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

NCT ID: NCT00657514

Last Updated: 2014-08-15

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE4
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-05-31
• Study Completion Date: 2009-06-30

Brief Summary

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

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:

1. Males age > 40 years.

2. 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.

3. 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

4. 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:

1. Non-atherosclerotic diseases of the peripheral circulation by clinical history

2. Unable to complete the first stage of the modified, extended Astrand treadmill protocol

3. Clinically significant ECG abnormalities or changes with exercise on the screening ECG

4. Evidence of critical limb ischemia (CLI)

5. Hepatic impairment (Child-Pugh Classes A [mild], B [moderate], or C [severe])

6. End stage renal disease requiring dialysis

7. Hemoglobin < 12 mg/dL.

8. Platelet count < 90,000/mL.

9. Planned surgical/endovascular intervention for coronary artery disease (CAD) or peripheral arterial disease (PAD) in the next 3 months

10. Maximal exercise is limited by symptoms other than claudication or angina

11. 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

12. Known allergy to ranolazine

13. 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

14. 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)

15. 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

16. The subject has previously received ranolazine within the 6-months prior to enrollment

17. The subject has received an investigational drug within 90 days prior to enrollment

18. Type 1 or type 2 diabetes mellitus

19. Congestive Heart Failure, ≥ New York Heart Association (NYHA) Class III

20. History of oxygen dependent Chronic Obstructive Pulmonary Disease (COPD)

21. Body Mass Index (BMI) >35

Conditions

Peripheral Arterial Disease; Angina

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

A

Drug arm - 500mg tablet po bid up to 1000mg (2 500mg tablets) po bid

Group Type: ACTIVE_COMPARATOR

Ranolazine

Intervention Type: DRUG

500mg tablet po bid up to 1000mg (2 500mg tablets) po bid

P

Placebo arm - 1 tablet po bid up to 2 tablets po bid if tolerated

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

1 tablet po bid up to 2 tablets po bid if tolerated

Interventions

Ranolazine

500mg tablet po bid up to 1000mg (2 500mg tablets) po bid

Intervention Type: DRUG

Placebo

1 tablet po bid up to 2 tablets po bid if tolerated

Intervention Type: DRUG

Other Intervention Names

Ranexa, extended-release tablets; CVT500; light orange; NDC Code: 67159-112-04

Eligibility Criteria

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

• Minimum Eligible Age: 40 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Colorado Prevention Center

OTHER

Sponsor Role: lead

Responsible Party

Mark Nehler, MD

Chief, Section of Vascular Surgery and EndoVascular Therapy and Podiatry

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Mark R Nehler, MD

Role: PRINCIPAL_INVESTIGATOR

The Univesity of Colorado at Denver

William R Hiatt, MD

Role: STUDY_CHAIR

Colorado Prevention Center

Locations

University of Colorado at Denver

Aurora, Colorado, United States

Denver Health and Hospital Authority (DHHA)

Denver, Colorado, United States

Department of Veteran Affairs Medical Center

Denver, Colorado, United States

Countries

United States

References

Bauer TA, Regensteiner JG, Brass EP, Hiatt WR. Oxygen uptake kinetics during exercise are slowed in patients with peripheral arterial disease. J Appl Physiol (1985). 1999 Aug;87(2):809-16. doi: 10.1152/jappl.1999.87.2.809.

Reference Type: BACKGROUND

PMID: 10444643 (View on PubMed)

Barstow TJ, Lamarra N, Whipp BJ. Modulation of muscle and pulmonary O2 uptakes by circulatory dynamics during exercise. J Appl Physiol (1985). 1990 Mar;68(3):979-89. doi: 10.1152/jappl.1990.68.3.979.

Reference Type: BACKGROUND

PMID: 2341363 (View on PubMed)

Bauer TA, Brass EP, Hiatt WR. Impaired muscle oxygen use at onset of exercise in peripheral arterial disease. J Vasc Surg. 2004 Sep;40(3):488-93. doi: 10.1016/j.jvs.2004.06.025.

Reference Type: BACKGROUND

PMID: 15337878 (View on PubMed)

Other Identifiers

07-PAD-01

Identifier Type: -

Identifier Source: org_study_id