Inorganic NItrate and EXercise Performance in Heart Failure (iNIX-HF): Dose Response

Study Overview
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Brief Summary
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The purpose of this study is to do the work that is necessary and sufficient for setting up an appropriate multi-center, randomized clinical trial (RCT) of a new therapy for heart failure: inorganic nitrate. The investigators will first determine the effects and palatability of  12.8mmol KNO3 (an oral pill) as compared to the roughly equivalent amount of nitrate in 2 beetroot juice (BRJ) Sports Shots (by James White Drinks). Next, the investigators will determine the effects of inorganic nitrate (KNO3 in an oral pill format) on blood pressure, blood nitrate levels, breath nitric oxide (NO) levels, and exercise performance in a dose-response study. Third, the investigators will perform a small phase II chronic treatment study that will allow them to determine the best primary endpoint and the numbers of patients the investigators will need to study in the large, multi-center RCT to follow this project. In the small study and in the RCT to follow, the investigators will determine whether inorganic nitrate can improve aerobic exercise capacity, muscle power, and speed of muscle contraction, and lessen the effort of breathing during exercise.

Detailed Description
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Subjects will be patients with Heart Failure (HF). All subjects will be consented. All subjects will give permission for the investigators to review their medical records. After consenting to participate, subjects will be instructed to refrain from spitting or the use of an antibacterial mouthwash, antacids, proton pump inhibitors, or chewing gum during the morning of each clinic visit. Subjects will have a physical examination. Subjects will undergo transthoracic echocardiographic imaging at rest (unless they had this performed within the past 6 months). Subjects will be asked to undergo a mouth swab for bacterial DNA analyses. Subjects will be asked to answer questionnaires regarding their medical health (basic health questionnaire, Minnesota living with heart failure questionnaire, a combined fatigue questionnaire. Dose visit 1: Subjects will receive 2 capsules containing either 10 or 20 mmol of potassium nitrate (KNO3). Before and at 3 hourly time points after receiving the KNO3, subjects will undergo phlebotomy for plasma nitrite levels, will have their blood pressure measured, and will blow into a small machine to assess the amount of nitric oxide in their breath. Exercise Test 1: Subjects will complete measurements of leg muscle power by doing knee extension exercises on a dynamometer (a device that measures voluntary muscle force production while controlling the speed of movement). Exercise Test 2: Subjects complete a measurement of peak aerobic capacity (VO2peak) while walking on a treadmill and breathing into a mouthpiece. Blood pressure, heart rate and heart rhythm will be monitored during this test. Subjects will undergo a 7 d washout period. Dose visit 2: Subjects will receive 2 capsules containing either 10 or 20 mmol of KNO3 (whichever dose they did not receive at dose visit 1). They will repeat the same assessments listed above in 10, 11, and 12.

Official Title
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Inorganic NItrate and EXercise Performance in Heart Failure (iNIX-HF): Dose Response

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: KNO3, potassium nitrate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Sex: females and males Age: at least 18 years and less than 75 years Diagnosis of heart failure with reduced ejection fraction (NYHA II-IV) Ejection fraction <45% as determined on an imaging study within 12 mo of enrollment Stable medical therapy - defined by no addition or removal (or change of more than 100%) of the following: beta-adrenergic blockade, angiotensin converting enzyme (ACE) inhibitors, or angiotensin receptor blocker (ARB or aldosterone antagonists) for 30 days prior to enrolment Exclusion Criteria: Vulnerable populations as defined by the U.S. Department of Health and Human Services, such as prisoners and children Pharmacologic, organic nitrate therapy within the last 3 months Major orthopedic, psychiatric, neurological, or other conditions that would impair performance of the exercise tests in this study Atrial fibrillation/flutter Estimated glomerular filtration rate < 50 ml/min on most recent clinical laboratories Systolic blood pressure < 95 mmHg or >180 mmHg at consent Diastolic blood pressure <40 mmHg or >100 mmHg at consent Previous adverse reaction to nitrates necessitating withdrawal of therapy Treatment with phosphodiesterase inhibitors within the last 3 months (patient must also be willing to not take them for the duration of the trial). Ejection fraction > 45% Primary hypertrophic cardiomyopathy Infiltrative cardiomyopathy (e.g., amyloid) Active myocarditis Complex congenital heart disease Active collagen vascular disease Active angina/ischemia from epicardial coronary disease Percutaneous coronary intervention, new bi-ventricular pacing, or coronary artery bypass grafting within the past 3 months More than mild mitral or aortic stenosis Valvular heart disease with severe regurgitation of any valve. Acute or chronic severe liver disease as evidenced by encephalopathy, international normalized ratio (INR) >1.7 without anticoagulation therapy, or variceal bleeding Patients requiring exogenous oxygen at rest or for exercise Terminal disease (other than heart failure) with expected survival < 1 y Enrollment in another therapeutic trial during the period of the study Pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 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: Crossover Assignment
Interventional Model Description: Subjects will receive one drug dose on the first dose visit and the second drug dose on the second dose visit. The order of the two drug doses (10 and 20 mmol KNO3) will be randomized, so that some subjects will receive the lower dose first and others will receive the higher dose first
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 10mmol KNO3<br>Intervention: Subjects with heart failure will receive a single oral dose of potassium nitrate (10 or 20 mmol KNO3) in 2 gelatin capsules during dose visit 1 and the other dose (10 or 20 mmol KNO3) during dose visit 2. The dose order will be randomized. | Drug: KNO3, potassium nitrate<br>* Potassium nitrate (KNO3) will be given orally in 2 gelatin capsules, which will be compounded by the Barnes-Jewish Hospital Pharmacy. The doses are 10 mmol and 20 mmol KNO3.<br>* Other names: saltpeter;|
| Experimental: 20mmol KNO3<br>Intervention: Subjects with heart failure will receive a single oral dose of potassium nitrate (10 or 20 mmol KNO3) in 2 gelatin capsules during dose visit 1 and the other dose (10 or 20 mmol KNO3) during dose visit 2. The dose order will be randomized. | Drug: KNO3, potassium nitrate<br>* Potassium nitrate (KNO3) will be given orally in 2 gelatin capsules, which will be compounded by the Barnes-Jewish Hospital Pharmacy. The doses are 10 mmol and 20 mmol KNO3.<br>* Other names: saltpeter;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| VO2peak | peak oxygen consumption during treadmill exercise | acute - 2.5 hours post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Muscle Power | Participants completed measurements of leg muscle power by doing knee extension exercises on a dynamometer (a device that measures voluntary muscle force production while controlling the speed of movement). | acute - 2 hours post dose | 
| Blood Nitrite Levels | concentrations of nitrite in the blood | time 0 (before receiving the KNO3 dose) and hourly after receiving KNO3 (1, 2, and 3 hours post-dose) | 
| Breath Nitric Oxide (NO) Level | Breath nitric oxide (NO) level will be taken via NIOX breath analyzer | time 0 (before receiving the KNO3 dose) and hourly after receiving KNO3 (1, 2, and 3 hours post-dose) |