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| ID | Type | Description | Link |
|---|---|---|---|
| R01HL115008 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institutes of Health (NIH) | NIH |
| National Heart, Lung, and Blood Institute (NHLBI) | NIH |
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Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature leading to elevated pulmonary pressure and right ventricular (RV) dysfunction with heart failure. Measures of RV function are better predictors of mortality and long term outcomes than pulmonary vascular resistance. The interaction between RV function and the pulmonary circulation is not fully understood, but increased after load appears insufficient to explain right heart failure. Yet, all approved PAH therapies target vasodilation of the pulmonary vasculature to lower pressures
Pulmonary arterial hypertension (PAH) is a serious condition characterized by endothelial dysfunction leading to pulmonary vascular constriction, smooth muscle and endothelial proliferation, and progressive right-sided heart failure. The severity of pulmonary hypertension is mostly determined by the response of the right ventricle (RV) to the increased afterload or pulmonary pressures, and RV failure is the leading cause of death in PAH. Most accepted therapies for PAH have been aimed at vasodilation of the pulmonary vasculature, and there has been little thought that PAH patients would benefit from traditional left heart failure treatments. A cornerstone therapy in left heart failure is £]-adrenergic receptor blockade because of its ability to reverse cardiac remodeling and improve clinical outcomes, despite decades of concern regarding its propensity to exacerbate heart failure. It has been reported to reduce mortality by about 30% in patients, and while the precise mechanisms that contribute to its beneficial effects remain to be elucidated, there is evidence that patients with underlying contractile reserve (i.e., via recruitment of viable myocardium with £]-adrenergic receptor stimulation) may experience greater recovery of their cardiac function. In a study using rats with pulmonary hypertension treated with £] blocker, RV function improved, and maladaptive myocardial remodeling was prevented.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Open Label Carvedilol | Active Comparator | Eligible subjects will receive open label carvedilol therapy at a dose 3.125 mg twice daily for one week. Subjects will be admitted overnight to the CRU (Clinical Research Unit) for the first-dose challenge of carvedilol. Subjects will take the medication for one week and at the end of one week, eligible subjects will be randomized to one of two groups (blinded). Group 1 will receive 3.125mg twice daily for six months.Group 2 will receive carvedilol in a dose escalation scheme. They will be given 3.125mg tablets to take twice daily for one week, followed by 6.25 mg twice daily for one week, followed by 12.5mg twice daily for one week with the option to increase to the max dose of 25mg twice daily for the remainder of the study. |
|
| Placebo Arm | Placebo Comparator | Eligible subjects will receive open label carvedilol therapy at a dose 3.125 mg twice daily for one week. Subjects will be admitted overnight for the first-dose challenge of carvedilol. After one week run in phase, subjects will be placed on placebo. Subjects and Investigators will be blinded to the group assignment for the duration of the study. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Carvedilol | Drug | Group 1 will receive 3.125mg carvedilol twice daily for six months.Group 2 will receive carvedilol in a dose escalation scheme. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Cardiac Glucose Uptake in FDG-PET (Fluorodeoxyglucose-Positron Emission Tomography) | We hypothesize that use of carvedilol in patients with PAH (Pulmonary Arterial Hypertension) will decrease the cardiac glucose utilization, and this will be measurable as a drop in fasting FDG-PET standardized uptake values of the heart at 6 months as compared to baseline | 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| Urinary cAMP (Cyclic Adenosine Monophosphate)/Creatinine | We hypothesize that use of carvedilol in patients with PAH will increase beta adrenergic receptor function and this will be measurable as an increase in cAMP measured in the urine at 6 months in participants in dose escalation carvedilol. | 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| Echocardiogram Right Ventricular Systolic Pressure (RVSP) | We hypothesized that RVSP might decrease in participants on carvedilol. | 6 months |
