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

May 12, 2025 updated by: Washington University School of Medicine
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

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and 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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
42

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
VO2peak
Time Frame: acute - 2.5 hours post dose
peak oxygen consumption during treadmill exercise
acute - 2.5 hours post dose

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Peak Muscle Power
Time Frame: 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).
acute - 2 hours post dose
Blood Nitrite Levels
Time Frame: 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
time 0 (before receiving the KNO3 dose) and hourly after receiving KNO3 (1, 2, and 3 hours post-dose)
Breath Nitric Oxide (NO) Level
Time Frame: 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
time 0 (before receiving the KNO3 dose) and hourly after receiving KNO3 (1, 2, and 3 hours post-dose)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Washington University School of Medicine

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • 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

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
October 31, 2017

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
October 31, 2021

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 15, 2021

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
May 25, 2016

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 7, 2016

First Posted (Estimated)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
June 13, 2016

Study Record Updates

Last Update Posted (Estimated)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
May 20, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 12, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
May 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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