Heart Failure With Normal Ejection Fraction
Conditions
Keywords
Heart failure, HFpEF, Nitrate supplement
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.
Interventions
DIETARY_SUPPLEMENTActive lozenge
nitric oxide generating lozenge
DRUGPlacebo
placebo tablet
Sponsors
HumanN
MaineHealth
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Masking will be done by the pharmacy. Active and placebo lozenges will look identical.
Intervention model description
Double-blind, placebo controlled crossover study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United States
Participant flow
Recruitment details
This study was a cross over case-control study (each subject was a control for themselves).
Participants by arm
| Arm | Count |
|---|---|
| Active Lozenge First Subject will take active lozenge for one week, perform cardiac testing then take placebo lozenge for one week and perform cardiac testing.
Active lozenge: nitric oxide generating lozenge | 4 |
| Placebo Lozenge First Subject will take placebo lozenge for one week, perform cardiac testing then take active lozenge for one week and perform cardiac testing.
Active lozenge: nitric oxide generating lozenge | 5 |
| Total | 9 |
Baseline characteristics
| Characteristic | Active Lozenge First | Placebo Lozenge First | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 3 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 2 Participants | 2 Participants |
| Diagnosis of HFpEF | 4 Participants | 5 Participants | 9 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 5 Participants | 9 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 4 participants | 5 participants | 9 participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 2 Participants | 4 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 9 |
| other Total, other adverse events | 0 / 9 | 0 / 9 |
| serious Total, serious adverse events | 0 / 9 | 0 / 9 |
Outcome results
Primary
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)
Time frame: after one week of active lozenges compared to one week of placebo lozenges
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Active Lozenge | E/E Prime | 1.93 ratio |
| Placebo | E/E Prime | -.05 ratio |
Primary
Estimated Right Ventricular Systolic Pressure
change in estimated right ventricular systolic pressure on echo
Time frame: after one week of active lozenges compared to one week of placebo lozenges
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Active Lozenge | Estimated Right Ventricular Systolic Pressure | 11.79 mmHg |
| Placebo | Estimated Right Ventricular Systolic Pressure | 8.6 mmHg |
Primary
Metabolic Equivalents
change in metabolic equivalents on treadmill
Time frame: after one week of active lozenges compared to one week of placebo lozenges
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Active Lozenge | Metabolic Equivalents | 7.99 cal/min |
| Placebo | Metabolic Equivalents | 8.46 cal/min |
Primary
Time on Treadmill
change in total time traveled on treadmill
Time frame: after one week of active lozenges compared to one week of placebo lozenges
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Active Lozenge | Time on Treadmill | 402.8 seconds |
| Placebo | Time on Treadmill | 181.2 seconds |