Heart Failure
Conditions
Brief summary
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
1. Subjects will be patients with Heart Failure (HF). 2. All subjects will be consented. 3. All subjects will give permission for the investigators to review their medical records. 4. 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. 5. Subjects will have a physical examination. 6. Subjects will undergo transthoracic echocardiographic imaging at rest (unless they had this performed within the past 6 months). 7. Subjects will be asked to undergo a mouth swab for bacterial DNA analyses. 8. Subjects will be asked to answer questionnaires regarding their medical health (basic health questionnaire, Minnesota living with heart failure questionnaire, a combined fatigue questionnaire. 9. Dose visit 1: Subjects will receive 2 capsules containing either 10 or 20 mmol of potassium nitrate (KNO3). 10. 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. 11. 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). 12. 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. 13. Subjects will undergo a 7 d washout period. 14. 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.
Interventions
DRUGKNO3, potassium nitrate
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.
Sponsors
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Both the participant and the investigator will be masked to which KNO3 dose is administered at each visit. However, it is known at the outset that each patient will receive 10 mmol KNO3 during one visit and 20 mmol KNO3 at another visit, with the order randomly assigned.
Intervention 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
Eligibility
Sex/Gender
ALL
Age
18 Years to 74 Years
Healthy volunteers
No
Inclusion criteria
1. Sex: females and males 2. Age: at least 18 years and less than 75 years 3. Diagnosis of heart failure with reduced ejection fraction (NYHA II-IV) 4. Ejection fraction \<45% as determined on an imaging study within 12 mo of enrollment 5. 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
1. Vulnerable populations as defined by the U.S. Department of Health and Human Services, such as prisoners and children 2. Pharmacologic, organic nitrate therapy within the last 3 months 3. Major orthopedic, psychiatric, neurological, or other conditions that would impair performance of the exercise tests in this study 4. Atrial fibrillation/flutter 5. Estimated glomerular filtration rate \< 50 ml/min on most recent clinical laboratories 6. Systolic blood pressure \< 95 mmHg or \>180 mmHg at consent 7. Diastolic blood pressure \<40 mmHg or \>100 mmHg at consent 8. Previous adverse reaction to nitrates necessitating withdrawal of therapy 9. Treatment with phosphodiesterase inhibitors within the last 3 months (patient must also be willing to not take them for the duration of the trial). 10. Ejection fraction \> 45% 11. Primary hypertrophic cardiomyopathy 12. Infiltrative cardiomyopathy (e.g., amyloid) 13. Active myocarditis 14. Complex congenital heart disease 15. Active collagen vascular disease 16. Active angina/ischemia from epicardial coronary disease 17. Percutaneous coronary intervention, new bi-ventricular pacing, or coronary artery bypass grafting within the past 3 months 18. More than mild mitral or aortic stenosis 19. Valvular heart disease with severe regurgitation of any valve. 20. Acute or chronic severe liver disease as evidenced by encephalopathy, international normalized ratio (INR) \>1.7 without anticoagulation therapy, or variceal bleeding 21. Patients requiring exogenous oxygen at rest or for exercise 22. Terminal disease (other than heart failure) with expected survival \< 1 y 23. Enrollment in another therapeutic trial during the period of the study 24. Pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| VO2peak | acute - 2.5 hours post dose | peak oxygen consumption during treadmill exercise |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peak Muscle Power | acute - 2 hours post dose | 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). |
| Blood Nitrite Levels | time 0 (before receiving the KNO3 dose) and hourly after receiving KNO3 (1, 2, and 3 hours post-dose) | concentrations of nitrite in the blood |
| Breath Nitric Oxide (NO) Level | time 0 (before receiving the KNO3 dose) and hourly after receiving KNO3 (1, 2, and 3 hours post-dose) | Breath nitric oxide (NO) level will be taken via NIOX breath analyzer |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants 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.
KNO3, potassium nitrate: 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. | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Study was put on hold due to COVID-19. Could not finish these subjects before funding ran out. | 18 | 18 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants |
| Age, Continuous | 49.3 years STANDARD_DEVIATION 11.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 4 Participants |
| Region of Enrollment United States | 6 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 0 / 6 | 0 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 |
Outcome results
Primary
VO2peak
peak oxygen consumption during treadmill exercise
Time frame: acute - 2.5 hours post dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 10mmol KNO3 | VO2peak | 17.7 mL/kg/min | Standard Deviation 3.4 |
| 20mmol KNO3 | VO2peak | 18.0 mL/kg/min | Standard Deviation 4.1 |
Secondary
Blood Nitrite Levels
concentrations of nitrite in the blood
Time frame: time 0 (before receiving the KNO3 dose) and hourly after receiving KNO3 (1, 2, and 3 hours post-dose)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 10mmol KNO3 | Blood Nitrite Levels | 0 hr | 0.489 micro M | Standard Deviation 0.295 |
| 10mmol KNO3 | Blood Nitrite Levels | 1 hr post-ingestion KNO3 | 0.568 micro M | Standard Deviation 0.244 |
| 10mmol KNO3 | Blood Nitrite Levels | 2 hr post-ingestion KNO3 | 0.658 micro M | Standard Deviation 0.277 |
| 10mmol KNO3 | Blood Nitrite Levels | 3 hr post-ingestion KNO3 | 0.646 micro M | Standard Deviation 0.261 |
| 20mmol KNO3 | Blood Nitrite Levels | 3 hr post-ingestion KNO3 | 0.769 micro M | Standard Deviation 0.529 |
| 20mmol KNO3 | Blood Nitrite Levels | 0 hr | 0.432 micro M | Standard Deviation 0.258 |
| 20mmol KNO3 | Blood Nitrite Levels | 2 hr post-ingestion KNO3 | 0.864 micro M | Standard Deviation 0.916 |
| 20mmol KNO3 | Blood Nitrite Levels | 1 hr post-ingestion KNO3 | 0.591 micro M | Standard Deviation 0.481 |
Secondary
Breath Nitric Oxide (NO) Level
Breath nitric oxide (NO) level will be taken via NIOX breath analyzer
Time frame: time 0 (before receiving the KNO3 dose) and hourly after receiving KNO3 (1, 2, and 3 hours post-dose)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 10mmol KNO3 | Breath Nitric Oxide (NO) Level | 2 hr | 28 ppb | Standard Deviation 9 |
| 10mmol KNO3 | Breath Nitric Oxide (NO) Level | 0 hr | 26 ppb | Standard Deviation 13 |
| 10mmol KNO3 | Breath Nitric Oxide (NO) Level | 3 hr | 32 ppb | Standard Deviation 7 |
| 10mmol KNO3 | Breath Nitric Oxide (NO) Level | 1 hr | 28 ppb | Standard Deviation 11 |
| 20mmol KNO3 | Breath Nitric Oxide (NO) Level | 3 hr | 43 ppb | Standard Deviation 16 |
| 20mmol KNO3 | Breath Nitric Oxide (NO) Level | 1 hr | 30 ppb | Standard Deviation 14 |
| 20mmol KNO3 | Breath Nitric Oxide (NO) Level | 2 hr | 36 ppb | Standard Deviation 21 |
| 20mmol KNO3 | Breath Nitric Oxide (NO) Level | 0 hr | 23 ppb | Standard Deviation 9 |
Secondary
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).
Time frame: acute - 2 hours post dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 10mmol KNO3 | Peak Muscle Power | 469.4 Watts/kg | Standard Deviation 188.8 |
| 20mmol KNO3 | Peak Muscle Power | 497.9 Watts/kg | Standard Deviation 173.8 |