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Study was stopped early due to inability to recruit additional participants
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treprostinil | Experimental | 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. |
|
| Placebo | Placebo Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Treprostinil | Drug | 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. |
|
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Gruschen Veldtman, MBChB | Children's Hospital Medical Center, Cincinnati | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cincinnati Children's Hospital Medical Center | Cincinnati | Ohio | 45229 | United States |
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.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Treprostinil, Then Placebo | 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. 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. 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. 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. |
| FG001 | Placebo, Then 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. 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. 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. 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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|
Fifteen participants began the study, however, only 14 completed both the study medication and placebo components of the trial.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Mean | Standard Deviation | m/s | At rest and following dose 2 |
|
Adverse events were assessed and recorded following signing of informed consent through two weeks following the last study visit (period ranging from 6-9 weeks).
Events that are unexpected and considered to be related or possibly related to the study procedures as well as breaches of confidentiality, and protocol violations were reported to the IRB as soon as possible after discovery of the event. All adverse events will be classified by the PI for relationship, severity, and expectedness. Events not meeting the criteria for prompt reporting were reported to the Institutional Review Board (IRB) at the time of continuing review.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Treprostinil | 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. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cough | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
This study had a small sample size and may have had selection bias towards well-functioning Fontan patients, who might benefit less from the use of pulmonary vasodilators. Additional physiological factors could have been assessed.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Katy Fischesser | Cincinnati Children's Hospital Medical Center | 513-803-5191 | katy.fischesser@cchmc.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jul 5, 2018 | Apr 10, 2020 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D006330 | Heart Defects, Congenital |
| ID | Term |
|---|---|
| D018376 | Cardiovascular Abnormalities |
| D002318 | Cardiovascular Diseases |
| D006331 | Heart Diseases |
| D000013 | Congenital Abnormalities |
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| ID | Term |
|---|---|
| C427248 | treprostinil |
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|
| Placebo | Drug | 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. |
|
| 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) |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Cardiac Anatomy | Count of Participants | Participants |
|
| Fontan Type | Count of Participants | Participants |
|
| OG001 |
| 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. 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. |
|
|
| 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. | Posted | Mean | Standard Deviation | mmHg | At rest and at peak incremental exercise |
|
|
|
| Secondary | Exercise Endurance Time (in Minutes) | A constant work rate exercise test will be performed to determine exercise endurance | Posted | Mean | Standard Deviation | Minutes | Immediately following dose 3 |
|
|
|
| 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. | Posted | Mean | Standard Deviation | ml/kg/min | Maximal exercise test (5-10 minutes) |
|
|
|
| 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. | Posted | Mean | Standard Deviation | unitless | Maximal exercise test (5-10 minutes) |
|
|
|
| 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 | Posted | Mean | Standard Deviation | ml/kg/min | Maximal exercise test (5-10 minutes) |
|
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| 0 |
| 14 |
| 0 |
| 14 |
| 11 |
| 14 |
| EG001 | 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. | 0 | 15 | 0 | 15 | 4 | 15 |
| Chest Tightness | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Systematic Assessment |
|
| Dizziness | Ear and labyrinth disorders | Systematic Assessment |
|
| Increase in Liver Lab Values | Hepatobiliary disorders | Systematic Assessment |
|
| Abnormal ECG Rhythm | Cardiac disorders | Systematic Assessment |
|
| Sore Throat | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Headache | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Weakness | General disorders | Systematic Assessment |
|
| Lowered blood pressure | Cardiac disorders | Systematic Assessment |
|
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| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |