Congenital Heart Disease
Conditions
Keywords
Congenital heart disease
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.
Interventions
DRUGTreprostinil
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.
DRUGPlacebo
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.
Sponsors
Children's Hospital Medical Center, Cincinnati
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
SUPPORTIVE_CARE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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. |
| 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. |
| 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 |
Countries
United States
Participant flow
Recruitment details
This was a randomized, placebo-controlled, double-blind, crossover trial conducted at one center. Healthy Fontan patients were recruited from within the medical center's Fontan management program for participation in this trial. Each patient completed three study visits over the course of six weeks.
Pre-assignment details
Each participant came in for a baseline visit initially and then for the second visit, they were randomly assigned to receiving either the study medication or placebo. At the third visit, the patient received the opposite of what they received at visit two.
Participants by arm
| Arm | Count |
|---|---|
| Treprostinil Crossover With Placebo Participants may receive either treprostinil or placebo at visit 2. They will receive the opposite at visit 3.
If receiving treprostinil, a 18mcg dose (3 breaths) will be administered using the Tyvaso® (treprostinil) inhalation system. Tyvaso® (treprostinil) 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: baseline, 1.5 hrs. post baseline and then again 2 hrs later following maximal exercise testing.
If receiving placebo, a dose of 3 breaths of placebo will be administered using the Tyvaso® (treprostinil) inhalation system. Placebo will be supplied in matching ampules to treprostinil. Volume will match that of treprostinil. Frequency and duration- 3 times over 1 study visit: baseline, 1.5 hrs. post baseline and then again 2 hrs later following maximal exercise testing. | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
Baseline characteristics
| Characteristic | Treprostinil Crossover With Placebo | — |
|---|---|---|
| Age, Categorical <=18 years | 0 Participants | — |
| Age, Categorical >=65 years | 0 Participants | — |
| Age, Categorical Between 18 and 65 years | 14 Participants | — |
| Cardiac Anatomy Double Inlet Left Ventricle | 2 Participants | — |
| Cardiac Anatomy Hypoplastic Left Heart Syndrome | 6 Participants | — |
| Cardiac Anatomy Pulmonary Atresia | 2 Participants | — |
| Cardiac Anatomy Tricuspid Atresia | 4 Participants | — |
| Fontan Type Atrio-pulmonary Fontan | 2 Participants | — |
| Fontan Type Extracardiac Conduit | 3 Participants | — |
| Fontan Type Lateral Tunnel | 9 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United States | 14 participants | — |
| Sex: Female, Male Female | 9 Participants | — |
| Sex: Female, Male Male | 5 Participants | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 15 |
| other Total, other adverse events | 11 / 14 | 4 / 15 |
| serious Total, serious adverse events | 0 / 14 | 0 / 15 |
Outcome results
Primary
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.
Time frame: At rest and following dose 2
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treprostinil | Reduction in Liver Stiffness Through the Measurement of Shear Wave Ultrasound Elastography (m/s) | Rest | 2.39 m/s | Standard Deviation 0.67 |
| Treprostinil | Reduction in Liver Stiffness Through the Measurement of Shear Wave Ultrasound Elastography (m/s) | Following maximal exercise | 2.79 m/s | Standard Deviation 0.54 |
| Placebo | Reduction in Liver Stiffness Through the Measurement of Shear Wave Ultrasound Elastography (m/s) | Rest | 2.38 m/s | Standard Deviation 0.71 |
| Placebo | Reduction in Liver Stiffness Through the Measurement of Shear Wave Ultrasound Elastography (m/s) | Following maximal exercise | 2.89 m/s | Standard Deviation 0.51 |
Secondary
Exercise Endurance Time (in Minutes)
A constant work rate exercise test will be performed to determine exercise endurance
Time frame: Immediately following dose 3
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treprostinil | Exercise Endurance Time (in Minutes) | 5.19 Minutes | Standard Deviation 0.89 |
| Placebo | Exercise Endurance Time (in Minutes) | 5.82 Minutes | Standard Deviation 1.23 |
Secondary
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.
Time frame: Maximal exercise test (5-10 minutes)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treprostinil | Minute Volume and Carbon Dioxide Volume Slope (VE/VCO2) During Incremental Exercise | 26.8 unitless | Standard Deviation 4.95 |
| Placebo | Minute Volume and Carbon Dioxide Volume Slope (VE/VCO2) During Incremental Exercise | 26.1 unitless | Standard Deviation 6.35 |
Secondary
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.
Time frame: Maximal exercise test (5-10 minutes)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treprostinil | Peak Volume of Oxygen Consumption (VO2) (ml/kg/Min) | 23.4 ml/kg/min | Standard Deviation 6.67 |
| Placebo | Peak Volume of Oxygen Consumption (VO2) (ml/kg/Min) | 24.6 ml/kg/min | Standard Deviation 9.04 |
Secondary
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.
Time frame: At rest and at peak incremental exercise
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treprostinil | Venous Pressure (mmHg) at Rest and Peak Exercise | Rest | 12.8 mmHg | Standard Deviation 3.08 |
| Treprostinil | Venous Pressure (mmHg) at Rest and Peak Exercise | Peak Incremental Exercise | 22.8 mmHg | Standard Deviation 6.16 |
| Placebo | Venous Pressure (mmHg) at Rest and Peak Exercise | Rest | 12.1 mmHg | Standard Deviation 2.43 |
| Placebo | Venous Pressure (mmHg) at Rest and Peak Exercise | Peak Incremental Exercise | 22.6 mmHg | Standard Deviation 8.04 |
Secondary
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
Time frame: Maximal exercise test (5-10 minutes)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treprostinil | VO2 (ml/kg/Min) at Anaerobic Threshold | 17.3 ml/kg/min | Standard Deviation 3.63 |
| Placebo | VO2 (ml/kg/Min) at Anaerobic Threshold | 18.1 ml/kg/min | Standard Deviation 5.36 |