| 6 Minute Walk Test | We hypothesized that carvedilol would not worsen 6 minute walk distance. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Serpil Erzurum, MD | The Cleveland Clinic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cleveland Clinic | Cleveland | Ohio | 44195 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28814664 | Result | Farha S, Saygin D, Park MM, Cheong HI, Asosingh K, Comhair SA, Stephens OR, Roach EC, Sharp J, Highland KB, DiFilippo FP, Neumann DR, Tang WHW, Erzurum SC. Pulmonary arterial hypertension treatment with carvedilol for heart failure: a randomized controlled trial. JCI Insight. 2017 Aug 17;2(16):e95240. doi: 10.1172/jci.insight.95240. eCollection 2017 Aug 17. | |
| 28597761 | Result | Saygin D, Highland KB, Farha S, Park M, Sharp J, Roach EC, Tang WHW, Thomas JD, Erzurum SC, Neumann DR, DiFilippo FP. Metabolic and Functional Evaluation of the Heart and Lungs in Pulmonary Hypertension by Gated 2-[18F]-Fluoro-2-deoxy-D-glucose Positron Emission Tomography. Pulm Circ. 2017 Apr-Jun;7(2):428-438. doi: 10.1177/2045893217701917. Epub 2017 Mar 10. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Low-fixed-dose Carvedilol | Eligible subjects will receive open label carvedilol therapy at a dose 3.125 mg twice daily for one week. Subjects will be admitted overnight to the CRU for the first-dose challenge of carvedilol. Subjects will take the medication for one week and at the end of one week, eligible subjects will be randomized to one of two groups (blinded). Group 1 will receive 3.125mg twice daily for six months. This is the low fixed dose Carvedilol |
| FG001 | Placebo Arm | Eligible subjects will receive open label carvedilol therapy at a dose 3.125 mg twice daily for one week. Subjects will be admitted overnight for the first-dose challenge of carvedilol. After one week run in phase, subjects will be placed on placebo. Subjects and Investigators will be blinded to the group assignment for the duration of the study. Carvedilol placebo: Placebo taken twice daily for 6 months |
| FG002 | Escalation-dose Carvedilol | Eligible subjects will receive open label carvedilol therapy at a dose 3.125 mg twice daily for one week. Subjects will be admitted overnight to the CRU for the first-dose challenge of carvedilol. Subjects will take the medication for one week and at the end of one week, eligible subjects will be randomized to one of two groups (blinded). Group 2 will receive carvedilol in a dose escalation scheme. They will be given 3.125mg tablets to take twice daily for one week, followed by 6.25 mg twice daily for one week, followed by 12.5mg twice daily for one week with the option to increase to the max dose of 25mg twice daily for the remainder of the study. This is the escalating dose Carvedilol |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Not provided
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| ID | Title | Description |
|---|---|---|
| BG000 | Low-fixed-dose Carvedilol | Eligible subjects will receive open label carvedilol therapy at a dose 3.125 mg twice daily for one week. Subjects will be admitted overnight to the CRU for the first-dose challenge of carvedilol. Subjects will take the medication for one week and at the end of one week, eligible subjects will be randomized to one of two groups (blinded). Group 1 will receive 3.125mg twice daily for six months. This is the low fixed dose Carvedilol |
| 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 | Cardiac Glucose Uptake in FDG-PET (Fluorodeoxyglucose-Positron Emission Tomography) | We hypothesize that use of carvedilol in patients with PAH (Pulmonary Arterial Hypertension) will decrease the cardiac glucose utilization, and this will be measurable as a drop in fasting FDG-PET standardized uptake values of the heart at 6 months as compared to baseline | Paired analyses of baseline to 6 month FDG-PET SUV (standardized uptake value) within each group. | Posted | Median | Inter-Quartile Range | standardized uptake value (SUV) | 6 months |
|
Adverse event data was collected during the duration the subject was consented to participate in the study; 24 weeks or until discontinuation
the definition of adverse event and/or serious adverse event reporting does not differ from the definition listed
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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 | Placebo Arm | Eligible subjects will receive open label carvedilol therapy at a dose 3.125 mg twice daily for one week. Subjects will be admitted overnight for the first-dose challenge of carvedilol. After one week run in phase, subjects will be placed on placebo. Subjects and Investigators will be blinded to the group assignment for the duration of the study. Carvedilol placebo: Placebo taken twice daily for 6 months |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Chest pain | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment | Chest pain attributed to pulmonary hypertension |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fatigue/vivid dreams | Nervous system disorders | Non-systematic Assessment |
We thought that there would be a possible limitation of hypotension that might limit dosage
