Acute Effects of Inhaled Treprostinil in Fontan Patients

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

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.

Study Overview

• Status: Terminated
• Conditions: Congenital Heart Disease
• Intervention / Treatment: Drug: Treprostinil; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients age 18 years and older
2. Single ventricle patients status post Fontan procedure

Exclusion Criteria:

1. 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.
2. Evidence of Fontan pathway or intra cardiac obstruction as identified on prior clinically indicated imaging studies (echocardiography and MRI);
3. 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;
4. Presence of uncontrolled arrhythmias;
5. 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
6. Currently pregnant and/or breastfeeding
7. Patient unable to provide informed consent
8. BMI > 30 mg/m2

Study Plan

How is the study designed?

Design Details

• Primary Purpose: SUPPORTIVE_CARE
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 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.	Drug: Treprostinil; 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.; Other Names: Tyvaso
PLACEBO_COMPARATOR: 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.	Drug: Placebo; 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.

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati
• Investigators: Principal Investigator: Gruschen Veldtman, MBChB, Children's Hospital Medical Center, Cincinnati

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 21, 2017
• Primary Completion (ACTUAL): September 21, 2018
• Study Completion (ACTUAL): September 21, 2018

Study Registration Dates

• First Submitted: May 10, 2016
• First Submitted That Met QC Criteria: May 10, 2016
• First Posted (ESTIMATE): May 11, 2016

Study Record Updates

• Last Update Posted (ACTUAL): July 29, 2020
• Last Update Submitted That Met QC Criteria: July 13, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: Congenital heart disease
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Diseases; Heart Defects, Congenital; Antihypertensive Agents; Treprostinil
• Other Study ID Numbers: 2015-1491

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No