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| ID | Type | Description | Link |
|---|---|---|---|
| 110344 | Other Identifier | UCSD Human Research Protections Program |
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| Name | Class |
|---|---|
| Gilead Sciences | INDUSTRY |
The purpose of this study is to determine whether treatment with Ranolazine will improve exercise capacity in patients with Heart Failure with preserved left ventricular ejection fraction, or HFPEF.
Denise Barnard, M.D., and her associates, are conducting a research study to find out more about ways to improve symptoms in patients with Heart Failure with Preserved Ejection Fraction (HFPEF). Heart failure with preserved ejection fraction is a condition where the heart squeezes well but is stiff. This stiffness in the heart muscle makes the heart unable to fill, leading to shortness of breath and decreased exercise tolerance. Subjects with HFPEF are asked to participate in this study. There will be approximately 40 participants enrolled in this study. The purpose of this study is to investigate the effects of Ranolazine (Ranexa) in patients with HFPEF. The study is sponsored by the manufacturers of the drug, Gilead Pharmaceuticals.
Ranolazine is a drug that affects the ion channels in the heart. In patients with heart failure, these ion channels do not work properly, and contribute to make the heart stiff. A stiff heart leads to the symptoms of shortness of breath which patients with HFPEF experience. Due to its properties, Ranolazine may improve this stiffness. Ranolazine could improve subject's shortness of breath and ability to exercise.
Currently, ranolazine carries FDA approval for the treatment of chronic angina only. We intend to study ranolazine in patients with HFPEF, in the absence of documented ischemia, to determine whether the drug's lusitropic properties can improve exercise capacity in HFPEF patients.
Previous trials of ranolazine in patients with chronic angina found that there was a dose-dependent relationship between improvements in exercise capacity and ranolazine. However, there did appear to be a plateau in which 1500 mg of ranolazine twice daily improved exercise capacity only slightly more than 1000 mg of ranolazine given twice daily. Additionally, there was a substantially higher rate of adverse events (mainly nausea, dizziness, and asthenia) with the higher dose. Given the desire to maximize benefit and minimize the risk of adverse events, ranolazine 1000 mg by mouth twice daily was chosen as the target dose.
To properly evaluate the effects of Ranolazine, this research study is set up as a double blind, placebo controlled study. Subjects will be randomly assigned (like rolling a dice) to either Ranolazine or placebo (inactive substance). Subjects will have a 50% chance of getting the study drug and 50% chance of getting placebo.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Ranolazine | Active Comparator | Patients with be given 500 mg by mouth twice a day for three days, and then the dose will be increased to 1000 mg by mouth twice daily thereafter. (patients who concurrently take moderate CYP3A inhibitors including diltiazem, verapamil, aprepitant, erythromycin, and fluconazole will continue to 500 mg by mouth twice a day for the entire dosing period) |
|
| Placebo | Placebo Comparator | Patients will be given 1 tab twice a day for 3 days, then increasing to 2 tabs twice a day thereafter (patients who concurrently take moderate CYP3A inhibitors, will be given 1 tab twice daily for the entire dosing period) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ranolazine | Drug | Patients with be given 500 mg by mouth twice a day for three days, and then the dose will be increased to 1000 mg by mouth twice daily thereafter. (patients who concurrently take moderate CYP3A inhibitors including diltiazem, verapamil, aprepitant, erythromycin, and fluconazole will continue to 500 mg by mouth twice a day for the entire dosing period) |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Exercise Capacity at 6 Weeks | Exercise capacity in terms of exercise duration (time in seconds) as described for the baseline value, is repeated at 6 weeks. | 6 weeks |
