The Inorganic Nitrate and eXercise Performance in Heart Failure (iNIX-HF) (iNIX-HF)

The Inorganic Nitrate and eXercise Performance in Heart Failure (iNIX-HF) -a Phase II Clinical Trial

The goals of this project are to determine the effectiveness of acute (2 hours after a single dose) and chronic (after 6 weeks of once-a-day dosing) KNO3 treatment (10mmol) vs. placebo on quadriceps muscle power and on aerobic exercise performance (V̇O2peak) in patients with HFrEF (left ventricular ejection fraction <45%). The investigators hypothesize that both acute and chronic dosing of 10mmol of KNO3 will improve exercise performance in HFrEF. To test this hypothesis, the investors will perform a randomized, double-blind, placebo-controlled, parallel-arm design study.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure
• Intervention / Treatment: Drug: KNO3; Drug: Placebo

Detailed Description

Visit 1 - Screening

Visit 1 will be considered the screening visit. Participants will not be required to fast for this visit. This visit will be conducted over approximately 1.5 to 2 hours. The following procedures will be completed during this visit:

1. Informed consent, if not already obtained previously.
2. Health questionnaire
3. Review of medical history and concomitant medication usage
4. Review of any patient reported eligibility criteria (e.g., agreeance to using birth control, not using phosphodiesterase, inhibitors, etc.)

5. Labs

   a. As this is the only blood sample collected during this visit, IV placement is not necessary at this visit.

6. Urine pregnancy test
7. Physical examination
8. NYHA classification
9. Vital signs measurements
10. Height and weight measurements
11. Resting TTE with or without contrast

At the conclusion of Visit 1, eligibility criteria for each participant will be reviewed and confirmed by the PI prior to the participant completing Visit 2 procedures.

Visit 2 - Baseline

Visit 2 will be considered the baseline visit. Participants will be required to fast for this visit. This visit will be conducted over approximately 4 to 5 hours. Upon the participant's arrival, the following will occur:

1. Review of any changes to medical history and concomitant medication usage
2. Review of compliance on restrictions
3. IV placement
4. Labs
5. Vital signs measurements
6. Height, weight, hip, and waist circumference measurements
7. Low nitrate snack consumption
8. PWV and PWA

After these procedures have been completed, the following procedures will occur each hour as follows in the order in which they are listed, if not being completed simultaneously:

1. 0 Hour

   1. Blood sampling for NO3- and NO2- and NT-proBNP
   2. Breath Nitric Oxide
   3. Hand grip strength assessment
   4. KCCQ and MLHFQ

2. 1 Hour

   1. Blood sampling for NO3- and NO2- only
   2. Vital signs measurements (BP and HR only)
   3. Breath Nitric Oxide
   4. PWV and PWA
   5. DXA Scan

3. 2 Hour

   1. Blood sampling for NO3- and NO2- only
   2. Vital signs measurements (BP and HR only)
   3. Breath Nitric Oxide
   4. Maximal muscle power test
   5. Aerobic capacity test

4. 3 Hour

   1. Blood sampling for NO3- and NO2- only
   2. Vital signs measurements (BP and HR only)
   3. Breath Nitric Oxide
   4. Hand grip strength assessment

5. 4 Hour

   1. Blood sampling for NO3- and NO2- only
   2. Vital signs measurements (BP and HR only)
   3. Breath Nitric Oxide

Note, blood sampling, vital signs, and breath nitric oxide measurements should be collected as close to the beginning of each hourly time point as possible. However, it will not be considered a protocol deviation if they are slightly delayed due to procedures such as exercise testing extending into the next hour. All other procedures can be completed within each hour as time permits.

After completion of the 4 hour time point, the participant will be discharged from the facility.