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Serpil Erzurum | Cleveland Clinic | 216-445-6624 | erzurus@ccf.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 | Jun 26, 2014 | Sep 21, 2017 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D006976 | Hypertension, Pulmonary |
| ID | Term |
|---|---|
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D006973 | Hypertension |
| D014652 | Vascular Diseases |
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| ID | Term |
|---|---|
| D000077261 | Carvedilol |
| ID | Term |
|---|---|
| D011412 | Propanolamines |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
| D009930 | Organic Chemicals |
Not provided
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|
| placebo | Drug | Placebo will be taken twice daily for 6 months |
|
| Beta-Adrenergic Receptor (Alprenolol Binding Assay) |
We hypothesize that use of carvedilol in patients with PAH will increase beta- adrenergic receptor availability, and this will be measurable as a increase in alprenolol binding over time of drug use. |
| 6 months |
| 6 months |
| NT-proBNP (N-terminal Pro-B Type Natriuretic Peptide) | We hypothesized that carvedilol would be safe and tolerable and thus that NT-BNP, a measure of heart failure, would not increase in participants on carvedilol. | 6 months |
| Echocardiogram Left Ventricular Cardiac Output | We hypothesized that carvedilol would be safe and tolerable and thus that Left ventricular cardiac output, a measure of heart function, would not decrease in participants on carvedilol. | 6 months |
| 26140151 | Result | Park JH, Park MM, Farha S, Sharp J, Lundgrin E, Comhair S, Tang WH, Erzurum SC, Thomas JD. Impaired Global Right Ventricular Longitudinal Strain Predicts Long-Term Adverse Outcomes in Patients with Pulmonary Arterial Hypertension. J Cardiovasc Ultrasound. 2015 Jun;23(2):91-9. doi: 10.4250/jcu.2015.23.2.91. Epub 2015 Jun 26. |
| 31242023 | Derived | Stephens OR, Weiss K, Frimel M, Rose JA, Sun Y, Asosingh K, Farha S, Highland KB, Prasad SVN, Erzurum SC. Interdependence of hypoxia and beta-adrenergic receptor signaling in pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol. 2019 Sep 1;317(3):L369-L380. doi: 10.1152/ajplung.00015.2019. Epub 2019 Jun 26. |
| 30619887 | Derived | Cheong HI, Farha S, Park MM, Thomas JD, Saygin D, Comhair SAA, Sharp J, Highland KB, Tang WHW, Erzurum SC. Endothelial Phenotype Evoked by Low Dose Carvedilol in Pulmonary Hypertension. Front Cardiovasc Med. 2018 Dec 12;5:180. doi: 10.3389/fcvm.2018.00180. eCollection 2018. |
| BG001 | Escalation-dose Carvedilol | Eligible subjects will receive open label carvedilol therapy at a dose 3.125 mg twice daily for one week. Subjects will be admitted overnight to the CRU for the first-dose challenge of carvedilol. Subjects will take the medication for one week and at the end of one week, eligible subjects will be randomized to one of two groups (blinded). Group 2 will receive carvedilol in a dose escalation scheme. They will be given 3.125mg tablets to take twice daily for one week, followed by 6.25 mg twice daily for one week, followed by 12.5mg twice daily for one week with the option to increase to the max dose of 25mg twice daily for the remainder of the study. This is the escalating dose Carvedilol |
| BG002 | Placebo Arm | Eligible subjects will receive open label carvedilol therapy at a dose 3.125 mg twice daily for one week. Subjects will be admitted overnight for the first-dose challenge of carvedilol. After one week run in phase, subjects will be placed on placebo. Subjects and Investigators will be blinded to the group assignment for the duration of the study. Carvedilol placebo: Placebo taken twice daily for 6 months |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants | No |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants | No |
|
| OG001 | Low-fixed-dose Carvedilol | Eligible subjects will receive open label carvedilol therapy at a dose 3.125 mg twice daily for one week. Subjects will be admitted overnight to the CRU for the first-dose challenge of carvedilol. Subjects will take the medication for one week and at the end of one week, eligible subjects will be randomized to one of two groups (blinded). Group 1 will receive 3.125mg twice daily for six months. This is the low fixed dose Carvedilol |
| OG002 | Escalation-dose Carvedilol | Eligible subjects will receive open label carvedilol therapy at a dose 3.125 mg twice daily for one week. Subjects will be admitted overnight to the CRU for the first-dose challenge of carvedilol. Subjects will take the medication for one week and at the end of one week, eligible subjects will be randomized to one of two groups (blinded). Group 2 will receive carvedilol in a dose escalation scheme. They will be given 3.125mg tablets to take twice daily for one week, followed by 6.25 mg twice daily for one week, followed by 12.5mg twice daily for one week with the option to increase to the max dose of 25mg twice daily for the remainder of the study. This is the escalating dose Carvedilol |
|
|
|
