Inorganic Nitrite to Amplify the Benefits and Tolerability of Exercise Training in Heart Failure With Preserved Ejection Fraction (HFpEF) (INABLE-Training)

Study Overview
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Brief Summary
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Participants with heart failure with preserved ejection fraction will undergo 12 weeks of cardiac rehabilitation for exercise training (ET) and be randomized to either sodium nitrite or placebo through the training period. Study drug is administered 3 times daily with one of these doses being 30 minutes prior to onset of ET sessions throughout the12 week trial. The objective is to determine if the sodium nitrite improves the clinical responses and tolerability of ET.

Official Title
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Inorganic Nitrite to Enhance Benefits From Exercise Training in Heart Failure With Preserved Ejection Fraction (HFpEF)

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: Placebo
* Drug: Sodium Nitrite
* Device: Accelerometer
* Other: Cardiac Exercise Training


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 40 years Symptoms of dyspnea (II-IV) without evidence of a non-cardiac or ischemic explanation for dyspnea Ejection Fraction (EF) of > or = 50% determined on most recent imaging study within the preceding 5 years, with no change in clinical status suggesting potential for deterioration in systolic function One of the following: Previous hospitalization for Heart Failure (HF) with radiographic evidence (pulmonary venous hypertension, vascular congestion, interstitial edema, pleural effusion) of pulmonary congestion or Catheterization documented elevated filling pressures at rest (Pulmonary Capillary Wedge Pressure (PCWP)= ≥15 or Left Ventricular End-Diastolic Pressure (LVEDP) ≥18) or with exercise (PCWP ≥25) or Elevated Natruretic Peptide-proBNP (>400 pg/ml) or B-Type Natriuretic Peptide (BNP)(>200 pg/ml) or Echo evidence of diastolic dysfunction/elevated filling pressures manifest by medial E/e' ratio≥15 and/or left atrial enlargement and chronic treatment with a diuretic for signs or symptoms of heart failure Heart failure is primary factor limiting activity as indicated by answering # 2 to the following question: My ability to be active is most limited by: Joint, foot, leg, hip or back pain Shortness of breath and/or fatigue and/or chest pain Unsteadiness or dizziness Lifestyle, weather, or I just don't like to be active No chronic nitrate therapy or not using intermittent sublingual nitroglycerin (requirement for >1 sublingual nitroglycerin per week). No daily use of phosphodiesterase 5 (PDE5) inhibitors or soluble guanylyl cyclase activators and willing to withhold as needed use of PDE5 inhibitors for duration of study Ambulatory (not wheelchair / scooter dependent) Body size allows wearing of the accelerometer belt as confirmed by ability to comfortably fasten the test belt provided for the screening process. Willingness to wear the accelerometer belt for the duration of the trial Exclusion Criteria: Recent (< 1 month) hospitalization for heart failure Ongoing requirement for PDE5 inhibitor, organic nitrate or soluble guanylyl cyclase activators Hemoglobin (Hgb) < 8.0 g/dl within 30 days prior to randomization Glomerular Filtration Rate (GFR) < 20 ml/min/1.73 m2 within 30 days prior to randomization Systolic blood pressure < 115 mmHg seated or < 90 mmHg standing Resting Heart Rate > 110 Previous adverse reaction to the study drug which necessitated withdrawal of therapy Significant chronic obstructive pulmonary disease that is a primary contributor to symptoms, in the opinion of the Investigator. Ischemia thought to contribute to dyspnea, in the opinion of the Investigator. Documentation of previous Ejection Fraction < 40% Acute coronary syndrome within 3 months defined by electrocardiographic (ECG) changes and biomarkers of myocardial necrosis (e.g., troponin) in an appropriate clinical setting (chest discomfort or anginal equivalent) Percutaneous Coronary Intervention, coronary artery bypass grafting, or new biventricular pacing within past 3 months Obstructive hypertrophic cardiomyopathy Known infiltrative cardiomyopathy (amyloid) Constrictive pericarditis or tamponade Active myocarditis Complex congenital heart disease Active collagen vascular disease More than mild aortic or mitral stenosis Intrinsic (prolapse, rheumatic) valve disease with more than moderate mitral, tricuspid or aortic regurgitation Acute or chronic severe liver disease as evidenced by any of the following: encephalopathy, variceal bleeding, International Normalized Ratio (INR) > 1.7 in the absence of anticoagulation treatment Terminal illness (other than HF) with expected survival of less than 1 year Enrollment or planned enrollment in another therapeutic clinical trial in next 3 months. Inability to comply with planned study procedures Pregnancy or breastfeeding mothers

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Subjects will undergo cardiac exercise training and receive inhaled or oral placebo three times per day for 12 weeks while wearing an accelerometer | Drug: Placebo<br>* administered orally or inhaled, taken every 4 hours or 3 times per day during waking hours for 12 weeks<br>Device: Accelerometer<br>* External triaxial accelerometer is worn externally at the hip during exercise training sessions, and day/night to continuously measure activity levels, removed for bathing only.<br>Other: Cardiac Exercise Training<br>* Cardiac rehabilitation exercise training consisting of supervised endurance and strength exercise training of approximately one hour, 3 times per week for 12 weeks.<br>|
| Active Comparator: Sodium Nitrite<br>Subjects will undergo cardiac exercise training and receive inhaled or oral sodium nitrite three times per day for 12 weeks while wearing an accelerometer | Drug: Sodium Nitrite<br>* administered orally or inhaled, 40 mg, taken every 4 hours or 3 times per day during waking hours for 12 weeks<br>* Other names: Nitrite;Device: Accelerometer<br>* External triaxial accelerometer is worn externally at the hip during exercise training sessions, and day/night to continuously measure activity levels, removed for bathing only.<br>Other: Cardiac Exercise Training<br>* Cardiac rehabilitation exercise training consisting of supervised endurance and strength exercise training of approximately one hour, 3 times per week for 12 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Peak Rate of Oxygen (VO2) | Exercise capacity as measured by the peak rate of oxygen (VO2) consumption achieved during exercising testing. Peak VO2 is expressed as milliliters of oxygen per kilogram of body mass per minute. | Baseline, 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Daily Activity Levels | The change in daily activity levels as assessed by accelerometer data and reported as average accelerometry units. | Baseline, 12 weeks | 
| Change in Cardiac Hemodynamics | The change in cardiac hemodynamics as measured by echocardiography. The E/e' ratio is a marker used to evaluate the left ventricular (LV) filling pressures during exercise. An E/e' ratio of <8 is considered to be normal, a ratio >15 is considered to reflect an increase in the LV filling pressure. | Baseline, 12 weeks | 
| Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score | The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a self-administered questionnaire that provides a measure of symptoms and physical limitations associated with heart failure. The overall summary score ranges from 0-100, where the higher the score the better the health status. | Baseline, 12 weeks | 
| Change in Six Minute Walk Test | The six minute walk test is an exercise test used to assess aerobic capacity and endurance. The total distance covered over six minutes is measured in meters. | Baseline, 12 weeks |