Ranolazine in Diastolic Heart Failure (RALI-DHF)

• Sponsor: Gilead Sciences
• Collaborator: University Medicine Göttingen, Cardiac Center
• Information provided by (Responsible Party): Gilead Sciences

Study Description

Brief Summary:

Patients with CAD and clinical symptoms of heart failure or patients with suspected heart failure with preserved ejection fraction (HFpEF) will be enrolled. Study drug will be given as continuous IV infusion followed by oral treatment for 13 days. LV pressures and hemodynamic data will be measured prior to and after administration of study drug. In addition, Doppler ECHO, cardiopulmonary exercise testing (CPET), and NT-pro-BNP determination will be performed. Adverse events and safety labs will be collected and monitored.

Condition or disease	Intervention/treatment	Phase
Diastolic Heart Failure	Drug: Ranolazine; Other: Saline 0.9% and placebo tablet	Phase 2

Detailed Description:

This is a randomized, double-blind, placebo-controlled proof-of-concept study of ranolazine in patients with heart failure with preserved ejection fraction (HFpEF). Patients will be randomized to receive ranolazine or placebo in a 1.5:1 ratio (12 ranolazine: 8 placebo).

Treatment will consist of intravenous infusion of study drug followed by oral treatment for a total of 14 days treatment period. Study contact will be made approximately 14 days after the treatment period to assess safety.

Cardiac catheterization will be performed for LV pressures and hemodynamic measurements before and after drug administration. Doppler ECHO, CPET, and NT-pro-BNP determination will be performed at screening and at end of study. Adverse events and safety labs will be monitored and collected.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Official Title: A Randomized, Double-blind, Placebo-controlled Study of Ranolazine in Patients With Heart Failure With Preserved Ejection Fraction
• Study Start Date: April 2010
• Actual Primary Completion Date: February 2011
• Actual Study Completion Date: February 2011

Arms and Interventions

Arm	Intervention/treatment
Experimental: Ranolazine	Drug: Ranolazine; Intravenous treatment followed oral treatment for 13 days.; Other Name: Ranexa
Placebo Comparator: Saline 0.9%; Saline 0.9% and placebo tablet	Other: Saline 0.9% and placebo tablet; Intravenous treatment followed by oral treatment for 13 days; Other Name: Normal Saline

Outcome Measures

Primary Outcome Measures :

1. Change from baseline to 30 minutes in cardiac catheterization hemodynamic parameters at both resting and paced conditions [ Time Frame: Baseline to 30 minutes ]

   Change from baseline to 30 minutes from initiation of study drug bolus No.1 in cardiac catheterization hemodynamic parameters at both resting and paced conditions:

   Time-constant of relaxation (tau)

   Left ventricular end-diastolic pressure (LVEDP)

   dP/dtmin (minimal rate of LV pressure change)

Secondary Outcome Measures :

1. Change from baseline to Day 14 in mitral E wave velocity/mitral annular velocity (E/E') ratio [ Time Frame: Baseline to Day 14 ]
2. Change from baseline to Day 14 in VO2 max [ Time Frame: Baseline to Day 14 ]
3. Change from baseline to Day 14 in N-terminal pro-brain B-type natriuretic peptide (NT-pro-BNP) [ Time Frame: Baseline to Day 14 ]

Eligibility Criteria

• Ages Eligible for Study: 40 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Males or females aged > 40 years
2. Clinical symptoms of heart failure (NYHA class II-III) at time of screening (e.g., dyspnea, paroxysmal nocturnal dyspnea, orthopnea, bilateral lower extremity edema)
3. Left ventricular ejection fraction (LVEF) > 45% at screening

4. With:

   • E/E' > 15 measured by Tissue Doppler echocardiography at screening
   • NT-pro-BNP > 220pg/mL at screening
   • Average resting LVEDP >18 mm Hg (refer to continued eligibility criteria),
   • Average resting time constant of relaxation (tau) > 50 ms at time of cardiac catheterization (refer to continued eligibility criteria)
5. Signed informed consent

