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

NCT01586156 | Completed Results DMC

• 2 other identifiers: 11-1198R01HL115008
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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

Conditions

Pulmonary Hypertension

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (2)

• Urinary cAMP (Cyclic Adenosine Monophosphate)/Creatinine

  6 months

• Beta-Adrenergic Receptor (Alprenolol Binding Assay)

  6 months

Other Outcomes (4)

• Echocardiogram Right Ventricular Systolic Pressure (RVSP)

  6 months

• 6 Minute Walk Test

  6 months

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

  6 months

Study Arms (2)

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.

Drug: Carvedilol

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.

Drug: placebo

Interventions

Carvedilol DRUG

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

Also known as: low fixed dose, escalating dose

Open Label Carvedilol

placebo DRUG

Placebo will be taken twice daily for 6 months

Placebo Arm

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• The Cleveland Clinic: lead
• National Institutes of Health (NIH): collaborator
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Related Publications (5)

• 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.

  PMID: 28814664 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.

  PMID: 28597761 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.

  PMID: 26140151 RESULT

• 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.

  PMID: 31242023 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.

  PMID: 30619887 DERIVED

MeSH Terms

Conditions

Hypertension, Pulmonary

Interventions

Carvedilol

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Hypertension; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Carbazoles; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 3-Ring

Limitations and Caveats

We thought that there would be a possible limitation of hypotension that might limit dosage

Results Point of Contact

• Title: Dr. Serpil Erzurum
• Organization: Cleveland Clinic

erzurus@ccf.org

216-445-6624

Study Officials

• Serpil Erzurum, MD

  The Cleveland Clinic

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Study Director

Study Record Dates

• First Submitted: April 23, 2012
• First Posted: April 26, 2012
• Study Start: December 1, 2012
• Primary Completion: July 1, 2016
• Study Completion: July 1, 2016
• Last Updated: December 5, 2018
• Results First Posted: November 30, 2017

Record last verified: 2018-11

Locations

US (1)