Pulmonary Hypertension
Conditions
Brief summary
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
Detailed description
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.
Interventions
DRUGCarvedilol
Group 1 will receive 3.125mg carvedilol twice daily for six months.Group 2 will receive carvedilol in a dose escalation scheme.
DRUGplacebo
Placebo will be taken twice daily for 6 months
Sponsors
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
The Cleveland Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Men and women age 18 or older not greater than age 65 years * Diagnosis of pulmonary arterial hypertension class 1, 3, 4, 5 (Dana Point 2008) * NYHA (New York Health Association)/WHO (World Health Organization) Class I-III * PAH medications must have been initiated according to the latest consensus statement recommendations and remained stable for the last 30 days * Women of child-bearing age must use a double-barrier local contraception till completion of the study * Subjects must demonstrate understanding of the study, sign the informed consent, and have a reliable method of communication for contact and ability to comply with the study requirements
Exclusion criteria
* Participation in any other treatment studies during enrollment * Significant illness in the past 30 days requiring hospitalization * Hepatic insufficiency (transaminase levels \> 4 fold the upper limit of normal or bilirubin \> 2 fold the upper limit of normal), * History of HIV, Hepatitis B or C * Serum creatinine \> 2.8 mg/dl * Pregnancy, breast-feeding, or lack of safe contraception * Acute decompensated heart failure within past 30 days * Known allergy or intolerance to carvedilol or other β blockers * Significant, persistent bradycardia (resting heart rate \< 50 bpm) or hypotension (systolic blood pressure \< 100 mmHg or mean blood pressure \< 70 mmHg) at the time of enrollment * Second or third-degree AV (Atrial Ventricular) block without pacemaker * Use of CYP2D6 isoenzyme inhibitors (such as quinidine, fluoxetine, paroxetine, propafenone) which increase drug levels and result in greater vasodilating effects and hypotension * Use of hypotensive drugs that deplete catecholamines (such as reserpine and monoamine oxidase inhibitors) which may lead to greater signs of hypotension or bradycardia * Other medical and psychosocial conditions as determined by principal investigator deemed unsuitable for enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cardiac Glucose Uptake in FDG-PET (Fluorodeoxyglucose-Positron Emission Tomography) | 6 months | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Urinary cAMP (Cyclic Adenosine Monophosphate)/Creatinine | 6 months | 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. |
| Beta-Adrenergic Receptor (Alprenolol Binding Assay) | 6 months | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Echocardiogram Right Ventricular Systolic Pressure (RVSP) | 6 months | We hypothesized that RVSP might decrease in participants on carvedilol. |
| Echocardiogram Left Ventricular Cardiac Output | 6 months | 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 Minute Walk Test | 6 months | We hypothesized that carvedilol would not worsen 6 minute walk distance. |
| NT-proBNP (N-terminal Pro-B Type Natriuretic Peptide) | 6 months | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 | 10 |
| 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 | 10 |
| 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 | 10 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Pregnancy | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Low-fixed-dose Carvedilol | Escalation-dose Carvedilol | Placebo Arm | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 10 Participants | 10 Participants | 30 Participants |
| Age, Continuous | 42 years STANDARD_DEVIATION 6 | 53 years STANDARD_DEVIATION 9 | 38 years STANDARD_DEVIATION 14 | 42 years STANDARD_DEVIATION 4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 10 Participants | 10 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 10 Participants | 6 Participants | 23 Participants |
| Region of Enrollment United States | 10 Participants | 10 Participants | 10 Participants | 30 Participants |
| Sex: Female, Male Female | 7 Participants | 6 Participants | 8 Participants | 21 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 2 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 2 / 10 | 2 / 10 | 7 / 10 |
| serious Total, serious adverse events | 0 / 10 | 1 / 10 | 3 / 10 |
Outcome results
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
Time frame: 6 months
Population: Paired analyses of baseline to 6 month FDG-PET SUV (standardized uptake value) within each group.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo Arm | Cardiac Glucose Uptake in FDG-PET (Fluorodeoxyglucose-Positron Emission Tomography) | baseline FDG-PET | 1.0 standardized uptake value (SUV) |
| Placebo Arm | Cardiac Glucose Uptake in FDG-PET (Fluorodeoxyglucose-Positron Emission Tomography) | 6 month FDG-PET | 0.8 standardized uptake value (SUV) |
| Low-fixed-dose Carvedilol | Cardiac Glucose Uptake in FDG-PET (Fluorodeoxyglucose-Positron Emission Tomography) | baseline FDG-PET | 0.6 standardized uptake value (SUV) |
| Low-fixed-dose Carvedilol | Cardiac Glucose Uptake in FDG-PET (Fluorodeoxyglucose-Positron Emission Tomography) | 6 month FDG-PET | 0.6 standardized uptake value (SUV) |
| Escalation-dose Carvedilol | Cardiac Glucose Uptake in FDG-PET (Fluorodeoxyglucose-Positron Emission Tomography) | 6 month FDG-PET | 0.7 standardized uptake value (SUV) |
| Escalation-dose Carvedilol | Cardiac Glucose Uptake in FDG-PET (Fluorodeoxyglucose-Positron Emission Tomography) | baseline FDG-PET | 0.9 standardized uptake value (SUV) |
p-value: 0.04ANOVA
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.