| Change in Oxygen Consumption (VO2) at 6 Weeks | Oxygen consumption (VO2) as described at baseline is remeasured after 6 weeks of drug vs placebo. | 6 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Quality of Life (QOL) Score | The Minnesota Living with Heart Failure (HF) Questionnaire was re-administered at the 6 week time point. The total quality of life (QOL) scores were compared to the baseline score. The well-validated Minnesota Living with Heart Failure questionnaire is self-administered, has 21 questions and takes 5-10 minutes to complete. The test measures perceived health-related QOL. Each question is scored from 0 to 5 on the Likert scale, where 0 is 'none', and 5 is 'very much'. QOL scores range from 0 to 105; a lower score represents a better quality of life. After an intervention, a decrease in score reflects an improvement in QOL. A minimally important difference in the total score is 5 points. |
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I. Inclusion Criteria
Age > 18 years old
Diagnosis of Heart Failure (HF) with Preserved Ejection Fraction (PEF)
Signs or symptoms of heart failure (breathlessness, pulmonary congestion, edema, fatigue), NYHA (New York Heart Association) Class II-III HF AND
LVEF (Left Ventricular Ejection Fraction) > 45% AND
Evidence of elevated LV filling pressures
Pulmonary Artery systolic pressure estimated at > 35 mm Hg on echocardiography
Stable medical management for at least 1 month
II. Exclusion Criteria
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| Name | Affiliation | Role |
|---|---|---|
| Denise D Barnard, MD | University of California, San Diego | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California, San Diego | San Diego | California | 92037 | United States |
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Pts meeting all inclusion criteria were most often excluded due to the presence of atrial fibrillation, being unable to perform the minimum exercise effort required, or walked > 550 meters on the 6MW test. The remaining pts were excluded for acute heart failure (HF) decompensation, baseline QTc > 500 ms or participation in another clinical trial .
Between 12/2011 and 3/2013, the UCSD Echo database of >4500 patients (pts) and their electronic medical records were screened. Of the 1200 pts with left ventricular (LV) ejection fraction (EF) >45%, only 60 pts met all inclusion criteria. Informed consent was obtained from 10 pts who were subsequently randomized and completed study protocols.
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| ID | Title | Description |
|---|---|---|
| FG000 | Ranolazine Group | Patients with be given 500 mg Ranolazine by mouth twice a day for three days, and then the dose will be increased to 1000 mg by mouth twice daily thereafter. (patients who concurrently take moderate CYP3A inhibitors including diltiazem, verapamil, aprepitant, erythromycin, and fluconazole will continue to 500 mg by mouth twice a day for the entire dosing period) |
| FG001 | Placebo Group | Patients will be given Placebo matching the appearance of Ranolazine as 1 tab twice a day for 3 days, then increasing to 2 tabs twice a day thereafter (patients who concurrently take moderate CYP3A inhibitors, will be given 1 tab twice daily for the entire dosing period) |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Ranolazine Group | Patients with be given 500 mg Ranolazine by mouth twice a day for three days, and then the dose will be increased to 1000 mg by mouth twice daily thereafter. (patients who concurrently take moderate CYP3A inhibitors including diltiazem, verapamil, aprepitant, erythromycin, and fluconazole will continue to 500 mg by mouth twice a day for the entire dosing period) |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Exercise Capacity at 6 Weeks | Exercise capacity in terms of exercise duration (time in seconds) as described for the baseline value, is repeated at 6 weeks. | Entire study population | Posted | Mean | Standard Deviation | seconds | 6 weeks |
|
Duration of trial, 6 weeks.
The definition of adverse events and serious adverse events are not different from those found in clinicaltrials.gov definitions. The study sponsor was provided with quarterly reports regarding any/all defined AE's and SAE's for patients in our study.
The sponsor provided us with safety letters and reports of AE/SAE's regarding ranolazine in all active clinical trials (globally).
