Study Design and Patient Selection
The RALI-DHF study is a prospective, single-center, randomized, double-blind, placebo-controlled proof-of-concept study to investigate the effect of ranolazine on diastolic function in patients with HFpEF. The trial is funded by a grant from Gilead Sciences Palo Alto, Inc. (Foster City, CA). The ClinicalTrials.gov registration number is NCT01163734.
Patients with clinical symptoms of HF undergoing cardiac catheterization as part of the routine diagnostic procedure for standard care will be screened for inclusion into the study. Twenty patients who fulfill the inclusion and exclusion criteria will be randomized to receive ranolazine or placebo in a 1.5:1 ratio (12 patients will receive ranolazine and 8 patients will receive placebo). Inclusion and exclusion criteria are listed in Tables 1 and 2.
Table 1. Ranolazine for the Treatment of Diastolic Heart Failure (RALI-DHF) Inclusion Criteria
|1. Males or females age ≥40 years|
|2. Clinical symptoms of heart failure (NYHA class II–III) at time of screening (eg, dyspnea, paroxysmal nocturnal dyspnea, orthopnea, bilateral lower extremity edema)|
|3. LVEF ≥ 50% at screening|
|4. With: |
E/E′ > 15 measured by tissue Doppler echocardiography at screening or
NT-proBNP >220 pg/mL at screening and
Average resting LVEDP ≥18 mm Hg (refer to continued eligibility criteria), and
Average resting time constant of relaxation (τ) ≥50 ms at time of cardiac catheterization (refer to continued eligibility criteria).
|5. For female patients only: must be postmenopausal (no menses for last 24 mo) or sterilized; or if of child-bearing potential, is not breastfeeding, has a negative pregnancy test at time of study, has no intention of becoming pregnant during the course of the study, and is using a safe contraceptive regimen.|
|6. Signed informed consent. Continued eligibility criteria: Patients must continue to meet eligibility criteria and have an average (of 3 measurements) resting LVEDP ≥18 mm Hg and resting τ≥50 ms at time of cardiac catheterization to be eligible to receive study drug.|
Table 2. Ranolazine for the Treatment of Diastolic Heart Failure (RALI-DHF) Exclusion Criteria
|1. Acute cardiac decompensation requiring mechanical ventilation|
|2. Hypotension with systolic/diastolic BP <90/50 mm Hg, respectively|
|3. Primary hypertrophic or restrictive cardiomyopathy or systemic illness associated with infiltrative heart disease (eg, 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 LV dysfunction|
|7. MI, UA, or CABG surgery within 90 days prior to screening, or PCI within 30 days prior to screening|
|8. Stroke within 90 days prior to screening|
|9. Clinically significant pulmonary disease in the opinion of the investigator, or requiring home oxygen or oral steroid therapy|
|10. History of serious cardiac dysrhythmias, including AF with resting heart rate >100 bpm|
|11. Need for treatment with class I or III antiarrhythmic medications|
|12. Implantable pacemaker, cardioverter-defibrillator, or LVAD|
|13. Clinically significant chronic hepatic impairment (Child-Pugh class B [moderate] or class C [severe])|
|14. Severe renal insufficiency defined as creatinine clearance ≤30 mL/min as calculated by Cockcroft-Gault formula or MDRD equation|
|15. History of congenital or a family history of long QT syndrome, or known acquired QT-interval prolongation|
|16. Inability to exercise due to other comorbidities that may affect performance of CPET (eg, osteoarthritis, PVD)|
|17. Current treatment with potent and moderate CYP3A inhibitors|
|18. Current treatment with potent CYP3A inducers (eg, rifampin/rifampicin, St. John's Wort, carbamazepin/carbamazepine)|
|19. Prior treatment with ranolazine|
|20. Participation in another trial of an investigational drug or device within 30 days prior to screening|
|21. Other conditions that in the opinion of the investigator may increase the risk to the patient (eg, weight ≤ 60 kg), prevent compliance with study protocol, or compromise the quality of the clinical trial|
Study Conduct and Procedures
Patients with clinical symptoms of HF will be consented and screened for eligibility. Complete medical history and physical examination will be recorded at screening. Echocardiography will be performed to determine cardiac dimensions, regional and global contractility, and cardiac valve functions. The measured and calculated parameters that are obtained by standard 2-D images, pulsed-wave and continuous-wave Doppler tracings, and tissue Doppler are listed in Table 3.
