RAND-CFR: Effects of Ranolazine on Coronary Flow Reserve in Symptomatic Diabetic Patients and CAD

• Sponsor: Brigham and Women's Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT01754259
• Collaborator: (none)
• Enrollment: 47
• Location: 1
• Arms: 2
• Duration (Months): 32
• Patients Per Site Per Month: 1.5

Study Details

Study Description

Brief Summary

Coronary vascular dysfunction is highly prevalent among patients with known or suspected Coronary Artery Disease (CAD)1, increases the severity of inducible myocardial ischemia (beyond the effects of upstream coronary obstruction)2, and identifies patients at high risk for serious adverse events, including cardiac death1, 3-5. Diabetic patients without known CAD with impaired coronary vascular function show a risk of cardiac death comparable to, and possibly higher, than that for non-diabetic patients with known CAD10. In the setting of increased oxygen demand, coronary vasodilator dysfunction can upset the supply-demand relationship and lead to myocardial ischemia, subclinical left ventricular dysfunction (diastolic and systolic), and symptoms.

The significance of microvascular coronary dysfunction is increasingly recognized as invasive and non-invasive (PET) methods of quantifying CFR become available.

Importantly, current treatment strategies for obstructive CAD, such as percutaneous coronary intervention with angioplasty and stenting, are not helpful in microvascular disease. Similarly, mortality-altering treatments for systolic heart failure, such as angiotensin converting enzyme inhibitors, have not been beneficial in treating diastolic dysfunction.

Condition or Disease	Intervention/Treatment	Phase
Diabetes, Type I; Diabetes, Type II; Angina; Coronary Artery Disease	Drug: Ranolazine; Drug: Placebo	Phase 3

Detailed Description

Ranolazine is a novel anti-anginal agent which inhibits the late sodium current in cardiomyocytes, decreasing sodium and calcium overload. In ischemia, excess of intracellular calcium may impair myocyte relaxation and contribute to ventricular diastolic stiffness, which in turn affects myocardial contractility and perfusion. Ranolazine is FDA-approved for treatment of chronic angina. In three randomized, placebo-controlled trials of patients with stable angina, it was shown to increase exercise time free of angina and ST-segment depression, increase exercise capacity and decrease angina when used in combination with established antianginal agents including diltiazem, amlodipine or atenolol, and reduce the frequency of angina on patients on maximum doses of amlodipine.Similarly, in a large population of patients with acute coronary syndromes, ranolazine also decreased exertional angina symptoms and incidence of arrhythmias, with no effect on mortality. Interestingly, in this same study, it significantly improved hemoglobin A1c and recurrent ischemia in patients with diabetes mellitus, and reduced the incidence of increased hemoglobin A1c in patients without known prior hyperglycemia.

Although the anti-ischemic effect of ranolazine is thought to be mediated in part by increased myocardial blood flow,there is currently limited evidence for such an effect on tissue perfusion. A previous study in women without overt CAD did not detect improved myocardial blood flow after treatment with ranolazine. In that study, however, coronary hyperemia was elicited with adenosine (which uncouples blood flow from cardiac work, and reflects predominantly endothelial-independent vasodilation) rather than exercise, which triggers a more complex interplay between metabolic demand, coronary hemodynamics, and vasodilator response. Thus, there is a need for additional investigation of whether the beneficial effects of ranolazine on exertional symptoms are directly related to improved global tissue perfusion. Such evidence would support the use of ranolazine as an anti-ischemic therapy in the challenging population of symptomatic patients with evidence of microvascular dysfunction without obstructive CAD.

Study Design

• Study Type: Interventional
• Actual Enrollment: 47 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Each patient will receive both ranolazine and placebo for 4 weeks, but both the investigator and subject are blinded to the order.Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Each patient will receive both ranolazine and placebo for 4 weeks, but both the investigator and subject are blinded to the order.
• Masking: Double (Participant, Investigator)
• Primary Purpose: Other
• Official Title: Effects of Ranolazine on Coronary Flow Reserve in Symptomatic Patients With Diabetes and Suspected or Known Coronary Artery Disease
• Study Start Date: Apr 1, 2013
• Actual Primary Completion Date: Oct 1, 2015
• Actual Study Completion Date: Dec 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ranolazine Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Each patient will receive both ranolazine and placebo for 4 weeks, but both the investigator and subject are blinded to the order.	Drug: Ranolazine; Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Each patient will receive both ranolazine and placebo for 4 weeks, but both the investigator and subject are blinded to the order.; Other Names: Ranexa
Placebo Comparator: Placebo Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Each patient will receive both ranolazine and placebo for 4 weeks, but both the investigator and subject are blinded to the order.	Drug: Placebo; Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Each patient will receive both ranolazine and placebo for 4 weeks, but both the investigator and subject are blinded to the order.; Other Names: Placebo pill

