Ranolazine Versus Placebo Effects on Exercise Tolerance in Patients With Heart Disease and Peripheral Arterial Disease

Study Overview
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Brief Summary
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After 6 weeks of maximal Ranolazine therapy, tissue hemoglobin desaturation kinetics will change compared to placebo in patients with chronic angina and peripheral arterial disease.

Detailed Description
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Study Endpoints: Primary Endpoint: • The primary endpoint of this study is the change in the kinetics of tissue hemoglobin oxygen desaturation (expressed as time constants) following the onset of exercise. Secondary endpoints of this study include percent and absolute change in: Peak oxygen consumption Pulmonary oxygen uptake on-kinetics Steady state level of tissue hemoglobin desaturation during exercise Recovery kinetics of tissue oxygen saturation following exercise Adverse events will be collected. Exploratory Endpoints Peak Walking Time (PWT) Claudication Onset Time (COT) Time to Onset of Angina (TOA) Study Design: Investigator-initiated, prospective, randomized, double-blind, placebo-controlled study. Inclusion Criteria: Males age > 40 years. Subjects must have chronic stable angina, meeting the labeled indications for ranolazine: • Ranolazine is indicated for the treatment of chronic angina. Ranolazine should be reserved for subjects who have not achieved an adequate response with other anti-anginal drugs. Subjects must have a resting ankle brachial index (ABI) of < 0.90 with a post-exercise decrement of ≥ 10% in at least one leg, OR a resting ABI of ≥0.90 to ≤ 1.00 with a post-exercise decrement of ≥ 20% in at least one leg The subject has provided written informed consent to participate, understands the requirements of the study, and agrees to return for the required assessments Exclusion Criteria: Non-atherosclerotic diseases of the peripheral circulation by clinical history Unable to complete the first stage of the modified, extended Astrand treadmill protocol Clinically significant ECG abnormalities or changes with exercise on the screening ECG Evidence of critical limb ischemia (CLI) Hepatic impairment (Child-Pugh Classes A [mild], B [moderate], or C [severe]) End stage renal disease requiring dialysis Hemoglobin < 12 mg/dL. Platelet count < 90,000/mL. Planned surgical/endovascular intervention for coronary artery disease (CAD) or peripheral arterial disease (PAD) in the next 3 months Maximal exercise is limited by symptoms other than claudication or angina Significant mental illness or drug abuse within 30 days of enrollment that in the opinion of the Investigator could impact the subject's ability to successfully complete the trial Known allergy to ranolazine Pre-existing QTc prolongation on a resting electrocardiogram (ECG) at Screening due to the risk of worsening of this condition with the use of ranolazine Treatment with QT prolonging drugs such as Class IA (e.g. quinidine) and Class III (e.g. sotalol, dofetilide), antiarrhythmics, amiodarone, and antipsychotics (e.g. thioridazine, ziprasidone) Treatment with potent or moderately potent CYP3A inhibitors including ketoconazole and other azole antifungals, diltiazem, verapamil, macrolide antibiotics, cyclosporine, rifampin or structurally related rifabutin and rifapentin, phenobarbital, phenytoin, carbamazepine, St. John's Wort, or human immunodeficiency virus (HIV) protease inhibitors The subject has previously received ranolazine within the 6-months prior to enrollment The subject has received an investigational drug within 90 days prior to enrollment Type 1 or type 2 diabetes mellitus Congestive Heart Failure, ≥ New York Heart Association (NYHA) Class III History of oxygen dependent Chronic Obstructive Pulmonary Disease (COPD) Body Mass Index (BMI) >35

Official Title
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Evaluation of Ranolazine on Skeletal Muscle Endpoints During Exercise In Subjects With Chronic Angina and Peripheral Arterial Disease

Conditions
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Peripheral Arterial Disease, Angina

Intervention / Treatment
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* Drug: Ranolazine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males age > 40 years. Subjects must have chronic stable angina, meeting the labeled indications for ranolazine: Ranolazine is indicated for the treatment of chronic angina. Ranolazine should be reserved for subjects who have not achieved an adequate response with other anti-anginal drugs. Subjects must have a resting ankle brachial index (ABI) of < 0.90 with a post-exercise decrement of ≥ 10% in at least one leg, OR a resting ABI of ≥0.90 to ≤ 1.00 with a post-exercise decrement of ≥ 20% in at least one leg The subject has provided written informed consent to participate, understands the requirements of the study, and agrees to return for the required assessments Exclusion Criteria: Non-atherosclerotic diseases of the peripheral circulation by clinical history Unable to complete the first stage of the modified, extended Astrand treadmill protocol Clinically significant ECG abnormalities or changes with exercise on the screening ECG Evidence of critical limb ischemia (CLI) Hepatic impairment (Child-Pugh Classes A [mild], B [moderate], or C [severe]) End stage renal disease requiring dialysis Hemoglobin < 12 mg/dL. Platelet count < 90,000/mL. Planned surgical/endovascular intervention for coronary artery disease (CAD) or peripheral arterial disease (PAD) in the next 3 months Maximal exercise is limited by symptoms other than claudication or angina Significant mental illness or drug abuse within 30 days of enrollment that in the opinion of the Investigator could impact the subject's ability to successfully complete the trial Known allergy to ranolazine Pre-existing QTc prolongation on a resting electrocardiogram (ECG) at Screening due to the risk of worsening of this condition with the use of ranolazine Treatment with QT prolonging drugs such as Class IA (e.g. quinidine) and Class III (e.g. sotalol, dofetilide), antiarrhythmics, amiodarone, and antipsychotics (e.g. thioridazine, ziprasidone) Treatment with potent or moderately potent CYP3A inhibitors including ketoconazole and other azole antifungals, diltiazem, verapamil, macrolide antibiotics, cyclosporine, or human immunodeficiency virus (HIV) protease inhibitors The subject has previously received ranolazine within the 6-months prior to enrollment The subject has received an investigational drug within 90 days prior to enrollment Type 1 or type 2 diabetes mellitus Congestive Heart Failure, ≥ New York Heart Association (NYHA) Class III History of oxygen dependent Chronic Obstructive Pulmonary Disease (COPD) Body Mass Index (BMI) >35

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A<br>Drug arm - 500mg tablet po bid up to 1000mg (2 500mg tablets) po bid | Drug: Ranolazine<br>* 500mg tablet po bid up to 1000mg (2 500mg tablets) po bid<br>* Other names: NDC Code: 67159-112-04;|
| Placebo Comparator: P<br>Placebo arm - 1 tablet po bid up to 2 tablets po bid if tolerated | Drug: Placebo<br>* 1 tablet po bid up to 2 tablets po bid if tolerated<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| skeletal muscle hemoglobin desaturation kinetics |  | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| peak exercise oxygen consumption |  | 6 weeks | 
| Pulmonary oxygen uptake on-kinetics |  | 6 weeks | 
| Steady state level of tissue hemoglobin desaturation during exercise |  | 6 weeks | 
| Recovery kinetics of tissue oxygen saturation following exercise |  | 6 weeks | 
| adverse events |  | 6 weeks | 
| Peak Walking Time (PWT) |  | 6 weeks | 
| Claudication Onset Time (COT) |  | 6 weeks | 
| Time to Onset of Angina (TOA) |  | 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hemoglobin desaturation kinetics, peripheral arterial disease, chronic angina, exercise tolerance