Table 3. Hemodynamic Data and Echocardiographic Parameters
|Hemodynamic Data and Pressure Measurements|
| Time constant of relaxation (τ)|
| Relaxation time|
| Left ventricular end-diastolic pressure (LVEDP)|
| Left ventricular end-systolic pressure (LVESP)|
| dP/dt minimum|
| Pulmonary capillary wedge pressure (PCWP)|
| Pulmonary artery pressure (systolic/diastolic/mean)|
| Systemic vascular resistance (SVR)|
| Pulmonary vascular resistance (PVR)|
| Cardiac output (CO) and cardiac index (CI)|
| Right atrial pressure (RAP)|
| Left ventricular end-diastolic volume/index (LVEDV)|
| Left ventricular end-systolic volume/index (LVESV)|
| Left ventricular stroke volume|
| Left ventricular ejection fraction (LVEF; Simpson method)|
| Mitral E wave velocity|
| Mitral A wave velocity|
| Mitral E/A ratio|
| Mitral annular velocity (E′, tissue Doppler)|
| E/E′ ratio|
Blood samples will be collected to determine the level of N-terminal pro-type brain natriuretic peptide (NT-pro-BNP) at screening. Other laboratory measurements include complete blood count, red blood cells, hemoglobin, hematocrit, platelet count, white blood count, coagulation test/international normalized ratio, aspartate transaminase, alanine transaminase, alkaline phosphatase, bilirubin, blood urea nitrogen, creatinine, gamma-glutamyl transferase, potassium, and sodium.
A standard 12-lead electrocardiogram (ECG) will be performed and reviewed for any clinically significant abnormalities to ensure patient safety. A symptom-limited cardiopulmonary exercise test (CPET) will be performed using a bicycle ergometer. The following parameters will be measured: peak oxygen uptake (Pk VO2), maximal oxygen uptake (VO2 max), anaerobic threshold, respiratory exchange ratio (RER), oxygen saturation (SpO2), exercise duration, and ventilation/carbon dioxide production ratio (VE/VCO2).
Patients who fulfill the inclusion and exclusion criteria will be randomized prior to catheterization. The cardiac catheterization itself is part of the diagnostic procedure of the standard of care for these patients. A catheter will be introduced into the right ventricle and into the pulmonary artery for measurement and analysis of right heart pressures. A conductance catheter will be advanced into the LV for measurement of LV pressures and pressure/volume relations. A transient pacemaker probe will be introduced into the right atrium for pacemaker stimulation. If clinically indicated, coronary angiography will be performed before any pressures and hemodynamic data are measured. Once all catheters are in stable position, 3 sets of pressures and hemodynamic assessments will be recorded at resting conditions. In addition, atrial pacing will be performed at 120 bpm and 3 sets of pressure and hemodynamic assessments will again be obtained. The parameters that will be obtained are listed in Table 3.
Administration of the study drug (placebo or ranolazine) will be initiated if the continued eligibility criteria (average resting LVEDP ≥ 18 mm Hg and τ ≥ 50 ms) are met. The study treatment will begin with an initial intravenous (IV) bolus injection at T = 0 minutes of 92 mg ranolazine or placebo (Figure 1). The initial 92 mg of study drug will be administered as 10-mL loading bolus over a period of 2 minutes. A second bolus injection of 92 mg ranolazine or placebo at the same dilution will be administered 15 minutes (T = 15 min) after initial bolus injection. Continuous infusion of ranolazine or placebo at a dose of 92 mg/hour (23 mL/h) will start at T = 20 minutes (5 min after the start of second bolus injection) and continue through to 24 hours (T = 24 h). To assess pharmacokinetic (PK) parameters, PK blood samples will be drawn at T = 10 minutes, T = 20 minutes (prior to continuous infusion), and T = 30 minutes.