Visit 3 - Acute Dose Administration

This visit will occur within 1 month after Visit 2. Participants will be required to fast for this visit. This visit will be conducted over approximately 4 to 5 hours. Upon the participant's arrival, the following will occur:

1. Review of any changes to medical history and concomitant medication usage
2. Review of compliance on restrictions
3. IV placement
4. Labs
5. Vital signs measurements
6. Height, weight, hip, and waist circumference measurements
7. Low nitrate snack consumption
8. PWV and PWA

After these procedures have been completed, the following procedures will occur each hour as follows in the order in which they are listed, if not being completed simultaneously:

1. 0 Hour

   1. Blood sampling for NO3- and NO2- and NT-proBNP
   2. Breath Nitric Oxide
   3. Ingestion of investigational product
   4. Hand grip strength assessment
   5. KCCQ and MLHFQ

2. 1 Hour

   1. Blood sampling for NO3- and NO2- only
   2. Vital signs measurements (BP and HR only)
   3. Breath Nitric Oxide
   4. PWV and PWA

3. 2 Hour

   1. Blood sampling for NO3- and NO2- only
   2. Vital signs measurements (BP and HR only)
   3. Breath Nitric Oxide
   4. Maximal muscle power test
   5. Aerobic capacity test

4. 3 Hour

   1. Blood sampling for NO3- and NO2- only
   2. Vital signs measurements (BP and HR only)
   3. Breath Nitric Oxide
   4. Hand grip strength assessment

5. 4 Hour

   1. Blood sampling for NO3- and NO2- only
   2. Vital signs measurements (BP and HR only)
   3. Breath Nitric Oxide
   4. Review of any adverse events specifically associated with investigational medication administration
   5. Dispense of 6 weeks' worth of investigational medication

Note, blood sampling, vital signs, and breath nitric oxide measurements should be collected as close to the beginning of each hourly time point as possible. However, it will not be considered a protocol deviation if they are slightly delayed due to procedures such as exercise testing extending into the next hour. All other procedures can be completed within each hour as time permits.

After completion of the 4 hour time point, the participant will be discharged from the facility.

Between Visits 3 and 4

Between visits 3 and 4, participants will take the study medication provided daily.

Every 2 weeks, participants will be asked to complete a Bi-weekly Adherence Survey to track compliance between Visits 3 and 4.

Visit 4 - 6 Week Follow Up/End of Study

Participants will be required to fast for this visit. This visit will be conducted over approximately 4 to 5 hours. Upon the participant's arrival, the following will occur:

1. Review of any changes to medical history and concomitant medication usage
2. Review of compliance on restrictions
3. Collection of any remaining investigational product
4. IV placement
5. Labs
6. Vital signs measurements
7. Height, weight, hip, and waist circumference measurements
8. Physical exam
9. Low nitrate snack consumption
10. Resting TTE with contrast
11. PWV and PWA

After these procedures have been completed, the following procedures will occur each hour as follows in the order in which they are listed, if not being completed simultaneously:

1. 0 Hour

   a. Blood sampling for NO3- and NO2- and NT-proBNP f. Breath Nitric Oxide g. Ingestion of investigational product h. Hand grip strength assessment i. KCCQ and MLHFQ

2. 1 Hour

   1. Blood sampling for NO3- and NO2- only
   2. Vital signs measurements (BP and HR only)
   3. Breath Nitric Oxide
   4. PWV and PWA
   5. DXA scan

3. 2 Hour

   1. Blood sampling for NO3- and NO2- only
   2. Vital signs measurements (BP and HR only)
   3. Breath Nitric Oxide
   4. Maximal muscle power test
   5. Aerobic capacity test

4. 3 Hour

   1. Blood sampling for NO3- and NO2- only
   2. Vital signs measurements (BP and HR only)
   3. Breath Nitric Oxide
   4. Hand grip strength assessment

5. 4 Hour

   1. Blood sampling for NO3- and NO2- only
   2. Vital signs measurements (BP and HR only)
   3. Breath Nitric Oxide

Note, blood sampling, vital signs, and breath nitric oxide measurements should be collected as close to the beginning of each hourly time point as possible. However, it will not be considered a protocol deviation if they are slightly delayed due to procedures such as exercise testing extending into the next hour. All other procedures can be completed within each hour as time permits.

