Acute Effects of Inhaled Treprostinil in Fontan Patients

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized, Placebo-Controlled Pilot Study to Determine the Acute Effects of Inhaled Treprostinil on Exercise, Vascular Function, and Exercise Induced Liver Stiffness in Fontan Patients

Conditions
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Congenital Heart Disease

Intervention / Treatment
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* Drug: Treprostinil
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients age 18 years and older Single ventricle patients status post Fontan procedure 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treprostinil<br>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. | Drug: Treprostinil<br>* A dose of 18mcg (3 breaths) will be administered 3 times: at baseline, 1.5 hrs. post baseline and then again 2 hrs later following maximal exercise testing.<br>* Other names: Tyvaso;|
| Placebo Comparator: Placebo<br>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. | Drug: Placebo<br>* 3 breaths of placebo (via inhalation devices) will be administered 3 times: at baseline, 1.5 hrs. post baseline and then again 2 hrs later following maximal exercise testing.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction in Liver Stiffness Through the Measurement of Shear Wave Ultrasound Elastography (m/s) | 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. | At rest and following dose 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Venous Pressure (mmHg) at Rest and Peak 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. | At rest and at peak incremental exercise | 
| Exercise Endurance Time (in Minutes) | A constant work rate exercise test will be performed to determine exercise endurance | Immediately following dose 3 | 
| Peak Volume of Oxygen Consumption (VO2) (ml/kg/Min) | 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. | Maximal exercise test (5-10 minutes) | 
| Minute Volume and Carbon Dioxide Volume Slope (VE/VCO2) During Incremental Exercise | 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. | Maximal exercise test (5-10 minutes) | 
| VO2 (ml/kg/Min) at Anaerobic Threshold | Measuring the difference in VO2 at anaerobic threshold of an incremental exercise test to assess the variance in response with treprostinil versus placebo | Maximal exercise test (5-10 minutes) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Congenital heart disease