The catheter probes stay in place during the initiation of the IV study drug administration. All invasive measurements will be repeated at 30 minutes after initiation of the first loading bolus (T = 30 min) at resting (3 sets) and paced (3 sets) conditions. Three measurements will be taken, and the average of the 3 will represent the value for that variable measured. When all assessments are complete, the catheters are removed and the patient is transferred to the cardiac ward for monitoring (continuous 3-lead ECG monitoring via telemetry, vital signs every 4 h). The IV study drug infusion will be continued through to 24 hours (T = 24 h). One hour prior to the end of the 24-hour infusion, patients will be started on oral study drug 1000 mg twice daily and will be continued until the end of the study on day 14. All echocardiography measurements will be repeated at T = 22 hours (within 60 min prior to administration of oral study drug). The 12-lead ECG will be repeated at this time point. Patients may be discharged at any time after T = 24 hours at the investigator's judgment per standard of care. Oral treatment will last for 13 days. Patients will be instructed to take 2 intact tablets of the study medication with water every day at 12-hour intervals (in the morning and in the evening).
Patients will be required to return to clinic for the end of study visit on day 14 (±2 d). The end-of-study visit procedures (specifically, echocardiography and CPET) will be performed within 2 to 6 hours after the morning dose. The following assessments will be performed: complete PE including vital signs and weight measurements, 12-lead ECG, echocardiography (prior to CPET), NT-pro-BNP determination and safety labs, CPET, serum pregnancy test (for females aged ≤65 years), adverse events, and concomitant medications.
Approximately 14 days after the end-of-study visit, the patient will be contacted either by phone or in person to assess and record adverse-event and concomitant medication status since the last visit (day 28 safety follow-up contact). The schedule of study events is depicted in Figure 2.
Figure 2. Schedule of events. Abbreviations: cath, catheterization; CPET, cardiopulmonary exercise test; ECG, electrocardiogram; ECHO, echocardiography; iv, intravenous; NT-proBNP, N-terminal pro-type brain natriuretic peptide; PK, pharmacokinetic.
Download figure to PowerPoint
The study will include the following exploratory endpoints:
Change from baseline to 30 minutes from initiation of study drug bolus No. 1 (T = 30 min) in cardiac catheterization hemodynamic parameters at both resting and paced conditions:
Time constant of relaxation (τ).
dP/dt min (minimal rate of LV pressure change).
Change from baseline to day 14 in:
Mitral E wave velocity/mitral annular velocity (E/E′) ratio assessed by tissue Doppler echocardiography.
VO2 max assessed by CPET.
Baseline is defined as the average of 3 measurements of each hemodynamic parameters taken at rest conditions and during pacing prior to start of study-drug infusion.
Detailed analyses of hemodynamic data and pressure measurements, echocardiography, and CPET parameters will be performed, pending on blinded review of the distributions of each measurement.
The current study is considered exploratory, and therefore the sample size selection is based on practical considerations.
All statistical tests for treatment difference between ranolazine vs placebo will be performed using 2-sided hypothesis tests at 5% significance level with no adjustment for multiple comparisons. Descriptive summaries will show counts and percentages for categorical variables and sample size, mean, SD, or SEM, minimum, median, and maximum for continuous variables by treatment. The Wilcoxon rank sum test will be applied to evaluate whether the reductions from baseline in primary and secondary efficacy endpoints are statistically significantly different between placebo vs ranolazine. The Cochran-Mantel-Haenszel test may be used to compare categorical variables between randomized treatments: row mean scores test for ordered categorical variables and general association test for nominal categorical variables. Analysis of variance, including effects for treatment, may be used to analyze continuous variables. All patients who receive ≥1 dose of randomized study medication will be included in the analyses for both efficacy and safety endpoints. Patients will be assigned to treatment group according to the treatment actually received.