After completion of the 4 hour time point, the participant will be discharged from the facility. At this time, the participant will be considered to have completed the study.

• Study Type: Interventional
• Enrollment (Estimated): 75
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Susan B Racette, PhD; Phone Number: 602-543-1563; Email: Susan.Racette@asu.edu
• Study Contact Backup: Name: Dawson A Haley, B.S.; Phone Number: 3147914455; Email: dhaley@wustl.edu

Study Locations

• United States
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University School Of Medicine
      • Contact: Linda R Peterson, MD; Phone Number: 314-362-4577; Email: lpeterso@wustl.edu
      • Principal Investigator: Linda R Peterson, MD
      • Sub-Investigator: Andrew Coggan, PhD
      • Contact: Dawson A Haley, B.S.; Phone Number: 314-791-4455; Email: dhaley@wustl.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

To participate in this study, a patient must meet all of the criteria listed below:

• Males and females aged greater than or equal to 18y and less than 80y at time of consent
• Diagnosis of heart failure with reduced ejection fraction
• New York Heart Association (NYHA) Class II-III at Visit 1
• Ejection fraction less than 45%, as evaluated through transthoracic echocardiography at Visit 1
• Stable medical therapy, defined by no addition or removal (or change of more than 100 percent) of the following for 60 days prior to Visit 1: beta-adrenergic blockade and angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blocker (ARB or aldosterone antagonists) or ARNI (ARB + sacubitril)
• Ability and willingness to sign an IRB approved written informed consent form; legally authorized representatives are not allowed in this study

Exclusion Criteria

To participate in this study, a patient must not meet any of the criteria listed below:

• Vulnerable populations as defined by the U.S. Department of Health and Human Services; prisoners and children will be excluded from this study
• Pharmacologic, organic nitrate therapy within 3 months prior to Visit 1
• Major orthopedic, psychiatric, neurological, or other conditions that would hinder the ability to complete the exercise tests at the time of Visit 1
• Estimated glomerular filtration rate less than 45 mL/min/1.73m2 on screening clinical laboratories measured at Visit 1
• Systolic blood pressure less than 90mmHg or greater than 180mmHg at Visit 1
• Diastolic blood pressure less than 40mmHg or greater than 100mmHg at Visit 1
• Previous adverse reaction to nitrate prior to Visit 1
• Treatment with phosphodiesterase inhibitors within the last 3 months prior to Visit 1; Patient must also be willing to not take them for the duration of the trial
• Diagnosis of primary hypertrophic cardiomyopathy, infiltrative cardiomyopathy (e.g., amyloid), active myocarditis, or complex congenital heart disease prior to Visit 1
• Active collagen vascular disease at time of Visit 1
• Percutaneous coronary intervention, new bi-ventricular pacing, or coronary artery bypass grafting within the 3 months prior to Visit 1
• Valvular heart disease with severe regurgitation or stenosis of any valve, as demonstrated on the echocardiogram at Visit 1
• Known severe liver disease as evidenced by encephalopathy or variceal bleeding;
• Terminal disease (other than heart failure) with expected survival less than 1 y at time of Visit 1
• Enrollment in another therapeutic trial at time of Visit 1
• Pregnant and breastfeeding women or postmenopausal women taking exogenous estrogen replacement therapy at time of Visit 1
• To meet this criterion, patients must have a negative urine pregnancy test and provide verbal confirmation that they are not breastfeeding at time of Visit 1.
• Note, post-menopausal is defined as last menstrual period occurring greater than or equal to 12 months prior to Visit 1 or confirmation of prior bilateral oophorectomy at least 6 months prior to first dose of study drug.

