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Ranolazine and Pulmonary Hypertension

Primary Purpose

Angina, Pulmonary Arterial Hypertension

Status

Completed

Phase

Phase 3

Locations

United States

Study Type

Interventional

Intervention

Ranolazine

About this trial

This is an interventional treatment trial for Angina focused on measuring Angina, Right Ventricular Ischemia, Pulmonary Arterial Hypertension, Pulmonary Hypertension

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria:

World Health Organization (WHO) Group 1 PAH, defined as a pulmonary hypertension with mean pulmonary artery pressure > 25 mmHg, pulmonary capillary wedge pressure < 15 mmHg, and pulmonary vascular resistance > 3 Wood units.
Right ventricular dysfunction, defined as RV fractional area change < 32% or RV tricuspid annular plane systolic excursion (TAPSE) < 15 mm.
Symptoms of angina or angina equivalent (exertional dyspnea, exertional epigastric pain, exertional nausea).
New York Heart Association functional class II or III symptoms.
Stable doses of pulmonary vasodilators (prostacyclins, endothelin receptor antagonists, phosphodiesterase inhibitors), with no new therapy initiation or dose escalation > 50% in the 4 weeks prior to randomization.
Age 18-80 years.

Exclusion criteria:

Acute coronary syndrome or coronary revascularization within the prior 3 months.
Patients with unstable angina.
Patients with Class IV congestive heart failure.
Planned revascularization, pacemaker or defibrillator placement during the study period.
Changes in antianginal medical therapy likely to occur during the study period.
Corrected QT interval measurement >500 ms.
Patients with pre-existing QT prolongation (including congenital long QT syndrome) or receiving other QT prolonging drugs (including Class Ia-e.g., quinidine, Class III-e.g., dofetilide, sotalol, antiarrhythmics; antipsychotics (e.g., thioridazine, ziprasidone), or known history of complex ventricular arrhythmias requiring antiarrhythmic medications or ICD implantation.
Patients with known history of hepatic dysfunction.
Current use of strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, saquinavir and diltizaem.
Patients with pacemakers, cochlear implants, aneurysm clips, who have worked with metal.
Patients with metallic hardware, implants, or prostheses will consult with the radiologist/cardiologist prior to the study.
Patients with severe or end stage renal disease (an estimated GFR < 30 mL/min/1.73 m).
Women who are pregnant or lactating
Any contraindications for the use of a right heart catheter including, but not limited to:
- Pulmonic or tricuspid valve stenosis
- Prosthetic pulmonic or tricuspid valve
- Right atrial or ventricular masses
- Previous pneumonectomy
- Risk of severe arrhythmias, including left bundle branch block (LBBB)
Subjects unable to perform cardiopulmonary exercise testing will be excluded (i.e. extensive musculoskeletal disease)

Sites / Locations

Northwestern University

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Ranolazine

Arm Description

1000 mg PO BID

Outcomes

Primary Outcome Measures

Improve Angina Symptoms

Assessed as average improvement in WHO Functional Class. The WHO Functional Class score ranges from 1 to 4, with higher scores indicating more impairment

6-Minute Walk Test

Improve Exercise Capacity measured by 6-Minute Walk Test

Improve Quality of Life

The Kansas City Cardiomyopathy Questionnaire is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. The scores are averaged and transformed to a range of 0-100, in which higher scores reflect better health status and was performed at the conclusion of the study.

Secondary Outcome Measures

RV Perfusion on Cardiac MRI

The majority of patients did not undergo cardiac MRI because it was difficult for the patients to tolerate the imaging study. Therefore, we were not able to assess change in RV perfusion.

Absolute RV Longitudinal Strain

Change in absolute right ventricular (RV) longitudinal strain as assessed by exercise stress echocardiography with speckle-tracking echocardiography at baseline and conclusion of the study. An increase in exercise-induced change in RV longitudinal strain between baseline to conclusion of the study is indicative of improved RV function. If absolute RV longitudinal strain increases with exercise, that is a sign that the RV is working well. If absolute RV longitudinal strain decreases with exercise, that is a sign that the RV is not working well. Therefore, between baseline and conclusion of the study, if exercise-induced change in RV strain increases that means that the RV is working better at the conclusion of the study.

Right Ventricular Hemodynamics

Mean pulmonary artery pressure was assessed invasively by right heart catheterization at the conclusion of the study to estimate right ventricular hemodynamics.

Full Information

NCT ID

NCT01174173

First Posted

July 23, 2010

Last Updated

April 10, 2018

Sponsor

Northwestern University

Collaborators

Gilead Sciences

1. Study Identification

Unique Protocol Identification Number

NCT01174173

Brief Title

Ranolazine and Pulmonary Hypertension

Official Title

Effects of Ranolazine in Patients With Angina Due to Right Ventricular Ischemia in Pulmonary Arterial Hypertension

Study Type

Interventional

2. Study Status

Record Verification Date

April 2018

Overall Recruitment Status

Completed

Study Start Date

June 2010 (undefined)

Primary Completion Date

January 2014 (Actual)

Study Completion Date

October 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Northwestern University

Collaborators

Gilead Sciences

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

The purpose of the study is to determine if the medication, ranolazine (study drug), can help improve blood flow to your heart, increase your exercise capacity and improve your quality of life (QOL). For this study, you will be asked to perform several tests in order to determine if your heart function, exercise capacity, chest pain and QOL have improved after 3 months of treatment with ranolazine. Ranolazine is approved by the U.S. Food and Drug Administration (FDA) for the treatment of angina.

