Treatment of HFpEF With Nitrate Supplement

Treatment of HFpEF With Nitrate Supplement: A Double-blind, Placebo Controlled Trial Including Patients With Atrial Fibrillation

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.

Study Overview

• Status: Completed
• Conditions: Heart Failure With Normal Ejection Fraction
• Intervention / Treatment: Drug: Placebo; Dietary supplement: Active lozenge

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.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Maine
    • Rockport, Maine, United States, 04856
      • Penobscot Bay Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active lozenge first; Subject will take active lozenge (Vitamin C, Vitamin B12, Nitric Oxide Blend, L-citrulline, Sodium Nitrite) for one week, perform cardiac testing then take placebo lozenge for one week and perform cardiac testing.	Drug: Placebo; placebo tablet; Dietary supplement: Active lozenge; nitric oxide generating lozenge
Active Comparator: Placebo lozenge first; Subject will take placebo lozenge for one week, perform cardiac testing then take active lozenge (Vitamin C, Vitamin B12, Nitric Oxide Blend, L-citrulline, Sodium Nitrite) for one week and perform cardiac testing.	Drug: Placebo; placebo tablet; Dietary supplement: Active lozenge; nitric oxide generating lozenge

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time on Treadmill	change in total time traveled on treadmill	after one week of active lozenges compared to one week of placebo lozenges
Metabolic Equivalents	change in metabolic equivalents on treadmill	after one week of active lozenges compared to one week of placebo lozenges
E/E Prime	change in E/E prime on exercise echo (E/E prime is a ratio between early mitral inflow velocity and mitral annular early diastolic velocity in order to measure diastolic dysfunction)	after one week of active lozenges compared to one week of placebo lozenges
Estimated Right Ventricular Systolic Pressure	change in estimated right ventricular systolic pressure on echo	after one week of active lozenges compared to one week of placebo lozenges

Collaborators and Investigators

• Sponsor: MaineHealth
• Collaborators: HumanN
• Investigators: Principal Investigator: Ralph Hamill, MD, MaineHealth

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 29, 2017
• Primary Completion (Actual): August 22, 2018
• Study Completion (Actual): August 22, 2018

Study Registration Dates

• First Submitted: September 18, 2017
• First Submitted That Met QC Criteria: September 18, 2017
• First Posted (Actual): September 21, 2017

Study Record Updates

• Last Update Posted (Actual): October 6, 2021
• Last Update Submitted That Met QC Criteria: September 16, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Heart failure; HFpEF; Nitrate supplement
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: Neo40 Study

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No