Ranolazine and Pulmonary Hypertension

• Sponsor: Northwestern University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01174173
• Collaborator: Gilead Sciences (Industry)
• Enrollment: 11
• Location: 1
• Arm: 1
• Duration (Months): 52
• Patients Per Site Per Month: 0.2

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Angina; Pulmonary Arterial Hypertension	Drug: Ranolazine	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 11 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Effects of Ranolazine in Patients With Angina Due to Right Ventricular Ischemia in Pulmonary Arterial Hypertension
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: Jan 1, 2014
• Actual Study Completion Date: Oct 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ranolazine 1000 mg PO BID	Drug: Ranolazine; ranolazine 1000 mg PO BID for 3 months; Other Names: Ranexa

Outcome Measures

Primary Outcome Measures

1. Improve Angina Symptoms [3 months]

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

2. 6-Minute Walk Test [3 Months]

   Improve Exercise Capacity measured by 6-Minute Walk Test

3. Improve Quality of Life [3 Months]

   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

1. RV Perfusion on Cardiac MRI [3 months]

   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.

2. Absolute RV Longitudinal Strain [3 months]

   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.

3. Right Ventricular Hemodynamics [3 months]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

1. 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.

2. Right ventricular dysfunction, defined as RV fractional area change < 32% or RV tricuspid annular plane systolic excursion (TAPSE) < 15 mm.

3. Symptoms of angina or angina equivalent (exertional dyspnea, exertional epigastric pain, exertional nausea).

4. New York Heart Association functional class II or III symptoms.

5. 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.

6. Age 18-80 years.

Exclusion criteria:

1. Acute coronary syndrome or coronary revascularization within the prior 3 months.

2. Patients with unstable angina.

3. Patients with Class IV congestive heart failure.

4. Planned revascularization, pacemaker or defibrillator placement during the study period.

5. Changes in antianginal medical therapy likely to occur during the study period.

6. Corrected QT interval measurement >500 ms.

7. 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.

8. Patients with known history of hepatic dysfunction.

9. Current use of strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, saquinavir and diltizaem.

10. Patients with pacemakers, cochlear implants, aneurysm clips, who have worked with metal.

11. Patients with metallic hardware, implants, or prostheses will consult with the radiologist/cardiologist prior to the study.

12. Patients with severe or end stage renal disease (an estimated GFR < 30 mL/min/1.73 m).

13. Women who are pregnant or lactating

14. 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)

1. Subjects unable to perform cardiopulmonary exercise testing will be excluded (i.e. extensive musculoskeletal disease)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwestern University	Chicago	Illinois	United States	60611

Sponsors and Collaborators

• Northwestern University
• Gilead Sciences

Investigators

• Principal Investigator: Sanjiv Shah, MD, Northwestern University

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Bluhm Cardiovascular Institute Clinical Trials Unit research studies

Publications

None provided.

• Responsible Party: Sanjiv Shah, Principal Invesitgator, Northwestern University
• ClinicalTrials.gov Identifier: NCT01174173
• Other Study ID Numbers: STU00030314
• First Posted: Aug 3, 2010
• Last Update Posted: May 11, 2018
• Last Verified: Apr 1, 2018

• Keywords provided by Sanjiv Shah, Principal Invesitgator, Northwestern University: Angina; Right Ventricular Ischemia; Pulmonary Arterial Hypertension; Pulmonary Hypertension
• Additional relevant MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension; Angina Pectoris; Ranolazine

Study Results

Participant Flow

Arm/Group Title	Ranolazine
Arm/Group Description	1000 mg PO BID Ranolazine: ranolazine 1000 mg PO BID for 3 months
Period Title: Overall Study
STARTED	11
COMPLETED	10
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Ranolazine
Arm/Group Description	1000 mg PO BID Ranolazine: ranolazine 1000 mg PO BID for 3 months
Overall Participants	11
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	10 90.9%
>=65 years	1 9.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48 (13)
Sex: Female, Male (Count of Participants)
Female	8 72.7%
Male	3 27.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	5 45.5%
White	5 45.5%
More than one race	0 0%
Unknown or Not Reported	1 9.1%
Region of Enrollment (participants) [Number]
United States	11 100%
Exercise stress echocardiography with strain (Ejection Fraction (%)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Ejection Fraction (%)]	63 (5)
Right heart catheterization (Mean pulmonary artery pressure (mm Hg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Mean pulmonary artery pressure (mm Hg)]	48 (14)
6-minute walk test (meters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [meters]	383 (60)