Time frame: 6 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm | Beta-Adrenergic Receptor (Alprenolol Binding Assay) | baseline | 92254 abritrary units | Standard Deviation 21469 |
| Placebo Arm | Beta-Adrenergic Receptor (Alprenolol Binding Assay) | 6 months | 79083 abritrary units | Standard Deviation 22337 |
| Low-fixed-dose Carvedilol | Beta-Adrenergic Receptor (Alprenolol Binding Assay) | baseline | 85230 abritrary units | Standard Deviation 18525 |
| Low-fixed-dose Carvedilol | Beta-Adrenergic Receptor (Alprenolol Binding Assay) | 6 months | 84554 abritrary units | Standard Deviation 22828 |
| Escalation-dose Carvedilol | Beta-Adrenergic Receptor (Alprenolol Binding Assay) | baseline | 82779 abritrary units | Standard Deviation 30406 |
| Escalation-dose Carvedilol | Beta-Adrenergic Receptor (Alprenolol Binding Assay) | 6 months | 83730 abritrary units | Standard Deviation 20455 |
p-value: 0.02Pearson
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.
Time frame: 6 months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo Arm | Urinary cAMP (Cyclic Adenosine Monophosphate)/Creatinine | baseline | 1.4 umol/g |
| Placebo Arm | Urinary cAMP (Cyclic Adenosine Monophosphate)/Creatinine | 6 months | 1.4 umol/g |
| Placebo Arm | Urinary cAMP (Cyclic Adenosine Monophosphate)/Creatinine | 1 month | 1.3 umol/g |
| Placebo Arm | Urinary cAMP (Cyclic Adenosine Monophosphate)/Creatinine | 3 months | 1.2 umol/g |
| Low-fixed-dose Carvedilol | Urinary cAMP (Cyclic Adenosine Monophosphate)/Creatinine | 3 months | 0.6 umol/g |
| Low-fixed-dose Carvedilol | Urinary cAMP (Cyclic Adenosine Monophosphate)/Creatinine | baseline | 0.6 umol/g |
| Low-fixed-dose Carvedilol | Urinary cAMP (Cyclic Adenosine Monophosphate)/Creatinine | 1 month | 0.8 umol/g |
| Low-fixed-dose Carvedilol | Urinary cAMP (Cyclic Adenosine Monophosphate)/Creatinine | 6 months | 0.7 umol/g |
| Escalation-dose Carvedilol | Urinary cAMP (Cyclic Adenosine Monophosphate)/Creatinine | 1 month | 0.7 umol/g |
| Escalation-dose Carvedilol | Urinary cAMP (Cyclic Adenosine Monophosphate)/Creatinine | baseline | 1.0 umol/g |
| Escalation-dose Carvedilol | Urinary cAMP (Cyclic Adenosine Monophosphate)/Creatinine | 6 months | 1.0 umol/g |
| Escalation-dose Carvedilol | Urinary cAMP (Cyclic Adenosine Monophosphate)/Creatinine | 3 months | 1.5 umol/g |
p-value: 0.04ANOVA
Other Pre-specified
6 Minute Walk Test
We hypothesized that carvedilol would not worsen 6 minute walk distance.
Time frame: 6 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm | 6 Minute Walk Test | 3 months | 412 meters | Standard Deviation 84 |
| Placebo Arm | 6 Minute Walk Test | baseline | 404 meters | Standard Deviation 84 |
| Placebo Arm | 6 Minute Walk Test | 6 months | 453 meters | Standard Deviation 60 |
| Low-fixed-dose Carvedilol | 6 Minute Walk Test | 3 months | 504 meters | Standard Deviation 93 |
| Low-fixed-dose Carvedilol | 6 Minute Walk Test | baseline | 504 meters | Standard Deviation 93 |
| Low-fixed-dose Carvedilol | 6 Minute Walk Test | 6 months | 486 meters | Standard Deviation 90 |
| Escalation-dose Carvedilol | 6 Minute Walk Test | baseline | 438 meters | Standard Deviation 158 |
| Escalation-dose Carvedilol | 6 Minute Walk Test | 6 months | 450 meters | Standard Deviation 180 |
| Escalation-dose Carvedilol | 6 Minute Walk Test | 3 months | 438 meters | Standard Deviation 159 |
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.
