RWISE: Treatment With Ranolazine in Microvascular Coronary Dysfunction (MCD): Impact on Angina Myocardial Ischemia

• Sponsor: Cedars-Sinai Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01342029
• Collaborator: University of Florida (Other)
• Enrollment: 142
• Locations: 2
• Arms: 2
• Actual Duration (Months): 67.1
• Patients Per Site: 71
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

This research study is designed to test the use of ranolazine in patients with angina (chest discomfort due to reduced blood supply to the heart) due to microvascular coronary dysfunction (MCD; abnormalities in the small blood vessels of the heart). This drug is approved by the U.S. Food and Drug Administration (FDA) for treatment of chronic angina. The FDA has approved this drug based on studies primarily on patients with chronic angina with major blockages of the arteries.

Condition or Disease	Intervention/Treatment	Phase
Microvascular Coronary Dysfunction (MCD)	Drug: Ranolazine; Drug: Placebo	N/A

Detailed Description

This is a randomized, double-blinded, placebo- controlled, and cross-over clinical trial. 147 subjects will be enrolled at two clinical sites, with projected 9-10% dropout and anticipated 134 completed subjects. To maintain blinding of the investigators, the study randomization table will be kept in Pharmacy Service. The sponsor will ship the study drug directly to the Pharmacy Service. The pharmacy service will also be responsible for dispersing the study drug.

There are 4 study visits (2 visits in each study period) in this study. Subjects will be in this study for about 6 weeks from Week 0 - baseline visit to Week 6 - exit visit. Besides the procedure of study medication mentioned above, other study procedures include informed consent, physical exam, questionnaires, EKG for safety assessment, blood collection for laboratory testing, cardiac MRI, and follow-up events. In sum, participants will be asked to undergo 2 cardiac MRI's and fill out questionnaires 4 times. They will be asked to participate for 6 weeks with two 2-week courses (with a treatment window period of 5 days), one with ranolazine and the other with placebo (without knowing which they are taking). There is a 2-week washout period between treatments. The participants will otherwise remain on all their usual medications. The physicians will also be blinded to which medication the subject is receiving.

Participation in this study will be approximately 6 weeks, which consists of two 2-week study periods and in between a 2-week washout period:

1. During the first 2-week period: Subjects will be randomized to first receive either the ranolazine or a placebo pill (sugar pill with no active medicine). Subjects will take the extended-release ranolazine or a placebo pill for a total of 2 weeks. Subjects will take 500 mg twice daily for the first 1 week and then 1000 mg twice daily for an additional 1 week. Subjects who are unable to take the higher dose due to side effects will remain on 500 mg twice daily for the entire study period. After the 2 weeks, the participant will have a Cardiac MRI and complete study questionnaires. These tools will allow us to evaluate if the participant is doing better on the medication.

2. 2-week washout period: Subject will then be asked to go 2 weeks without any study medication (ranolazine or placebo).

3. During the second 2-week period: Subject will then be given either extended release ranolazine or placebo depending on which was received the first time for a total of 2 weeks. Subjects will take 500 mg twice daily for the first 1 week and then 1000 mg twice daily for an additional 1 week. Subjects who are unable to take the higher dose due to side effects will remain on 500 mg twice daily for entire study period. This 2-week period will again be followed by a final Cardiac MRI and questionnaire completion.

Study Design

• Study Type: Interventional
• Actual Enrollment: 142 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Treatment With Ranolazine in Microvascular Coronary Dysfunction (MCD): Impact on Angina Myocardial Ischemia
• Actual Study Start Date: May 1, 2011
• Actual Primary Completion Date: Dec 1, 2016
• Actual Study Completion Date: Dec 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ranolazine 147 subjects, with projected 9-10% dropout and anticipated 134 completed subjects will undergo baseline testing and then be randomized into a clinical cross-over trial of stepped dosing of ranolazine or placebo 500-1,000 mg po bid for 2 weeks with exit testing followed by cross-over to the alternate ranolazine or placebo and repeat exit testing.	Drug: Ranolazine; This drug is approved by the U.S. Food and Drug Administration (FDA) for treatment of chronic angina. 500-1,000 mg po bid for 2 weeks; Other Names: Ranexa
Placebo Comparator: Placebo 147 subjects, with projected 9-10% dropout and anticipated 134 completed subjects will undergo baseline testing and then be randomized into a clinical cross-over trial of stepped dosing of ranolazine or placebo 500-1,000 mg po bid for 2 weeks with exit testing followed by cross-over to the alternate ranolazine or placebo and repeat exit testing.	Drug: Placebo; 500-1,000 mg po bid for 2 weeks

