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

Primary Purpose

Heart Failure

Status

Active

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

KNO3, potassium nitrate

About this trial

This is an interventional treatment trial for Heart Failure

Eligibility Criteria

18 Years - 74 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Sex: females and males
Age: at least 18 years and less than 75 years
Diagnosis of heart failure with reduced ejection fraction (NYHA II-IV)
Ejection fraction <45% as determined on an imaging study within 12 mo of enrollment
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:

"Vulnerable populations" as defined by the U.S. Department of Health and Human Services, such as prisoners and children
Pharmacologic, organic nitrate therapy within the last 3 months
Major orthopedic, psychiatric, neurological, or other conditions that would impair performance of the exercise tests in this study
Atrial fibrillation/flutter
Estimated glomerular filtration rate < 50 ml/min on most recent clinical laboratories
Systolic blood pressure < 95 mmHg or >180 mmHg at consent
Diastolic blood pressure <40 mmHg or >100 mmHg at consent
Previous adverse reaction to nitrates necessitating withdrawal of therapy
Treatment with phosphodiesterase inhibitors within the last 3 months (patient must also be willing to not take them for the duration of the trial).
Ejection fraction > 45%
Primary hypertrophic cardiomyopathy
Infiltrative cardiomyopathy (e.g., amyloid)
Active myocarditis
Complex congenital heart disease
Active collagen vascular disease
Active angina/ischemia from epicardial coronary disease
Percutaneous coronary intervention, new bi-ventricular pacing, or coronary artery bypass grafting within the past 3 months
More than mild mitral or aortic stenosis
Valvular heart disease with severe regurgitation of any valve.
Acute or chronic severe liver disease as evidenced by encephalopathy, international normalized ratio (INR) >1.7 without anticoagulation therapy, or variceal bleeding
Patients requiring exogenous oxygen at rest or for exercise
Terminal disease (other than heart failure) with expected survival < 1 y
Enrollment in another therapeutic trial during the period of the study
Pregnancy

Sites / Locations

Washington University School of Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

10mmol KNO3

20mmol KNO3

Arm Description

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.

Outcomes

Primary Outcome Measures

VO2peak

peak oxygen consumption during treadmill exercise

Secondary Outcome Measures

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).

Blood Nitrite Levels

concentrations of nitrite in the blood

Breath Nitric Oxide (NO) Level

Breath nitric oxide (NO) level will be taken via NIOX breath analyzer

Full Information

NCT ID

NCT02797184

First Posted

May 25, 2016

Last Updated

January 23, 2023

Sponsor

Washington University School of Medicine

1. Study Identification

Unique Protocol Identification Number

NCT02797184

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

October 31, 2017 (Actual)

Primary Completion Date

October 31, 2021 (Actual)

Study Completion Date

December 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Washington University School of Medicine

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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

Subjects will be patients with Heart Failure (HF). All subjects will be consented. All subjects will give permission for the investigators to review their medical records. 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. Subjects will have a physical examination. Subjects will undergo transthoracic echocardiographic imaging at rest (unless they had this performed within the past 6 months). Subjects will be asked to undergo a mouth swab for bacterial DNA analyses. Subjects will be asked to answer questionnaires regarding their medical health (basic health questionnaire, Minnesota living with heart failure questionnaire, a combined fatigue questionnaire. Dose visit 1: Subjects will receive 2 capsules containing either 10 or 20 mmol of potassium nitrate (KNO3). 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. 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). 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. Subjects will undergo a 7 d washout period. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Heart Failure

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Crossover Assignment

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

Masking

ParticipantInvestigator

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.

Allocation

Randomized

Enrollment

42 (Actual)

8. Arms, Groups, and Interventions

Arm Title

10mmol KNO3

Arm Type

Experimental

Arm Description

Arm Title

20mmol KNO3

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

KNO3, potassium nitrate

Other Intervention Name(s)

saltpeter

Intervention Description

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.

Primary Outcome Measure Information:

Title

VO2peak

Description

peak oxygen consumption during treadmill exercise

Time Frame

acute - 2.5 hours post dose

Secondary Outcome Measure Information:

Title

Peak Muscle Power

Description

Time Frame

acute - 2 hours post dose

Title

Blood Nitrite Levels

Description

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)

Title

Breath Nitric Oxide (NO) Level

Description

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)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

74 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Sex: females and males Age: at least 18 years and less than 75 years Diagnosis of heart failure with reduced ejection fraction (NYHA II-IV) Ejection fraction <45% as determined on an imaging study within 12 mo of enrollment 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: "Vulnerable populations" as defined by the U.S. Department of Health and Human Services, such as prisoners and children Pharmacologic, organic nitrate therapy within the last 3 months Major orthopedic, psychiatric, neurological, or other conditions that would impair performance of the exercise tests in this study Atrial fibrillation/flutter Estimated glomerular filtration rate < 50 ml/min on most recent clinical laboratories Systolic blood pressure < 95 mmHg or >180 mmHg at consent Diastolic blood pressure <40 mmHg or >100 mmHg at consent Previous adverse reaction to nitrates necessitating withdrawal of therapy Treatment with phosphodiesterase inhibitors within the last 3 months (patient must also be willing to not take them for the duration of the trial). Ejection fraction > 45% Primary hypertrophic cardiomyopathy Infiltrative cardiomyopathy (e.g., amyloid) Active myocarditis Complex congenital heart disease Active collagen vascular disease Active angina/ischemia from epicardial coronary disease Percutaneous coronary intervention, new bi-ventricular pacing, or coronary artery bypass grafting within the past 3 months More than mild mitral or aortic stenosis Valvular heart disease with severe regurgitation of any valve. Acute or chronic severe liver disease as evidenced by encephalopathy, international normalized ratio (INR) >1.7 without anticoagulation therapy, or variceal bleeding Patients requiring exogenous oxygen at rest or for exercise Terminal disease (other than heart failure) with expected survival < 1 y Enrollment in another therapeutic trial during the period of the study Pregnancy

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Linda R Peterson, MD

Organizational Affiliation

Washington University School of Medicine

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Andrew R Coggan, PhD

Organizational Affiliation

Washington University School of Medicine

Official's Role

Principal Investigator

Facility Information:

Facility Name

Washington University School of Medicine

City

Saint Louis

State/Province

Missouri

ZIP/Postal Code

63110

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

HIPPA-related data will not be available for publishing. Study results will be published in accordance with journal, institution, and HIPPA guidelines.

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

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