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

Peripheral Arterial Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT00657514
• Other study ID #: 07-PAD-01
• Status: Withdrawn
• Phase: Phase 4
• First received: April 8, 2008
• Last updated: August 13, 2014
• Start date: May 2008
• Est. completion date: June 2009

Study information

• Verified date: August 2014
• Source: Colorado Prevention Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: June 2009
• Est. primary completion date: June 2009
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 40 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Angina
• Peripheral Arterial Disease
• Peripheral Vascular Diseases

Intervention

Drug:
• Ranolazine
500mg tablet po bid up to 1000mg (2 500mg tablets) po bid
• Placebo
1 tablet po bid up to 2 tablets po bid if tolerated

Locations

Country	Name	City	State
United States	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

Sponsors (1)

Lead Sponsor	Collaborator
Colorado Prevention Center

Country where clinical trial is conducted

United States, 

References & Publications (3)

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	skeletal muscle hemoglobin desaturation kinetics		6 weeks	No
Secondary	peak exercise oxygen consumption		6 weeks	No
Secondary	Pulmonary oxygen uptake on-kinetics		6 weeks	No
Secondary	Steady state level of tissue hemoglobin desaturation during exercise		6 weeks	No
Secondary	Recovery kinetics of tissue oxygen saturation following exercise		6 weeks	No
Secondary	adverse events		6 weeks	Yes
Secondary	Peak Walking Time (PWT)		6 weeks	No
Secondary	Claudication Onset Time (COT)		6 weeks	No
Secondary	Time to Onset of Angina (TOA)		6 weeks	No