Outcome Measures

Primary Outcome Measures

1. Seattle Angina Questionnaire (SAQ) [2 weeks (first intervention) and 6 weeks (second intervention)]

   Questionnaires will be completed (SAQ - Seattle Angina Questionnaire) at the end of each treatment period. The Seattle Angina Questionnaire (SAQ) is a self-administered, 19-item questionnaire, a cardiac disease-related quality-of-life measure. The SAQ is well validated and sensitive to clinical changes. It has five subscales: physical limitation, angina stability, angina frequency, treatment satisfaction, and quality of life. The possible range of scores for each of the five subscales is 0 to 100, with higher scores indicating better quality of life. A change of 10 points in any of the subscales is considered to be clinically important.

Secondary Outcome Measures

1. Cardiac Magnetic Resonance (CMRs) [2 weeks (first intervention) and 6 weeks (second intervention)]

   Cardiac Magnetic Resonance (CMRs) (CMR 1 and CMR 2) end of the 2nd week of treatment 1 and treatment 2 respectively, 4 hours after the morning dose of study drug was performed to measure myocardial perfusion reserve index. Myocardial perfusion reserve index (MPRI) was assessed using the first-pass perfusion intensity curves during stress and rest cardiac magnetic resonance imaging. First-pass perfusion images were analysed using CAAS MRV CMRI analysis software Version 3.3 (Pie Medical Imaging B.V., Maastricht, the Netherlands). Global MPRI was calculated as the ratio of stress/rest relative perfusion upslope, corrected for LV cavity upslope. Higher MPRI represents better myocardial perfusion reserve. Since MPRI is an index, there is no unit.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Men or women age >18 from diverse racial/ethnic groups;

2. Competent to give informed consent;

3. Patients with chronic angina or its equivalent;

4. Coronary angiogram revealing MCD with no obstructive CAD (epicardial coronary stenosis <50% luminal diameter stenosis);

5. Left ventricular ejection fraction > or = 45%;

6. Objective evidence of ischemia by noninvasive methods such as exercise stress test, stress Echo, MRI, or SPECT;

7. Patients with 10% myocardial ischemia by Cardiac magnetic resonance imaging (CMRI) myocardial perfusion reserve index ≤ 2.0 or abnormal coronary reactivity testing (CFR < 2.5, or ACH response of no dilation or constriction, determined by local site read).

Exclusion Criteria:

1. Acute coronary syndrome (defined by WHO), cardiogenic shock or requiring inotropic or intra-aortic balloon support;

2. Planned percutaneous coronary intervention or CABG or established obstructive CAD with ischemia eligible for revascularization, acute MI;

3. Prior non-cardiac illness with an estimated life expectancy <4 years;

4. Unable to give informed consent;

5. Allergy or contra-indication to CMRI testing, including renal failure, claustrophobia, and asthma, uncontrolled moderate hypertension (sitting blood pressure >160/95mmHg with measurements recorded on at least 2 occasions), conditions likely to influence outcomes: Severe lung, creatinine >1.8 or CrCl ≤ 50ml/min) or hepatic disease;

6. Surgically uncorrected significant congenital or valvular heart disease and other disease likely to be fatal or require frequent hospitalization within the next six months;

7. Adherence or retention reasons;

8. Unwilling to complete follow-up evaluation including repeat testing, documented obstructive hypertrophic cardiomyopathy;

9. Aortic stenosis (valve area <1.5cm);

10. LV dysfunction (ejection fraction ≤35%);

11. History of significant cocaine or amphetamine abuse;

12. Taking potent CYP3A4 inhibitors (ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir);

13. Women who are pregnant.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	127 S. San Vicente Blvd, Suite A9303	Los Angeles	California	United States	90048
2	University of Florida	Gainesville	Florida	United States	32610

Sponsors and Collaborators

• Cedars-Sinai Medical Center
• University of Florida

Investigators

• Principal Investigator: C. Noel Bairey Merz, MD, Cedars-Sinai Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Noel Bairey Merz, Director, Cedars-Sinai Medical Center
• ClinicalTrials.gov Identifier: NCT01342029
• Other Study ID Numbers: IN-US-259-0124 - RWISE
• First Posted: Apr 26, 2011
• Last Update Posted: Apr 24, 2019
• Last Verified: Apr 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Noel Bairey Merz, Director, Cedars-Sinai Medical Center: Microvascular Coronary Dysfunction (MCD)
• Additional relevant MeSH terms: Myocardial Ischemia; Coronary Artery Disease; Ischemia; Ranolazine