Outcome Measures

Primary Outcome Measures

1. Change in Post-exercise Coronary Vasodilator Reserve [4 weeks]

   Change (from baseline) in post-exercise coronary vasodilator reserve, as measured by PET imaging at 4 weeks post randomization. Per-patient global coronary flow reserve (CFR) was calculated as the ratio of absolute MBF at stress over rest for the entire left ventricle. Quantitation of MBF was performed by two operators blinded to patient, treatment period and treatment order.

Secondary Outcome Measures

1. Change in LV Diastolic Function [4 weeks]

   Change (from baseline) in LV diastolic function reflected primarily in mitral annular early diastolic relaxation velocity (E') at 4 weeks post randomization. LV end-diastolic and end-systolic volumes (used to calculate LVEF), left atrial volume, septal and lateral peak early diastolic tissue velocity (e'), septal and lateral peak systolic tissue velocity (s'), and mitral inflow velocity (E) were all measured in accordance with ASE guidelines.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

1. type 1 or 2 diabetes mellitus

2. anginal symptoms and/or exertional dyspnea;

3. ability to exercise and achieve an exercise tolerance of at least 3 METS but not higher than 9 METS either on a treadmill or bicycle exercise tolerance test;

4. perfusion sum stress score (SSS) ≤ 6, as assessed by initial PET

Exclusion Criteria

1. patients not fulfilling inclusion criteria

2. patients with evidence of unprotected left main coronary artery stenosis >50%

3. patients with evidence of new obstructive CAD not on optimal medical therapy

4. evidence of angiographic disease and/or inducible myocardial ischemia on stress testing planning to undergo revascularization within the following 3 months

5. history of cardiomyopathy (LVEF <40%) or significant valvular heart disease

6. uncontrolled hypertension (SBP >180 mm Hg at screening)

7. gait instability, lower extremity amputations preventing exercise

8. significant liver dysfunction (LFTs >3x upper limits of normal), including cirrhosis 10. prolonged QT (QTc >450 and >470 ms for men and women, respectively) or concomitant use of drugs that prolong QT interval (including methadone and antiarrhythmics such as sotalol, amiodarone, and quinidine) 11. use of drugs that inhibit CYP3A such as ketoconazole, itraconazole, fluconazole, clarithromycin, erythromycin, diltiazem, verapamil, nefazodone, nelfinavir, ritonavir, lopinavir, ritonavir, indinavir, and saquinavir 12. use of drugs that induce CYP3A such rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John's wort 13. atrial fibrillation / inability to hold breath for ≥ 10 seconds (in patients in whom CTA will be performed) 14. eGFR < 50 ml/min or end stage renal disease on dialysis 15. allergy to intravenous contrast 16. pregnant or lactating women, or women of childbearing potential not using an acceptable form of birth control (negative pregnancy test also required) 17. inability to fit safely in PET/CT scanner

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Brigham and Women's Hospital

Investigators

• Principal Investigator: Marcelo Di Carli, MD, Brigham and Women's Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Marcelo F. Di Carli, MD, FACC, Chief, Nuclear Medicine, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT01754259
• Other Study ID Numbers: 2012P002537
• First Posted: Dec 21, 2012
• Last Update Posted: Jul 24, 2017
• Last Verified: Jun 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Marcelo F. Di Carli, MD, FACC, Chief, Nuclear Medicine, Brigham and Women's Hospital: type 1 diabetes; type 2 diabetes; exertion angina; suspected CAD; known CAD
• Additional relevant MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Diabetes Mellitus; Ranolazine

Study Results

Participant Flow

Pre-assignment Detail	The order of ranolazine and placebo exposure was randomly assigned in a 1:1 ratio by the Investigational Drug Service at BWH. During the 28-day treatment periods, ranolazine and matching placebo were administered as 500 mg by mouth twice daily for 1 week and increased to 1000 mg by mouth twice daily for 3 weeks, as tolerated.