Exclusion Criteria:

1. Acute cardiac decompensation requiring mechanical ventilation
2. Hypotension with blood pressure < 90/50 mm Hg
3. Primary hypertrophic or restrictive cardiomyopathy or systemic illness associated with infiltrative heart disease (e.g., cardiac amyloidosis)
4. Pericardial constriction
5. Hemodynamically significant uncorrected obstructive or regurgitant valvular disease
6. Cor pulmonale or other causes of right heart failure not associated with left ventricular dysfunction
7. Clinically significant pulmonary disease in the opinion of the Investigator or requiring home oxygen or oral steroid therapy
8. History of serious cardiac dysrrhythmias including atrial fibrillation with resting heart rate of > 100 beats per minute
9. Need for treatment with Class I or III antiarrhythmic medications
10. Implantable pacemaker, cardioverter-defibrillator, or left ventricular assist device
11. Clinically significant chronic hepatic impairment (Child-Pugh Class B [moderate] or Class C [severe])
12. Severe renal insufficiency defined as creatinine clearance ≤30 mL/min as calculated by Cockcroft-Gault formula or Modified Diet in Renal Disease (MDRD) equation.
13. History of congenital or a family history of long QT syndrome, or known acquired QT interval prolongation
14. Inability to exercise due to other co-morbidities that may affect performance of cardiopulmonary exercise test (CPET) (e.g., osteoarthritis, peripheral vascular disease)
15. Current treatment with potent and moderate CYP3A inhibitors
16. Current treatment with potent CYP3A inducers (e.g., rifampin/rifampicin, St. John's Wort, carbamazepin/carbamazepine)
17. Prior treatment with ranolazine
18. Other conditions that in the opinion of the investigator may increase the risk to the patient (e.g. pts with weight ≤60 kg), prevent compliance with study protocol or compromise the quality of the clinical trial

Continued Eligibility Criteria:

Patients must continue to meet eligibility criteria and have an average (of 3 measurements) resting LVEDP > 18 mm Hg and resting tau > 50 ms at time of cardiac catheterization to receive study drug.

Contacts and Locations

Locations

Germany

University Medicine Goettingen (UMG)

Goettingen, Germany

Sponsors and Collaborators

Gilead Sciences

University Medicine Göttingen, Cardiac Center

Investigators

• Principal Investigator: Lars S. Maier, MD; University Medicine Göttingen, Cardiac Center

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Maier LS, Layug B, Karwatowska-Prokopczuk E, Belardinelli L, Lee S, Sander J, Lang C, Wachter R, Edelmann F, Hasenfuss G, Jacobshagen C. RAnoLazIne for the treatment of diastolic heart failure in patients with preserved ejection fraction: the RALI-DHF proof-of-concept study. JACC Heart Fail. 2013 Apr;1(2):115-22. doi: 10.1016/j.jchf.2012.12.002. Epub 2013 Apr 1.

Jacobshagen C, Belardinelli L, Hasenfuss G, Maier LS. Ranolazine for the treatment of heart failure with preserved ejection fraction: background, aims, and design of the RALI-DHF study. Clin Cardiol. 2011 Jul;34(7):426-32. doi: 10.1002/clc.20897. Epub 2011 Apr 27.

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT01163734 History of Changes
• Other Study ID Numbers: GS-US-270-0101
• First Posted: July 16, 2010
• Last Update Posted: July 12, 2012
• Last Verified: March 2011

Keywords provided by Gilead Sciences:

Heart Failure with Preserved Ejection Fraction (HFpEF); Coronary Artery Disease (CAD)

Additional relevant MeSH terms:

Heart Failure; Heart Failure, Diastolic; Heart Diseases; Cardiovascular Diseases; Ranolazine; Sodium Channel Blockers; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action