Study Results

Participant Flow

Arm/Group Title	Ranolazine First, Then Placebo	Placebo First, Then Ranolazine
Arm/Group Description	147 subjects, with projected 9-10% dropout and anticipated 134 completed subjects will undergo baseline testing and then be randomized into a clinical cross-over trial of stepped dosing of ranolazine or placebo 500-1,000 mg po bid for 2 weeks with exit testing followed by cross-over to the alternate ranolazine or placebo and repeat exit testing. Ranolazine: This drug is approved by the U.S. Food and Drug Administration (FDA) for treatment of chronic angina. 500-1,000 mg po bid for 2 weeks	147 subjects, with projected 9-10% dropout and anticipated 134 completed subjects will undergo baseline testing and then be randomized into a clinical cross-over trial of stepped dosing of ranolazine or placebo 500-1,000 mg po bid for 2 weeks with exit testing followed by cross-over to the alternate ranolazine or placebo and repeat exit testing. Placebo: 500-1,000 mg po bid for 2 weeks
Period Title: Period 1
STARTED	70	72
Dropout	3	1
COMPLETED	67	71
NOT COMPLETED	3	1
Period Title: Period 1
STARTED	67	71
COMPLETED	67	67
NOT COMPLETED	0	4
Period Title: Period 1
STARTED	67	67
Dropout	2	0
COMPLETED	65	67
NOT COMPLETED	2	0

Baseline Characteristics

Arm/Group Title	Ranolazine/Placebo
Arm/Group Description	147 subjects will be enrolled at two clinical sites, with projected 9-10% dropout and anticipated 134 completed subjects. For Ranolazine first group, subjects will undergo baseline testing and then be randomized into a clinical cross-over trial of stepped dosing of ranolazine or placebo 500-1,000 mg po bid for 2 weeks with exit testing followed by cross-over to the alternate ranolazine or placebo and repeat exit testing. For Placebo first group, subjects will undergo baseline testing and then be randomized into a clinical cross-over trial of stepped dosing of ranolazine or placebo 500-1,000 mg po bid for 2 weeks with exit testing followed by cross-over to the alternate ranolazine or placebo and repeat exit testing.
Overall Participants	142
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	142 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.2 (9.8)
Sex: Female, Male (Count of Participants)
Female	135 95.1%
Male	7 4.9%
Region of Enrollment (Count of Participants)
United States	142 100%

Outcome Measures

1. Primary Outcome

Title	Seattle Angina Questionnaire (SAQ)
Description	Questionnaires will be completed (SAQ - Seattle Angina Questionnaire) at the end of each treatment period. The Seattle Angina Questionnaire (SAQ) is a self-administered, 19-item questionnaire, a cardiac disease-related quality-of-life measure. The SAQ is well validated and sensitive to clinical changes. It has five subscales: physical limitation, angina stability, angina frequency, treatment satisfaction, and quality of life. The possible range of scores for each of the five subscales is 0 to 100, with higher scores indicating better quality of life. A change of 10 points in any of the subscales is considered to be clinically important.
Time Frame	2 weeks (first intervention) and 6 weeks (second intervention)

Outcome Measure Data

Analysis Population Description

Not all participants answered every question in the SAQ, thus the numbers are different for each question.

Arm/Group Title	Ranolazine	Placebo
Arm/Group Description	147 subjects, with projected 9-10% dropout and anticipated 134 completed subjects will undergo baseline testing and then be randomized into a clinical cross-over trial of stepped dosing of ranolazine or placebo 500-1,000 mg po bid for 2 weeks with exit testing followed by cross-over to the alternate ranolazine or placebo and repeat exit testing. Ranolazine: This drug is approved by the U.S. Food and Drug Administration (FDA) for treatment of chronic angina. 500-1,000 mg po bid for 2 weeks	147 subjects, with projected 9-10% dropout and anticipated 134 completed subjects will undergo baseline testing and then be randomized into a clinical cross-over trial of stepped dosing of ranolazine or placebo 500-1,000 mg po bid for 2 weeks with exit testing followed by cross-over to the alternate ranolazine or placebo and repeat exit testing. Placebo: 500-1,000 mg po bid for 2 weeks
Measure Participants	128	128
Physical Limitation	68.09 (23.34)	66.7 (23.34)
Angina Stability	58.4 (26.11)	51.17 (27.68)
Angina Frequency	63.91 (26.09)	62.73 (25.95)
Treatment Satisfaction	74.16 (21.23)	74.17 (21.08)
Quality of Life	56.05 (23.09)	54.17 (23.31)
SAQ Overall	62.49 (19.32)	60.97 (20.11)

2. Secondary Outcome

Title	Cardiac Magnetic Resonance (CMRs)
Description	Cardiac Magnetic Resonance (CMRs) (CMR 1 and CMR 2) end of the 2nd week of treatment 1 and treatment 2 respectively, 4 hours after the morning dose of study drug was performed to measure myocardial perfusion reserve index. Myocardial perfusion reserve index (MPRI) was assessed using the first-pass perfusion intensity curves during stress and rest cardiac magnetic resonance imaging. First-pass perfusion images were analysed using CAAS MRV CMRI analysis software Version 3.3 (Pie Medical Imaging B.V., Maastricht, the Netherlands). Global MPRI was calculated as the ratio of stress/rest relative perfusion upslope, corrected for LV cavity upslope. Higher MPRI represents better myocardial perfusion reserve. Since MPRI is an index, there is no unit.
Time Frame	2 weeks (first intervention) and 6 weeks (second intervention)

Outcome Measure Data

Analysis Population Description

Out of 142 randomized, there were 10 dropouts and 4 missing treatment periods. Therefore 128 was included in analysis

Arm/Group Title	Ranolazine	Placebo
Arm/Group Description	147 subjects, with projected 9-10% dropout and anticipated 134 completed subjects will undergo basel...	147 subjects with projected 9-10% dropout
Measure Participants	128	128
Mean (Standard Deviation) [myocardial perfusion reserve index]	1.98 (0.46)	1.96 (0.42)

Adverse Events

Time Frame	6 weeks
Adverse Event Reporting Description	The SAEs are based on the publication which represent all SAEs throughout the study.
Arm/Group Title	Ranolazine		Placebo
Arm/Group Description	147 subjects, with projected 9-10% dropout and anticipated 134 completed subjects will undergo baseline testing and then be randomized into a clinical cross-over trial of stepped dosing of ranolazine or placebo 500-1,000 mg po bid for 2 weeks with exit testing followed by cross-over to the alternate ranolazine or placebo and repeat exit testing. Ranolazine: This drug is approved by the U.S. Food and Drug Administration (FDA) for treatment of chronic angina. 500-1,000 mg po bid for 2 weeks Placebo: 500-1,000 mg po bid for 2 weeks		147 subjects, with projected 9-10% dropout and anticipated 134 completed subjects will undergo baseline testing and then be randomized into a clinical cross-over trial of stepped dosing of ranolazine or placebo 500-1,000 mg po bid for 2 weeks with exit testing followed by cross-over to the alternate ranolazine or placebo and repeat exit testing. Ranolazine: This drug is approved by the U.S. Food and Drug Administration (FDA) for treatment of chronic angina. 500-1,000 mg po bid for 2 weeks Placebo: 500-1,000 mg po bid for 2 weeks
All Cause Mortality
	Ranolazine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/142 (9.9%)		11/142 (7.7%)
Serious Adverse Events
	Ranolazine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/142 (4.2%)		1/142 (0.7%)
Cardiac disorders
NSTEMI	1/142 (0.7%)	1	0/142 (0%)	0
Bronchospasm	1/1 (100%)	1	0/142 (0%)	0
Chest pain, dizziness, and pre-syncope	2/142 (1.4%)	2	0/142 (0%)	0
syncope	1/142 (0.7%)	1	0/142 (0%)	0
Chest pain	1/142 (0.7%)	1	0/142 (0%)	0
Bradycardia	0/142 (0%)	0	1/142 (0.7%)	1
Other (Not Including Serious) Adverse Events
	Ranolazine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/142 (5.6%)		10/142 (7%)
Blood and lymphatic system disorders
Hematemesis	0/142 (0%)	0	1/142 (0.7%)	1
Cardiac disorders
Sinus infection	0/142 (0%)	0	1/142 (0.7%)	1
chest pain	0/142 (0%)	0	4/142 (2.8%)	4
Excessive Sweating	1/142 (0.7%)	1	0/142 (0%)	0
Palpitations and Afib	0/142 (0%)	0	1/142 (0.7%)	1
Endocrine disorders
Renal change	1/142 (0.7%)	1	0/142 (0%)	0
Rectocele	0/142 (0%)	0	1/142 (0.7%)	1
General disorders
Nausea and dizziness	3/142 (2.1%)	3	0/142 (0%)	0
Back pain	1/142 (0.7%)	1	0/142 (0%)	0
Throat pain, swelling and tightness	1/142 (0.7%)	1	1/142 (0.7%)	1
cough	0/142 (0%)	0	1/142 (0.7%)	1
Nervous system disorders
Arm shaking	1/142 (0.7%)	1	0/142 (0%)	0

Limitations/Caveats

[Not Specified]

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.