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Analysis was performed on all participants who completed as average change in WHO Functional class score from baseline to 3 months (Baseline, 3 months)

Arm/Group Title	Ranolazine
Arm/Group Description	1000 mg PO BID Ranolazine: ranolazine 1000 mg PO BID for 3 months
Measure Participants	8
Mean (Standard Deviation) [units on a scale]	1.75 (0.46)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranolazine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0013
	Comments	A two-sided t-test was performed with p-value < 0.05 was considered statistically significant a priori.
	Method	t-test, 2 sided
	Comments

2. Primary Outcome

Title	6-Minute Walk Test
Description	Improve Exercise Capacity measured by 6-Minute Walk Test
Time Frame	3 Months

Outcome Measure Data

Analysis Population Description

Analysis was performed in all participants who completed the study and had a 6-minute walk test at baseline and at the conclusion of the study.

Arm/Group Title	Ranolazine
Arm/Group Description	1000 mg PO BID Ranolazine: ranolazine 1000 mg PO BID for 3 months
Measure Participants	6
Mean (Standard Deviation) [meters]	419 (80)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranolazine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.09
	Comments	A two-sided t-test was performed for change in 6-minute walk test and p-value < 0.05 was considered statistically significant a priori.
	Method	t-test, 2 sided
	Comments

3. Primary Outcome

Title	Improve Quality of Life
Description	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.
Time Frame	3 Months

Outcome Measure Data

Analysis Population Description

Analysis was performed on the 8 participants who completed the KCCQ questionnaire at baseline and at the conclusion of the study (month 3)

Arm/Group Title	Ranolazine
Arm/Group Description	1000 mg PO BID Ranolazine: ranolazine 1000 mg PO BID for 3 months
Measure Participants	8
Baseline	60.3 (19.7)
Month 3	64.2 (17.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranolazine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.37
	Comments	A two-sided t-test was performed for difference from baseline and 3-month KCCQ score. A p-value of <0.05 was considered statistically significant a priori.
	Method	t-test, 2 sided
	Comments

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ranolazine 1000 mg po Bid
Arm/Group Description	MRI was not analyzable due to inability of patients to undergo MRI due to technical issues
Measure Participants	0

5. Secondary Outcome

Title	Absolute RV Longitudinal Strain
Description	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.
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

Analysis was performed on all participants who completed exercise stress echocardiography at baseline and conclusion of the study (month 3)

Arm/Group Title	Ranolazine
Arm/Group Description	1000 mg PO BID Ranolazine: ranolazine 1000 mg PO BID for 3 months
Measure Participants	8
Baseline	-1.4 (0.7)
Month 3	1.0 (0.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranolazine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.037
	Comments
	Method	t-test, 2 sided
	Comments

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Analysis was performed on all participants who completed right heart catheterization at the conclusion of the study

Arm/Group Title	Ranolazine
Arm/Group Description	1000 mg PO BID Ranolazine: ranolazine 1000 mg PO BID for 3 months
Measure Participants	8
Mean (Standard Deviation) [mm Hg]	48 (6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranolazine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.66
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	3 months
Arm/Group Title	Ranolazine
Arm/Group Description	Ranolazine: ranolazine 1000 mg PO BID for 3 months
All Cause Mortality
	Ranolazine
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Ranolazine
	Affected / at Risk (%)	# Events
Total	1/11 (9.1%)
Nervous system disorders
Inpatient hospitalization	1/11 (9.1%)	1
Other (Not Including Serious) Adverse Events
	Ranolazine
	Affected / at Risk (%)	# Events
Total	6/11 (54.5%)
Gastrointestinal disorders
Constipation	3/11 (27.3%)	3
nausea	2/11 (18.2%)	2
Musculoskeletal and connective tissue disorders
Myalgias	1/11 (9.1%)	1

Limitations/Caveats

This study was a small pilot Interventional study to test safety and tolerability of ranolazine in 11 patients with sx WHO Group 1 PAH patients.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.