Clinical trial NCT03289481: Treatment of HFpEF With Nitrate Supplement
Official title: Treatment of HFpEF With Nitrate Supplement: A Double-blind, Placebo Controlled Trial Including Patients With Atrial Fibrillation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Heart Failure With Normal Ejection Fraction
Keywords: Heart failure
HFpEF
Nitrate supplement
Lead sponsor: MaineHealth
Sponsor class: OTHER
Collaborators: name: HumanN
First posted: 2017-09-21
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Double-blind, placebo controlled crossover study
Primary purpose: TREATMENT

Brief summary: The objective of this project is to determine if Neo40, a nitric oxide generating lozenge, when consumed twice daily by subjects with HFpEF, will increase exercise tolerance, decrease symptoms and improve quality of life for patients.

Detailed description: Heart failure (HF) is the most common principal diagnosis for hospital admission in patients over 65 years old. There are two types of HF, those with reduced ejection fraction (HFrEF) and those with preserved ejection fraction (HFpEF). Approximately half of patients with the clinical syndrome of HF have preserved systolic function. HEpEF is becoming more prevalent with aging of the population and obesity. There are only two class I recommendations for the treatment of HFpEF, which are controlling blood pressure and the use of diuretics to relieve symptoms. Exercise training is another approach to improving symptoms, however it may be poorly tolerated.

Nitrate supplement in the form of concentrated beetroot juice was recently shown to improve exercise tolerance in patients with HFpEF. (1) Beetroot juice contains high concentration of nitrate (NO3). This is metabolized to nitrite (NO2). It enters the blood stream, where it is further reduced to nitric oxide (NO) resulting in intense vasodilation.

Patients with diastolic dysfunction are often asymptomatic at rest but complain of dyspnea with exertion. Increase in heart rate with exercise causes reduced diastolic filling time and increases left sided filling pressure. Borloug, et al demonstrated this with right heart catheterization and supine exercise in patients with diastolic dysfunction. Infusion of NO2 resulted in decreased filling pressures and increased cardiac output. (2)

Neo40 is a new product made from concentrated beetroot juice in the form of a lozenge designed to dissolve on the tongue. NO3 supplement causes vasodilatation only in the setting of hypoxia and acidosis resulting in targeted vasodilatation.

Eligibility criteria: Inclusion Criteria:

1. Diagnosis of HFpEF, defined as:

   * symptomatic with one of more of the following: orthopnea, paroxysmal nocturnal dyspnea, lower-extremity edema, dyspnea on exertion; AND
   * ejection fraction \>50%
   * ratio of early mitral inflow velocity to septal tissue dopler velocity \>8; AND
   * one or more of the following: left atrium measurement \>34 mL/m2, elevated N-terminal pro-brain natriuretic peptide level within the past 12 months, long term loop diuretic use for control of symptoms or elevated filling pressures on prior cardiac catheterization
2. Stable medical therapy, defined as: no change in cardiac medications within 30 days
3. Willing to comply with the protocol and provide written informed consent

Exclusion Criteria:

1. Non-cardiac condition causing limitation of exercise tolerance
2. Acute coronary syndrome, myocardial infarction or cardiac revascularization within 60 days
3. Clinically significant valvular disease, defined as moderate-severe or severe stenosis or insufficiency
4. Significant ischemia seen on stress testing within the past 12 months that was not revascularized
5. Subject has taken and investigational medication within the past 30 days
6. History of allergy to beets
7. Systolic blood pressure of \<100 at screening
8. Significant medical condition that would interfere with treatment, safety or compliance with the protocol

Primary outcomes:
measure: Time on Treadmill
timeFrame: after one week of active lozenges compared to one week of placebo lozenges
measure: Metabolic Equivalents
timeFrame: after one week of active lozenges compared to one week of placebo lozenges
measure: E/E Prime
timeFrame: after one week of active lozenges compared to one week of placebo lozenges
measure: Estimated Right Ventricular Systolic Pressure
timeFrame: after one week of active lozenges compared to one week of placebo lozenges
Secondary outcomes:
Other outcomes:
Locations:
city: Rockport
country: United States
facility: Penobscot Bay Medical Center
state: Maine
Study officials:
affiliation: MaineHealth
name: Ralph Hamill, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Eggebeen J, Kim-Shapiro DB, Haykowsky M, Morgan TM, Basu S, Brubaker P, Rejeski J, Kitzman DW. One Week of Daily Dosing With Beetroot Juice Improves Submaximal Endurance and Blood Pressure in Older Patients With Heart Failure and Preserved Ejection Fraction. JACC Heart Fail. 2016 Jun;4(6):428-37. doi: 10.1016/j.jchf.2015.12.013. Epub 2016 Feb 10.
citation: Borlaug BA, Koepp KE, Melenovsky V. Sodium Nitrite Improves Exercise Hemodynamics and Ventricular Performance in Heart Failure With Preserved Ejection Fraction. J Am Coll Cardiol. 2015 Oct 13;66(15):1672-82. doi: 10.1016/j.jacc.2015.07.067.