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PAHTCH Pulmonary Arterial Hypertension Treatment With Carvedilol for Heart Failure (Carvedilol) (PAHTCH)

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01586156
First Posted: April 26, 2012
Last Update Posted: November 30, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Samar Farha, MD, The Cleveland Clinic
April 23, 2012
April 26, 2012
August 16, 2017
November 30, 2017
November 30, 2017
December 2012
July 2016   (Final data collection date for primary outcome measure)
Cardiac Glucose Uptake in FDG-PET (Fluorodeoxyglucose-Positron Emission Tomography) [ Time Frame: 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
Biochemical abnormalities (HIF activation, NO synthesis, beta-adrenergic receptor recovery) [ Time Frame: Throughout 1-5 years of the program ]
We hypothesize that use of carvedilol in patients with PAH will improve right and left ventricular function, decrease right and left ventricular size, and improve exercise and functional capacity.
Complete list of historical versions of study NCT01586156 on ClinicalTrials.gov Archive Site
  • Urinary cAMP (Cyclic Adenosine Monophosphate)/Creatinine [ Time Frame: 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) [ Time Frame: 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.
Not Provided
  • Echocardiogram Right Ventricular Systolic Pressure (RVSP) [ Time Frame: 6 months ]
    We hypothesized that RVSP might decrease in participants on carvedilol.
  • 6 Minute Walk Test [ Time Frame: 6 months ]
    We hypothesized that carvedilol would not worsen 6 minute walk distance.
  • NT-proBNP (N-terminal Pro-B Type Natriuretic Peptide) [ Time Frame: 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.
  • Echocardiogram Left Ventricular Cardiac Output [ Time Frame: 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.
Not Provided
 
PAHTCH Pulmonary Arterial Hypertension Treatment With Carvedilol for Heart Failure (Carvedilol)
Pulmonary Arterial Hypertension Treatment With Carvedilol for Heart Failure
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.
Interventional
Not Provided
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Pulmonary Hypertension
  • Drug: Carvedilol
    Group 1 will receive 3.125mg carvedilol twice daily for six months.Group 2 will receive carvedilol in a dose escalation scheme.
    Other Name: low fixed dose, escalating dose
  • Drug: placebo
    Placebo will be taken twice daily for 6 months
  • Active Comparator: Open Label 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 (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.
    Intervention: Drug: Carvedilol
  • Placebo Comparator: 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.
    Intervention: Drug: placebo
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
30
July 2016
July 2016   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
18 Years to 65 Years   (Adult)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT01586156
11-1198
R01HL115008 ( U.S. NIH Grant/Contract )
Yes
Not Provided
Not Provided
Samar Farha, MD, The Cleveland Clinic
The Cleveland Clinic
  • National Institutes of Health (NIH)
  • National Heart, Lung, and Blood Institute (NHLBI)
Principal Investigator: Serpil Erzurum, MD The Cleveland Clinic
The Cleveland Clinic
November 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP