Treatment of HFpEF With Nitrate Supplement

Early Phase 1

Completed

• Conditions: Heart Failure With Normal Ejection Fraction
• Interventions: Dietary Supplement: Active lozenge; Drug: Placebo

• Registration Number: NCT03289481
• Lead Sponsor: MaineHealth

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.

Study Timeline

• Study Start: 2017-06-29
• Study First Submitted: 2017-09-18
• Study First Submitted QC: 2017-09-18
• Study First Posted: 2017-09-21
• Primary Completion: 2018-08-22
• Study Completion: 2018-08-22
• Results First Submitted: 2019-02-14
• Results First Submitted QC: 2019-08-22
• Results First Posted: 2019-08-26
• Status Verified: 2021-09
• Last Update Submitted: 2021-09-16
• Last Update Posted: 2021-10-06

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 13

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Active lozenge first	Active lozenge	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.
Active lozenge first	Placebo	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.
Placebo lozenge first	Active lozenge	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.
Placebo lozenge first	Placebo	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.

Primary Outcome Measures

Name	Time	Method
Time on Treadmill	after one week of active lozenges compared to one week of placebo lozenges	change in total time traveled on treadmill
Metabolic Equivalents	after one week of active lozenges compared to one week of placebo lozenges	change in metabolic equivalents on treadmill
E/E Prime	after one week of active lozenges compared to one week of placebo lozenges	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)
Estimated Right Ventricular Systolic Pressure	after one week of active lozenges compared to one week of placebo lozenges	change in estimated right ventricular systolic pressure on echo

Trial Locations

Locations (1)

Penobscot Bay Medical Center; 🇺🇸 Rockport, Maine, United States