Time frame: 6 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm | Echocardiogram Left Ventricular Cardiac Output | 3 months | 4.7 L/min | Standard Deviation 1.2 |
| Placebo Arm | Echocardiogram Left Ventricular Cardiac Output | baseline | 4.7 L/min | Standard Deviation 1.7 |
| Placebo Arm | Echocardiogram Left Ventricular Cardiac Output | 6 months | 4.5 L/min | Standard Deviation 0.9 |
| Low-fixed-dose Carvedilol | Echocardiogram Left Ventricular Cardiac Output | 3 months | 4.6 L/min | Standard Deviation 1.2 |
| Low-fixed-dose Carvedilol | Echocardiogram Left Ventricular Cardiac Output | baseline | 5.2 L/min | Standard Deviation 2 |
| Low-fixed-dose Carvedilol | Echocardiogram Left Ventricular Cardiac Output | 6 months | 4.7 L/min | Standard Deviation 1.6 |
| Escalation-dose Carvedilol | Echocardiogram Left Ventricular Cardiac Output | baseline | 4.5 L/min | Standard Deviation 0.9 |
| Escalation-dose Carvedilol | Echocardiogram Left Ventricular Cardiac Output | 6 months | 4.9 L/min | Standard Deviation 1.7 |
| Escalation-dose Carvedilol | Echocardiogram Left Ventricular Cardiac Output | 3 months | 4.8 L/min | Standard Deviation 1.1 |
p-value: 0.8ANOVA
Other Pre-specified
Echocardiogram Right Ventricular Systolic Pressure (RVSP)
We hypothesized that RVSP might decrease in participants on carvedilol.
Time frame: 6 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm | Echocardiogram Right Ventricular Systolic Pressure (RVSP) | 3 months | 78 mm Hg | Standard Deviation 21 |
| Placebo Arm | Echocardiogram Right Ventricular Systolic Pressure (RVSP) | baseline | 76 mm Hg | Standard Deviation 22 |
| Placebo Arm | Echocardiogram Right Ventricular Systolic Pressure (RVSP) | 6 months | 66 mm Hg | Standard Deviation 23 |
| Low-fixed-dose Carvedilol | Echocardiogram Right Ventricular Systolic Pressure (RVSP) | 3 months | 59 mm Hg | Standard Deviation 18 |
| Low-fixed-dose Carvedilol | Echocardiogram Right Ventricular Systolic Pressure (RVSP) | baseline | 63 mm Hg | Standard Deviation 28 |
| Low-fixed-dose Carvedilol | Echocardiogram Right Ventricular Systolic Pressure (RVSP) | 6 months | 51 mm Hg | Standard Deviation 22 |
| Escalation-dose Carvedilol | Echocardiogram Right Ventricular Systolic Pressure (RVSP) | baseline | 63 mm Hg | Standard Deviation 31 |
| Escalation-dose Carvedilol | Echocardiogram Right Ventricular Systolic Pressure (RVSP) | 6 months | 64 mm Hg | Standard Deviation 32 |
| Escalation-dose Carvedilol | Echocardiogram Right Ventricular Systolic Pressure (RVSP) | 3 months | 54 mm Hg | Standard Deviation 24 |
p-value: 0.05ANOVA
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.
Time frame: 6 months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo Arm | NT-proBNP (N-terminal Pro-B Type Natriuretic Peptide) | 1 month | 183 pg/ml |
| Placebo Arm | NT-proBNP (N-terminal Pro-B Type Natriuretic Peptide) | 6 months | 293 pg/ml |
| Placebo Arm | NT-proBNP (N-terminal Pro-B Type Natriuretic Peptide) | 3 months | 152 pg/ml |
| Placebo Arm | NT-proBNP (N-terminal Pro-B Type Natriuretic Peptide) | baseline | 170 pg/ml |
| Low-fixed-dose Carvedilol | NT-proBNP (N-terminal Pro-B Type Natriuretic Peptide) | 1 month | 92 pg/ml |
| Low-fixed-dose Carvedilol | NT-proBNP (N-terminal Pro-B Type Natriuretic Peptide) | baseline | 57 pg/ml |
| Low-fixed-dose Carvedilol | NT-proBNP (N-terminal Pro-B Type Natriuretic Peptide) | 6 months | 52 pg/ml |
| Low-fixed-dose Carvedilol | NT-proBNP (N-terminal Pro-B Type Natriuretic Peptide) | 3 months | 79 pg/ml |
| Escalation-dose Carvedilol | NT-proBNP (N-terminal Pro-B Type Natriuretic Peptide) | 6 months | 146 pg/ml |
| Escalation-dose Carvedilol | NT-proBNP (N-terminal Pro-B Type Natriuretic Peptide) | 3 months | 169 pg/ml |
| Escalation-dose Carvedilol | NT-proBNP (N-terminal Pro-B Type Natriuretic Peptide) | baseline | 127 pg/ml |
| Escalation-dose Carvedilol | NT-proBNP (N-terminal Pro-B Type Natriuretic Peptide) | 1 month | 120 pg/ml |
p-value: >0.05ANOVA