• Women of childbearing potential or men with childbearing potential partners must agree that the participant and/or their partner will use at least two of the following highly effective method of birth control from study entry until 48 hours after completing study therapy, if not abstaining from sexual activity:

  • Barrier method contraception (e.g., male or female condoms with or without a spermicidal agent, diaphragm, or cervical cap with spermicide)
  • Stable dose of injectable, depot, oral, implanted, intravaginal, or transdermal hormonal contraception for at least 30 days before sexual activity
  • Intrauterine device (IUD) with or without hormones
  • Surgical sterilization
  • For women, this includes hysterectomy, bilateral oophorectomy with or without hysterectomy, or bilateral tubal ligation, bilateral salpingectomy, completed at least 6 months before first dose of study drug.
  • For men, this includes vasectomy.
• Patients requiring exogenous oxygen at rest or during exercise prior to Visit 1
• Patients with active angina at time of Visit 1 or ischemia due to epicardial coronary disease prior to or at time of Visit 1
• Patients taking xanthine oxidase inhibitors at time of Visit 1

• Individuals taking proton pump inhibitors and/or antacids at time of Visit 1, if unable to stop these medications for the duration of the study.

  • Note, while patients will be asked to refrain from taking these medications for the duration of the study, they may take tums. However, patients must discontinue Tums for 5 days prior to study visits 2, 3, and 4.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Potassium Nitrate (KNO3) treatment arm; 10 mmol of KNO3 via a single gel capsule to be consumed orally once per day for 6 weeks.	Drug: KNO3; 10 mmol of KNO3 via a single gel capsule to be consumed orally once per day for 6 weeks.; Other Names: Potassium nitrate
Placebo Comparator: Placebo-controlled arm; 10 mmol of placebo via a single gel capsule to be consumed orally once per day for 6 weeks.	Drug: Placebo; 10 mmol of placebo via a single gel capsule to be consumed orally once per day for 6 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
VO2 Peak Testing	peak oxygen consumption during treadmill exercise	Determined at Baseline visit, Acute Dose Visit, and Chronic Dose Visit, which will be scheduled throughout 8 weeks.
Maximal muscle power	assessment of quadriceps power	Determined at Baseline visit, Acute Dose Visit, and Chronic Dose Visit, which will be scheduled throughout 8 weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MLHFQ questionnaire	Minnesota Living with Heart Failure Questionnaire	Determined at Baseline visit, Acute Dose Visit, and Chronic Dose Visit, which will be scheduled throughout 8 weeks.
KCCQ questionnaire	Kansas City Cardiomyopathy Questionnaire	Determined at Baseline visit, Acute Dose Visit, and Chronic Dose Visit, which will be scheduled throughout 8 weeks.
Maximal muscle velocity	assessment of quadriceps velocity	Determined at Baseline visit, Acute Dose Visit, and Chronic Dose Visit, which will be scheduled throughout 8 weeks.
Maximal exercise time on treadmill	Maximum time spent on treadmill during the VO2 peak test	Determined at Baseline visit, Acute Dose Visit, and Chronic Dose Visit, which will be scheduled throughout 8 weeks.
Plasma nitrate and nitrite	concentrations of nitrate and nitrite in the blood	Determined at Baseline visit, Acute Dose Visit, and Chronic Dose Visit, which will be scheduled throughout 8 weeks.
Breath nitric oxide (NO) level	breath NO level	Determined at Baseline visit, Acute Dose Visit, and Chronic Dose Visit, which will be scheduled throughout 8 weeks.

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: Linda R Peterson, MD, Washington University School Of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): March 31, 2023
• Primary Completion (Estimated): May 31, 2027
• Study Completion (Estimated): July 31, 2027

Study Registration Dates

• First Submitted: September 21, 2022
• First Submitted That Met QC Criteria: September 29, 2022
• First Posted (Actual): September 30, 2022

Study Record Updates

• Last Update Posted (Actual): May 6, 2026
• Last Update Submitted That Met QC Criteria: May 4, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Heart Failure; potassium nitrate
• Other Study ID Numbers: 202204141

Drug and device information, study documents

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