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

Phase 2

Completed

Conditions: Heart Failure

Interventions: Drug: Placebo
Drug: Sodium Nitrite
Device: Accelerometer
Other: Cardiac Exercise Training

Registration Number: NCT02713126

Lead Sponsor: Barry Borlaug

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 92

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Subjects will undergo cardiac exercise training and receive inhaled or oral placebo three times per day for 12 weeks while wearing an accelerometer
Placebo	Accelerometer	Subjects will undergo cardiac exercise training and receive inhaled or oral placebo three times per day for 12 weeks while wearing an accelerometer
Placebo	Cardiac Exercise Training	Subjects will undergo cardiac exercise training and receive inhaled or oral placebo three times per day for 12 weeks while wearing an accelerometer
Sodium Nitrite	Sodium Nitrite	Subjects will undergo cardiac exercise training and receive inhaled or oral sodium nitrite three times per day for 12 weeks while wearing an accelerometer
Sodium Nitrite	Accelerometer	Subjects will undergo cardiac exercise training and receive inhaled or oral sodium nitrite three times per day for 12 weeks while wearing an accelerometer
Sodium Nitrite	Cardiac Exercise Training	Subjects will undergo cardiac exercise training and receive inhaled or oral sodium nitrite three times per day for 12 weeks while wearing an accelerometer

Primary Outcome Measures

Name	Time	Method
Change in Peak Rate of Oxygen (VO2)	Baseline, 12 weeks	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.

Secondary Outcome Measures

Name	Time	Method
Change in Daily Activity Levels	Baseline, 12 weeks	The change in daily activity levels as assessed by accelerometer data and reported as average accelerometry units.
Change in Cardiac Hemodynamics	Baseline, 12 weeks	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.
Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score	Baseline, 12 weeks	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.
Change in Six Minute Walk Test	Baseline, 12 weeks	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.