Inorganic NItrate and EXercise Performance in Heart Failure (iNIX-HF): Dose Response

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.

Study Overview

• Status: Completed
• Conditions: Heart Failure
• Intervention / Treatment: Drug: KNO3, potassium nitrate

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.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 74 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 10mmol KNO3; 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.	Drug: 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.; Other Names: saltpeter
Experimental: 20mmol KNO3; 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.	Drug: 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.; Other Names: saltpeter

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
VO2peak	peak oxygen consumption during treadmill exercise	acute - 2.5 hours post dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	acute - 2 hours post dose
Blood Nitrite Levels	concentrations of nitrite in the blood	time 0 (before receiving the KNO3 dose) and hourly after receiving KNO3 (1, 2, and 3 hours post-dose)
Breath Nitric Oxide (NO) Level	Breath nitric oxide (NO) level will be taken via NIOX breath analyzer	time 0 (before receiving the KNO3 dose) and hourly after receiving KNO3 (1, 2, and 3 hours post-dose)

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: Andrew R Coggan, PhD, Washington University School of Medicine; Principal Investigator: Linda R Peterson, MD, Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): October 31, 2017
• Primary Completion (Actual): October 31, 2021
• Study Completion (Actual): December 15, 2021

Study Registration Dates

• First Submitted: May 25, 2016
• First Submitted That Met QC Criteria: June 7, 2016
• First Posted (Estimated): June 13, 2016

Study Record Updates

• Last Update Posted (Estimated): May 20, 2025
• Last Update Submitted That Met QC Criteria: May 12, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Heart Failure
• Other Study ID Numbers: 2016_11111

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: HIPPA-related data will not be available for publishing. Study results will be published in accordance with journal, institution, and HIPPA guidelines.

Drug and device information, study documents

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