Detailed Description

This study is looking to enroll patients with pulmonary hypertension (PH). PH is abnormally high blood pressure in the arteries of the lungs. It makes the right side of the heart need to work harder than normal and is usually caused by a narrowing of the small arteries of the lung. This narrowing makes it harder for the right side of the heart to circulate the blood to the lungs. Over time, the right side of the heart may become enlarged and symptoms (such as angina [chest pain] shortness of breath, fatigue, edema) begin to appear. Ranolazine is a safe, well-tolerated, and FDA-approved medication for the treatment of chronic stable angina. Ranolazine may potentially improve blood flow to the right ventricle (RV), thereby relieving angina while simultaneously improving RV performance and contractility. This latter effect may increase stroke volume and cardiac output which could translate into benefits in exercise capacity and improved quality of life. The purpose of this single center, non-randomized, prospective pilot study is to investigate the effects of 3 months treatment with ranolazine on pulmonary artery hemodynamics, exercise capacity and quality of life in patients with PAH and symptoms of angina or angina equivalent.

6. Conditions and Keywords

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

Angina, Pulmonary Arterial Hypertension

Keywords

Angina, Right Ventricular Ischemia, Pulmonary Arterial Hypertension, Pulmonary Hypertension

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

11 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Ranolazine

Arm Type

Experimental

Arm Description

1000 mg PO BID

Intervention Type

Drug

Intervention Name(s)

Ranolazine

Other Intervention Name(s)

Ranexa

Intervention Description

ranolazine 1000 mg PO BID for 3 months

Primary Outcome Measure Information:

Title

Improve Angina Symptoms

Description

Assessed as average improvement in WHO Functional Class. The WHO Functional Class score ranges from 1 to 4, with higher scores indicating more impairment

Time Frame

3 months

Title

6-Minute Walk Test

Description

Improve Exercise Capacity measured by 6-Minute Walk Test

Time Frame

3 Months

Title

Improve Quality of Life

Description

Time Frame

3 Months

Secondary Outcome Measure Information:

Title

RV Perfusion on Cardiac MRI

Description

The majority of patients did not undergo cardiac MRI because it was difficult for the patients to tolerate the imaging study. Therefore, we were not able to assess change in RV perfusion.

Time Frame

3 months

Title

Absolute RV Longitudinal Strain

Description

Time Frame

3 months

Title

Right Ventricular Hemodynamics

Description

Mean pulmonary artery pressure was assessed invasively by right heart catheterization at the conclusion of the study to estimate right ventricular hemodynamics.

Time Frame

3 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion criteria: World Health Organization (WHO) Group 1 PAH, defined as a pulmonary hypertension with mean pulmonary artery pressure > 25 mmHg, pulmonary capillary wedge pressure < 15 mmHg, and pulmonary vascular resistance > 3 Wood units. Right ventricular dysfunction, defined as RV fractional area change < 32% or RV tricuspid annular plane systolic excursion (TAPSE) < 15 mm. Symptoms of angina or angina equivalent (exertional dyspnea, exertional epigastric pain, exertional nausea). New York Heart Association functional class II or III symptoms. Stable doses of pulmonary vasodilators (prostacyclins, endothelin receptor antagonists, phosphodiesterase inhibitors), with no new therapy initiation or dose escalation > 50% in the 4 weeks prior to randomization. Age 18-80 years. Exclusion criteria: Acute coronary syndrome or coronary revascularization within the prior 3 months. Patients with unstable angina. Patients with Class IV congestive heart failure. Planned revascularization, pacemaker or defibrillator placement during the study period. Changes in antianginal medical therapy likely to occur during the study period. Corrected QT interval measurement >500 ms. Patients with pre-existing QT prolongation (including congenital long QT syndrome) or receiving other QT prolonging drugs (including Class Ia-e.g., quinidine, Class III-e.g., dofetilide, sotalol, antiarrhythmics; antipsychotics (e.g., thioridazine, ziprasidone), or known history of complex ventricular arrhythmias requiring antiarrhythmic medications or ICD implantation. Patients with known history of hepatic dysfunction. Current use of strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, saquinavir and diltizaem. Patients with pacemakers, cochlear implants, aneurysm clips, who have worked with metal. Patients with metallic hardware, implants, or prostheses will consult with the radiologist/cardiologist prior to the study. Patients with severe or end stage renal disease (an estimated GFR < 30 mL/min/1.73 m). Women who are pregnant or lactating Any contraindications for the use of a right heart catheter including, but not limited to: Pulmonic or tricuspid valve stenosis Prosthetic pulmonic or tricuspid valve Right atrial or ventricular masses Previous pneumonectomy Risk of severe arrhythmias, including left bundle branch block (LBBB) Subjects unable to perform cardiopulmonary exercise testing will be excluded (i.e. extensive musculoskeletal disease)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Sanjiv Shah, MD

Organizational Affiliation

Northwestern University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Northwestern University

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60611

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

26401256

Citation

Khan SS, Cuttica MJ, Beussink-Nelson L, Kozyleva A, Sanchez C, Mkrdichian H, Selvaraj S, Dematte JE, Lee DC, Shah SJ. Effects of ranolazine on exercise capacity, right ventricular indices, and hemodynamic characteristics in pulmonary arterial hypertension: a pilot study. Pulm Circ. 2015 Sep;5(3):547-56. doi: 10.1086/682427.

Results Reference

derived

Links:

URL

http://www.feinberg.northwestern.edu/ctu/current_research/heart_failure/index.htm

Description

Bluhm Cardiovascular Institute Clinical Trials Unit research studies

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Ranolazine and Pulmonary Hypertension

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