocol 
version 2, baseline MLHFQ will be administered at re-consent 
(+/-4 weeks). 
5. This will be a double blinded placebo control study design. All 
participants will be randomized 1:1 to sildenafil or placebo for a total 
of 12 months therapy.  
6. Sildenafil will be initiated at 5 mg 3 times per day for the first week, 
and titrated to 10 mg 3 times per day for the second week and 20 mg 3 
times per day from the 3rd week to the end of the study period. The 
patients will be required to check their pulse rate and blood pressure 
daily during the first month of drug therapy. Patient who experience 
hypotension (blood pressure < 90/50 plus symptoms such as 
dizziness) during dose titration will be asked to remain on the 
previous tolerated dose. Patients who cannot tolerate 10 mg 3 times 
daily will be asked to withdraw from the study and will be asked to 


Version 5.0,   07/31/2019 
7 
continue checking their blood pressure for three days after stopping 
the medication. 
7. After 12 months (+/- 4 weeks) of therapy, all tests listed in #3 and #4 
will be repeated.  
8. These same tests listed in #3 and #4 will be repeated for the patients 
who have follow-up up to 24 months (+/- 4 weeks).  
9. Adverse event and compliance monitoring: During the first month of 
enrollment (initiation and dose titration), adverse events will be 
collected by subject report and by weekly telephone or email 
interview (±7 days) with dedicated research personnel. For the rest of 
the study period, adverse events will be collected by subject report 
and by monthly telephone or email interview (±14 days) with 
dedicated research personnel. The research personnel will be 
responsible for sending out the monthly supply of medications and 
obtaining a count of the remaining number pills as a measure of 
compliance. All participants will be provided with a pamphlet 
containing all the side effects of sildenafil, and contact information of 
research team for reporting any adverse event of concerns about the 
study. 
Up to three voicemail messages will be left for each follow-up.  
 
 
H. Statistical analysis and power considerations: 
Sample size and power 
We have determined that a total of 40 patients who complete the study (20 
patients in the treatment arm and 20 patients in the placebo) will adequately 
power the study accounting for approximately a 10% attrition rate. In a prior 


Version 5.0,   07/31/2019 
8 
study from the Mayo Clinic,13 the distribution of MRE stiffness score in the 
adult Fontan population was 4,900 ± 1,100 Pa. Assuming that the standard 
deviation of MRE is 1,000 both for before and after treatment measures, and 
that the within subject correlation between before and after measures is at 
least moderate in strength and positive (i.e. ρ≥0.5), then the variance in the 
difference between pre- and post-treatment MRE stiffness score is no more 
than 250 Pa. A sample of 40 patients in the treatment arm will provide 80% 
power for a two-sided two-sample t-test with a 0.05 Type I error rate to 
detect a mean difference of at least 500 Pa in treatment effect, as measured 
by the difference within patient MRE stiffness score.  
 
Interim Analysis 
An interim analysis of subjects who have completed 12 months of Sildenafil 
vs. Placebo therapy will be conducted at the end of the grant period (August 
2019). Those still on Sildenafil vs. Placebo at that time will remain blinded 
until their completion of 12 months on Sildenafil vs. Placebo. 
 
 
I. Human studies issues (consent or research authorization)  
Consent 
An informed consent will be obtained from the patients at the time of 
enrollment in the study. The consent will authorize a member of the research 
team to contact each patient by phone, email, or questionnaire. The study 
participants will be notified of the very limited evidence supporting the use 
of sildenafil in this population.  
 
 


Version 5.0,   07/31/2019 
9 
Data and Safety Monitoring 
The Food and Drug Administration approved Sildenafil for the treatment of 
pulmonary hypertension. The patients will be notified that the use of 
sildenafil in this study is off-label. We will implement an internal safety 
monitoring system consisting of two members (not immediately affiliated 
with the study) to review reported side effects of sildenafil at the mid-point 
and completion of the study. Finally, and as always, extreme caution and 
monitoring of study participants will be undertaken throughout the study and 
in follow up to ensure no untoward events as a direct result of the study 
substance. Please see data safety monitoring plan. 
 
 


Version 5.0,   07/31/2019 
10
M. Literature cited  
1. 
Fontan F and Baudet E. Surgical repair of tricuspid atresia. Thorax. 
1971;26:240-8. 
2. 
Rychik J. Forty years of the Fontan operation: a failed strategy. 
Seminars in thoracic and cardiovascular surgery Pediatric cardiac surgery 
annual. 2010;13:96-100. 
3. 
Gewillig M. The Fontan circulation. Heart. 2005;91:839-46. 
4. 
Rychik J, Veldtman G, Rand E, Russo P, Rome JJ, Krok K, Goldberg 
DJ, Cahill AM and Wells RG. The precarious state of the liver after a Fontan 
operation: summary of a multidisciplinary symposium. Pediatr Cardiol. 
2012;33:1001-12. 
5. 
Yoo SJ, Prsa M, Schantz D, Grosse-Wortmann L, Seed M, Kim TK, 
Wald R and Chaturvedi R. MR assessment of abdominal circulation in 
Fontan physiology. The international journal of cardiovascular imaging. 
2014;30:1065-72. 
6. 
Pundi K, Pundi KN, Kamath PS, Cetta F, Li Z, Poterucha JT, Driscoll 
DJ and Johnson JN. Liver Disease in Patients After the Fontan Operation. 
The American journal of cardiology. 2016;117:456-60. 
7. 
Greenway SC, Crossland DS, Hudson M, Martin SR, Myers RP, 
Prieur T, Hasan A and Kirk R. Fontan-associated liver disease: Implications 
for heart transplantation. The Journal of heart and lung transplantation : the 
official publication of the International Society for Heart Transplantation. 
2016;35:26-33. 
8. 
Lindsay I, Johnson J, Everitt MD, Hoffman J and Yetman AT. Impact 
of liver disease after the fontan operation. The American journal of 
cardiology. 2015;115:249-52. 


Version 5.0,   07/31/2019 
11
9. 
Egbe A, Uppu S, Stroustrup A, Lee S, Ho D and Srivastava S. 
Incidences and sociodemographics of specific congenital heart diseases in 
the United States of America: an evaluation of hospital discharge diagnoses. 
Pediatr Cardiol. 2014;35:975-82. 
10. 
Egbe A, Uppu S, Lee S, Ho D and Srivastava S. Changing prevalence 
of severe congenital heart disease: a population-based study. Pediatr 
Cardiol. 2014;35:1232-8. 
11. 
http://www.census.gov/topics/population.html (last accessed August 
29, 2016). 
12. 
Nakano T, Kado H, Tatewaki H, Hinokiyama K, Oda S, Ushinohama 
H, Sagawa K, Nakamura M, Fusazaki N and Ishikawa S. Results of 
extracardiac conduit total cavopulmonary connection in 500 patients. 
European journal of cardio-thoracic surgery : official journal of the 
European Association for Cardio-thoracic Surgery. 2015;48:825-32; 
discussion 832. 
13. 
Poterucha JT, Johnson JN, Qureshi MY, O'Leary PW, Kamath PS, 
Lennon RJ, Bonnichsen CR, Young PM, Venkatesh SK, Ehman RL, Gupta 
S, Smyrk TC, Dearani JA, Warnes CA and Cetta F. Magnetic Resonance 
Elastography: A Novel Technique for the Detection of Hepatic Fibrosis and 
Hepatocellular Carcinoma After the Fontan Operation. Mayo Clinic 
proceedings Mayo Clinic. 2015;90:882-94. 
14. 
Hebert A, Mikkelsen UR, Thilen U, Idorn L, Jensen AS, Nagy E, 
Hanseus K, Sorensen KE and Sondergaard L. Bosentan improves exercise 
capacity in adolescents and adults after Fontan operation: the TEMPO 
(Treatment With Endothelin Receptor Antagonist in Fontan Patients, a 
Randomized, Placebo-Controlled, Double-Blind Study Measuring Peak 
Oxygen Consumption) study. Circulation. 2014;130:2021-30. 


Version 5.0,   07/31/2019 
12
15. 
Rhodes J, Ubeda-Tikkanen A, Clair M, Fernandes SM, Graham DA, 
Milliren CE, Daly KP, Mullen MP and Landzberg MJ. Effect of inhaled 
iloprost on the exercise function of Fontan patients: a demonstration of 
concept. International journal of cardiology. 2013;168:2435-40. 
16. 
Derk G, Houser L, Miner P, Williams R, Moriarty J, Finn P, Alejos J 
and Aboulhosn J. Efficacy of endothelin blockade in adults with Fontan 
physiology. Congenital heart disease. 2015;10:E11-6.