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

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ClinicalTrials.gov Identifier: NCT02797184
Recruitment Status : Recruiting
First Posted : June 13, 2016
Last Update Posted : December 31, 2018
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine

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.

Condition or disease Intervention/treatment Phase
Heart Failure Drug: KNO3, potassium nitrate Phase 1 Phase 2

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 nitrate and 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Intervention Model: Single Group Assignment
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
Masking: None (Open Label)
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.
Primary Purpose: Treatment
Official Title: Inorganic NItrate and EXercise Performance in Heart Failure (iNIX-HF): Dose Response
Actual Study Start Date : October 31, 2017
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : December 2025


Arm Intervention/treatment
Experimental: Aim 1. KNO3 dose response
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 Name: saltpeter




Primary Outcome Measures :
  1. VO2peak [ Time Frame: acute - 2.5 hours post dose ]
    peak oxygen consumption during treadmill exercise


Secondary Outcome Measures :
  1. Peak muscle power [ Time Frame: acute - 2 hours post dose ]
    assessment of quadriceps power

  2. Blood nitrate and 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 nitrate and nitrite in the blood

  3. 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 NO level



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Ages Eligible for Study:   18 Years to 74 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02797184


Contacts
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Contact: Deb Koudelis 314-747-3876 delanod@wustl.edu

Locations
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United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Dakkota Thies    314-747-3839    thiesd@mir.wustl.edu   
Contact: Linda R Peterson, MD    314-362-4577    lpeterso@dom.wustl.edu   
Principal Investigator: Linda R Peterson, MD         
Sub-Investigator: Andrew R Coggan, PhD         
Sponsors and Collaborators
Washington University School of Medicine
Investigators
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Principal Investigator: Linda R Peterson, MD Washington University School of Medicine
Principal Investigator: Andrew R Coggan, PhD Washington University School of Medicine

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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT02797184     History of Changes
Other Study ID Numbers: 2016_11111
First Posted: June 13, 2016    Key Record Dates
Last Update Posted: December 31, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases