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

Primary Purpose

Pulmonary Hypertension

Status

Completed

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Carvedilol

placebo

About this trial

This is an interventional treatment trial for Pulmonary Hypertension

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Cleveland Clinic

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Open Label Carvedilol

Placebo Arm

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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.

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.

Full Information

NCT ID

NCT01586156

First Posted

April 23, 2012

Last Updated

November 12, 2018

Sponsor

The Cleveland Clinic

Collaborators

National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI)

1. Study Identification

Unique Protocol Identification Number

NCT01586156

Brief Title

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

Acronym

PAHTCH

Official Title

Pulmonary Arterial Hypertension Treatment With Carvedilol for Heart Failure

Study Type

Interventional

2. Study Status

Record Verification Date

November 2018

Overall Recruitment Status

Completed

Study Start Date

December 2012 (undefined)

Primary Completion Date

July 2016 (Actual)

Study Completion Date

July 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

The Cleveland Clinic

Collaborators

National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Pulmonary Hypertension

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

30 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Open Label Carvedilol

Arm Type

Active Comparator

Arm Description

Arm Title

Placebo Arm

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Carvedilol

Other Intervention Name(s)

low fixed dose, escalating dose

Intervention Description

Group 1 will receive 3.125mg carvedilol twice daily for six months.Group 2 will receive carvedilol in a dose escalation scheme.

Intervention Type

Drug

Intervention Name(s)

placebo

Intervention Description

Placebo will be taken twice daily for 6 months

Primary Outcome Measure Information:

Title

Cardiac Glucose Uptake in FDG-PET (Fluorodeoxyglucose-Positron Emission Tomography)

Description

Time Frame

6 months

Secondary Outcome Measure Information:

Title

Urinary cAMP (Cyclic Adenosine Monophosphate)/Creatinine

Description

Time Frame

6 months

Title

Beta-Adrenergic Receptor (Alprenolol Binding Assay)

Description

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

Other Pre-specified Outcome Measures:

Title

Echocardiogram Right Ventricular Systolic Pressure (RVSP)

Description

We hypothesized that RVSP might decrease in participants on carvedilol.

Time Frame

6 months

Title

6 Minute Walk Test

Description

We hypothesized that carvedilol would not worsen 6 minute walk distance.

Time Frame

6 months

Title

NT-proBNP (N-terminal Pro-B Type Natriuretic Peptide)

Description

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

Title

Echocardiogram Left Ventricular Cardiac Output

Description

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Serpil Erzurum, MD

Organizational Affiliation

The Cleveland Clinic

Official's Role

Principal Investigator

Facility Information:

Facility Name

Cleveland Clinic

City

Cleveland

State/Province

Ohio

ZIP/Postal Code

44195

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

28814664

Citation

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.

Results Reference

result

PubMed Identifier

28597761

Citation

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.

Results Reference

result

PubMed Identifier

26140151

Citation

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.

Results Reference

result

PubMed Identifier

31242023

Citation

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.

Results Reference

derived

PubMed Identifier

30619887

Citation

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.

Results Reference

derived

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

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