Acute Effects of Inhaled Treprostinil in Fontan Patients

Phase 2

Terminated

Brief Summary: In this pilot study investigators propose to explore the effects of a locally delivered inhaled pulmonary vasodilator (inhaled treprostinil) on exercise performance, pulmonary blood flow, venous pressure response and vascular function in stable Fontan patients. Investigators will also assess the effects of resting and acute rises in exercise induced systemic venous pressure on liver stiffness and will also assess whether treprostinil will attenuate the acute stiffness increase that investigators expect to see. This will be a prospective, randomized, double-blinded placebo controlled, crossover trial. Following recruitment and informed consent, each participant will undergo three study visits, including baseline testing (visit 1), followed by two sets of exercise and vascular function tests (visit 2 and visit 3) at CCHMC. Twenty-six patients will be enrolled in this study.

Recruitment & Eligibility

Inclusion Criteria

Exclusion Criteria

Clinically unstable: these are patients who are experiencing new cardiovascular symptoms such as worsening shortness of breath, new onset arrhythmia, uncontrolled heart failure, or evidence of clinically significant cirrhosis or renal failure.
Evidence of Fontan pathway or intra cardiac obstruction as identified on prior clinically indicated imaging studies (echocardiography and MRI);
Evidence of left or right systemic ventricular systolic dysfunction with an Ejection fraction of <40% on either echocardiogram or MRI from previously documented clinical data;
Presence of uncontrolled arrhythmias;
Unable to perform exercise testing for any reason or if deemed by the PI or designee that exercise testing would not be in the best interest of the participant
Currently pregnant and/or breastfeeding
Patient unable to provide informed consent
BMI > 30 mg/m2

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	A dose of 3 breaths of placebo will be administered using the Tyvaso® (treprostinil) inhalation system. Placebo will be supplies in matching ampules to treprostinil. Volume will match that of treprostinil. Frequency and duration- 3 times over 1 study visit.
Treprostinil	Treprostinil	A dose of 18mcg (3 breaths) will be administered using the Tyvaso® (treprostinil) inhalation system. Tyvaso® (treprostinil) inhalation solution is supplied in 2.9 mL clear ampules packaged as four ampules in a foil pouch. Frequency and duration- 3 times over 1 study visit.

Primary Outcome Measures

Name	Time	Method
Reduction in Liver Stiffness Through the Measurement of Shear Wave Ultrasound Elastography (m/s)	At rest and following dose 2	At rest and then following maximal exercise, shear wave ultrasound elastography will be performed to assess if the study medication shows an improvement in liver stiffness (reduction in m/s number) following maximal exercise versus at rest.

Secondary Outcome Measures

Name	Time	Method
Minute Volume and Carbon Dioxide Volume Slope (VE/VCO2) During Incremental Exercise	Maximal exercise test (5-10 minutes)	Measuring the difference in peak/maximal VE/VCO2 during incremental exercise testing to assess if the response during peak exercise is different when utilizing treprostinil versus a placebo. The VE/VCO2 slope is used to show the relationship between minute ventilation and carbon dioxide production.
Venous Pressure (mmHg) at Rest and Peak Exercise	At rest and at peak incremental exercise	Venous pressure was measured both at rest and during an incremental ramp exercise test. Comparison was made to evaluate if the treprostinil study medication had a different effect in venous pressure measurements during peak exercise versus placebo.
Exercise Endurance Time (in Minutes)	Immediately following dose 3	A constant work rate exercise test will be performed to determine exercise endurance
VO2 (ml/kg/Min) at Anaerobic Threshold	Maximal exercise test (5-10 minutes)	Measuring the difference in VO2 at anaerobic threshold of an incremental exercise test to assess the variance in response with treprostinil versus placebo
Peak Volume of Oxygen Consumption (VO2) (ml/kg/Min)	Maximal exercise test (5-10 minutes)	Measuring the difference in peak/maximal VO2 during incremental exercise testing to assess if the response during peak exercise is different when utilizing treprostinil versus a placebo.