Arm/Group Title	Ranolazine	Placebo
Arm/Group Description	subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Ranolazine: Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor.	Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Placebo Pill: Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor.
Period Title: Overall Study
STARTED	23	24
COMPLETED	18	18
NOT COMPLETED	5	6

Baseline Characteristics

Arm/Group Title	Ranolazine	Placebo	Total
Arm/Group Description	subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Ranolazine: Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor.	Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Placebo Pill: Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor.	Total of all reporting groups
Overall Participants	23	24	47
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	7 30.4%	12 50%	19 40.4%
>=65 years	16 69.6%	12 50%	28 59.6%
Sex: Female, Male (Count of Participants)
Female	11 47.8%	13 54.2%	24 51.1%
Male	12 52.2%	11 45.8%	23 48.9%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	16 69.6%	18 75%	34 72.3%
Black	4 17.4%	6 25%	10 21.3%
Asian	2 8.7%	0 0%	2 4.3%
Indian	1 4.3%	0 0%	1 2.1%
Region of Enrollment (Count of Participants)
United States	23 100%	24 100%	47 100%

Outcome Measures

1. Primary Outcome

Title	Change in Post-exercise Coronary Vasodilator Reserve
Description	Change (from baseline) in post-exercise coronary vasodilator reserve, as measured by PET imaging at 4 weeks post randomization. Per-patient global coronary flow reserve (CFR) was calculated as the ratio of absolute MBF at stress over rest for the entire left ventricle. Quantitation of MBF was performed by two operators blinded to patient, treatment period and treatment order.
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ranolazine	Placebo
Arm/Group Description	subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Ranolazine: Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor.	Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Placebo Pill: Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor.
Measure Participants	23	24
Number [% change]	-4	2

2. Secondary Outcome

Title	Change in LV Diastolic Function
Description	Change (from baseline) in LV diastolic function reflected primarily in mitral annular early diastolic relaxation velocity (E') at 4 weeks post randomization. LV end-diastolic and end-systolic volumes (used to calculate LVEF), left atrial volume, septal and lateral peak early diastolic tissue velocity (e'), septal and lateral peak systolic tissue velocity (s'), and mitral inflow velocity (E) were all measured in accordance with ASE guidelines.
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ranolazine	Placebo
Arm/Group Description	subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Ranolazine: Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor.	Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Placebo Pill: Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor.
Measure Participants	23	24
Number [% change]	1	-2

Adverse Events

Time Frame	Adverse events were collected from the time of informed consent through the telephone follow-up on Day 74.
Adverse Event Reporting Description	The definition of adverse events and serious adverse events are the same as the clinicaltrials.gov definitions.
Arm/Group Title	Ranolazine		Placebo
Arm/Group Description	subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Ranolazine: Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor.		Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Placebo Pill: Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor.
All Cause Mortality
	Ranolazine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/24 (0%)
Serious Adverse Events
	Ranolazine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		1/24 (4.2%)
Nervous system disorders
Fall complicated by non-fatal intracerebral hemorrhage	0/23 (0%)	0	1/24 (4.2%)	1
Other (Not Including Serious) Adverse Events
	Ranolazine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/23 (52.2%)		2/24 (8.3%)
Cardiac disorders
Chest pain requiring evaluation	0/23 (0%)	0	1/24 (4.2%)	1
Endocrine disorders
Hypoglycemia	1/23 (4.3%)	1	0/24 (0%)	0
Hepatobiliary disorders
Transaminitis	1/23 (4.3%)	1	0/24 (0%)	0
Nervous system disorders
Nausea and Dizziness	9/23 (39.1%)	9	0/24 (0%)	0
Renal and urinary disorders
Renal abnormality	1/23 (4.3%)	1	0/24 (0%)	0
Hematuria	0/23 (0%)	0	1/24 (4.2%)	1
Nephrolithiasis	1/23 (4.3%)	1	0/24 (0%)	0

Limitations/Caveats

The limitations for our study include a relatively small cohort size of 47 patients, that our mechanistic trial was not designed to assess clinical outcomes and that our experimental design allowed for inclusion of patients with non-obstructive CAD.

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.