| Secondary | Urinary cAMP (Cyclic Adenosine Monophosphate)/Creatinine | We hypothesize that use of carvedilol in patients with PAH will increase beta adrenergic receptor function and this will be measurable as an increase in cAMP measured in the urine at 6 months in participants in dose escalation carvedilol. | Posted | Median | Inter-Quartile Range | umol/g | 6 months |
|
|
|
|
| Secondary | Beta-Adrenergic Receptor (Alprenolol Binding Assay) | We hypothesize that use of carvedilol in patients with PAH will increase beta- adrenergic receptor availability, and this will be measurable as a increase in alprenolol binding over time of drug use. | Posted | Mean | Standard Deviation | abritrary units | 6 months |
|
|
|
|
| Other Pre-specified | Echocardiogram Right Ventricular Systolic Pressure (RVSP) | We hypothesized that RVSP might decrease in participants on carvedilol. | Posted | Mean | Standard Deviation | mm Hg | 6 months |
|
|
|
|
| Other Pre-specified | 6 Minute Walk Test | We hypothesized that carvedilol would not worsen 6 minute walk distance. | Posted | Mean | Standard Deviation | meters | 6 months |
|
|
|
| Other Pre-specified | NT-proBNP (N-terminal Pro-B Type Natriuretic Peptide) | We hypothesized that carvedilol would be safe and tolerable and thus that NT-BNP, a measure of heart failure, would not increase in participants on carvedilol. | Posted | Median | Inter-Quartile Range | pg/ml | 6 months |
|
|
|
|
| Other Pre-specified | Echocardiogram Left Ventricular Cardiac Output | We hypothesized that carvedilol would be safe and tolerable and thus that Left ventricular cardiac output, a measure of heart function, would not decrease in participants on carvedilol. | Posted | Mean | Standard Deviation | L/min | 6 months |
|
|
|
|
| 0 |
| 10 |
| 0 |
| 10 |
| 2 |
| 10 |
| EG001 | Low-fixed-dose Carvedilol | Eligible subjects will receive open label carvedilol therapy at a dose 3.125 mg twice daily for one week. Subjects will be admitted overnight to the CRU for the first-dose challenge of carvedilol. Subjects will take the medication for one week and at the end of one week, eligible subjects will be randomized to one of two groups (blinded). Group 1 will receive 3.125mg twice daily for six months. This is the low fixed dose Carvedilol | 0 | 10 | 1 | 10 | 2 | 10 |
| EG002 | Escalation-dose Carvedilol | Eligible subjects will receive open label carvedilol therapy at a dose 3.125 mg twice daily for one week. Subjects will be admitted overnight to the CRU for the first-dose challenge of carvedilol. Subjects will take the medication for one week and at the end of one week, eligible subjects will be randomized to one of two groups (blinded). Group 2 will receive carvedilol in a dose escalation scheme. They will be given 3.125mg tablets to take twice daily for one week, followed by 6.25 mg twice daily for one week, followed by 12.5mg twice daily for one week with the option to increase to the max dose of 25mg twice daily for the remainder of the study. This is the escalating dose Carvedilol | 0 | 10 | 3 | 10 | 7 | 10 |
|
| Dyspnea/wheezing | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment | Asthma attack brought on from stressor |
|
| Leg swelling | Cardiac disorders | Non-systematic Assessment |
|
| Nausea/vomiting | Gastrointestinal disorders | Non-systematic Assessment | complications to chemotherapy |
|
| Dyspnea | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment | shortness of breath due to allergies and weather |
|
| Cough/leg swelling | Cardiac disorders | Non-systematic Assessment |
|
| Blurry vision | Eye disorders | Non-systematic Assessment |
|
| Cholecystitis | Gastrointestinal disorders | Non-systematic Assessment |
|
| Bronchitis | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment | sinusitis/bronchitis |
|
| Broken arm | Musculoskeletal and connective tissue disorders | Non-systematic Assessment | due to fall and unrelated |
|
| Dizziness | Nervous system disorders | Non-systematic Assessment |
|
| Site infection/acute bronchitis | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Bloating | Reproductive system and breast disorders | Non-systematic Assessment | in association with menstruation |
|
| Leg swelling | Cardiac disorders | Non-systematic Assessment |
|
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| D002318 |
| Cardiovascular Diseases |
| D020005 |
| Propanols |
| D000588 | Amines |
| D002227 | Carbazoles |
| D007211 | Indoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D006575 | Heterocyclic Compounds, 3-Ring |
|
| 3 months |
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| 6 months |
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| 6 months |
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| 6 months |
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| 3 months |
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| 6 months |
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| 6 months |
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