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Ranolazine Group | Patients with be given 500 mg Ranolazine by mouth twice a day for three days, and then the dose will be increased to 1000 mg by mouth twice daily thereafter. (patients who concurrently take moderate CYP3A inhibitors including diltiazem, verapamil, aprepitant, erythromycin, and fluconazole will continue to 500 mg by mouth twice a day for the entire dosing period) |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Minor adverse event | General disorders | SNOMED CT | Systematic Assessment | Headache, resolved without intervention |
Due to slower than anticipated enrollment, only 10 subjects out of an intended 40 completed the study in the time allowed by the sponsor. The statistical analyses and inferences are restricted by low sample size and population baseline differences.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Denise Barnard, MD | UCSD MED CLINICAL TRIALS | 858 246-2996 | dbarnard@ucsd.edu |
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| ID | Term |
|---|---|
| D006333 | Heart Failure |
| ID | Term |
|---|---|
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D000069458 | Ranolazine |
| ID | Term |
|---|---|
| D000083 | Acetanilides |
| D000813 | Anilides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D000814 |
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| Placebo | Drug | Patients will be given 1 tab twice a day for 3 days, then increasing to 2 tabs twice a day thereafter (patients who concurrently take moderate CYP3A inhibitors, will be given 1 tab twice daily for the entire dosing period) |
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| 6 weeks |
| Change in Doppler Echocardiographic Parameters, Septal E/e' Ratio (E/e') | Doppler echo allows non-invasive evaluation of diastolic cardiac function. The mitral inflow velocity (E) correlates with LV filling pressure, but is influenced by myocardial relaxation time (RT) and filling pressure. The early diastolic septal mitral annular tissue velocity (e') varies with RT alone. The unitless ratio of the E to e' velocities (E/e') is considered a reliable surrogate of LV filling pressure. Prediction of normal diastolic filling pressure is most reliable when E/e' is < 8; and of abnormal filling pressure when E/e' is > 15. The percent change is reported. | 6 weeks |
| BG001 | Placebo Group | Patients will be given Placebo matching the appearance of Ranolazine as 1 tab twice a day for 3 days, then increasing to 2 tabs twice a day thereafter (patients who concurrently take moderate CYP3A inhibitors, will be given 1 tab twice daily for the entire dosing period) |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Exercise Duration | Total exercise time, measured as the duration in seconds that the subject is able to walk on a maximal effort standardized Naughton protocol treadmill test. | Mean | Standard Deviation | seconds |
|
| Peak Oxygen Uptake (VO2) | Integrative exercise performance is assessed using cardiopulmonary stress testing and expired gas analysis. The degree of reduction in peak or maximal oxygen uptake (VO2) has strong prognostic implications in HF pts. VO2 is measured as ml O2/kg/min. The modified Naughton treadmill protocol used increases the workload by approximately 3.5 ml O2/kg/min for each 2-minute stage and maximizes performance. Normally, V02 can increase from a resting value of about 3.5 ml O2/kg/min to 10-15 times the resting value. | Mean | Standard Deviation | mL O2/kg/min |
|
| 6MW test distance | The Six-minute Walk (6MW) test was designed and validated by the American Thoracic Society. It is a sub-maximal exercise test used to assess aerobic capacity and endurance. The 6MW test has the moderate ability to predict peak VO2 in patients with HF who walk less than 490 meters. Stronger correlation occurs in advanced heart failure where pts who walk less than 300 meters in 6 minutes have a low (<10 mL/kg/min) peak VO2. Normal persons average a 6MW distance of 659±62 m (range 484-820 m). Males walk on average 59±13 m further than females. | Mean | Standard Deviation | meters |
|
| BNP | Brain Natriuretic Peptide (BNP) plasma level. This biomarker reflects ventricular wall stress, often reflecting cardiac volume status or abnormal hemodynamics. Normal reference ranges are predominantly age and gender-specific but range from 0-100 pg/mL. Levels above 400 pg/ml are considered high. HF-PEF patients tend to have lower levels of BNP than patients with HF and reduced EF. | Mean | Standard Deviation | pg/mL |
|
| Quality of Life (QOL) Score | Quality of Life (QOL) in HF patients is reproducibly measured by the well-validated Minnesota Living with Heart Failure questionnaire. It is self-administered, has 21 questions and takes 5-10 minutes to complete. The test measures perceived health-related QOL. Each question is scored from 0 to 5 on the Likert scale, where 0 is 'none', and 5 is 'very much'. QOL scores range from 0 to 105; a lower score represents a better quality of life. After an intervention, a decrease in score reflects an improvement in QOL. A minimally important difference in the total score is 5 points. | Mean | Standard Deviation | units on a scale |
|
| Septal E/e' Doppler velocity ratio | Doppler echo allows non-invasive evaluation of diastolic cardiac function. The mitral inflow velocity (E) correlates with LV filling pressure, but is influenced by myocardial relaxation time (RT) and filling pressure. The early diastolic septal mitral annular tissue velocity (e') varies with RT alone. The unitless ratio of the E to e' velocities (E/e') is considered a reliable surrogate of LV filling pressure. Prediction of normal diastolic filling pressure is most reliable when E/e' is < 8; and of abnormal filling pressure when E/e' is > 15. | Mean | Standard Deviation | unitless |
|
Patients will be given Placebo matching the appearance of Ranolazine as 1 tab twice a day for 3 days, then increasing to 2 tabs twice a day thereafter (patients who concurrently take moderate CYP3A inhibitors, will be given 1 tab twice daily for the entire dosing period)
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| Primary | Change in Oxygen Consumption (VO2) at 6 Weeks | Oxygen consumption (VO2) as described at baseline is remeasured after 6 weeks of drug vs placebo. | Entire study population | Posted | Mean | Standard Deviation | ml/kg/min | 6 weeks |
|
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| Secondary | Change in Quality of Life (QOL) Score | The Minnesota Living with Heart Failure (HF) Questionnaire was re-administered at the 6 week time point. The total quality of life (QOL) scores were compared to the baseline score. The well-validated Minnesota Living with Heart Failure questionnaire is self-administered, has 21 questions and takes 5-10 minutes to complete. The test measures perceived health-related QOL. Each question is scored from 0 to 5 on the Likert scale, where 0 is 'none', and 5 is 'very much'. QOL scores range from 0 to 105; a lower score represents a better quality of life. After an intervention, a decrease in score reflects an improvement in QOL. A minimally important difference in the total score is 5 points. | The analysis population is comprised of the 10 patients who were eligible and consented for participation in the trial. Six patients were assigned to the Ranolazine group and four to the placebo group, randomization was by chance. | Posted | Mean | Standard Deviation | units on a scale | 6 weeks |
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| Secondary | Change in Doppler Echocardiographic Parameters, Septal E/e' Ratio (E/e') | Doppler echo allows non-invasive evaluation of diastolic cardiac function. The mitral inflow velocity (E) correlates with LV filling pressure, but is influenced by myocardial relaxation time (RT) and filling pressure. The early diastolic septal mitral annular tissue velocity (e') varies with RT alone. The unitless ratio of the E to e' velocities (E/e') is considered a reliable surrogate of LV filling pressure. Prediction of normal diastolic filling pressure is most reliable when E/e' is < 8; and of abnormal filling pressure when E/e' is > 15. The percent change is reported. | Entire Study Population | Posted | Mean | Standard Deviation | percent change | 6 weeks |
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| 0 |
| 6 |
| 0 |
| 6 |
| 1 |
| 6 |
| EG001 | Placebo Group | Patients will be given Placebo matching the appearance of Ranolazine as 1 tab twice a day for 3 days, then increasing to 2 tabs twice a day thereafter (patients who concurrently take moderate CYP3A inhibitors, will be given 1 tab twice daily for the entire dosing period) | 0 | 4 | 0 | 4 | 1 | 4 |
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| Aniline Compounds |
| D000588 | Amines |
| D010879 | Piperazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |