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Effect of KNO3 Compared to KCl on Oxygen UpTake in Heart Failure With Preserved Ejection Fraction (KNO3CK OUT HFPEF)

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ClinicalTrials.gov Identifier: NCT02840799
Recruitment Status : Recruiting
First Posted : July 21, 2016
Last Update Posted : September 3, 2020
Sponsor:
Collaborator:
Northwestern University
Information provided by (Responsible Party):
University of Pennsylvania

Tracking Information
First Submitted Date  ICMJE June 13, 2016
First Posted Date  ICMJE July 21, 2016
Last Update Posted Date September 3, 2020
Study Start Date  ICMJE August 2016
Estimated Primary Completion Date November 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 18, 2016)
  • Change in peak oxygen consumption (Vo2) from phase 1 to phase 2 [ Time Frame: 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control) ]
    Subjects will perform a maximal-effort peak oxygen consumption test using a supine bicycle exercise test with expired gas analysis.
  • Change in total work performed during a maximal-effort exercise test from phase 1 to phase 2 [ Time Frame: 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control) ]
    Subjects will perform a maximal-effort supine bicycle exercise test.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 18, 2016)
  • Effect of potassium nitrate (KNO3) on quality of life (QOL) [ Time Frame: All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control) ]
    QOL will be assessed with the Kansas City Cardiomyopathy Questionnaire.
  • Effect of KNO3 on the systemic vasodilatory response to exercise: The change in systemic vascular resistance reserve during exercise during a maximal effort exercise test [ Time Frame: 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control) ]
  • Effect of potassium nitrate (KNO3) on muscle blood flow during exercise: Muscle blood flow during exercise, measured with arterial MRI spin labeling during a standardized plantar flexion exercise test [ Time Frame: 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control) ]
    MRI studies will be performed at rest and immediately after a standardized plantar flexion exercise. Arterial spin labeling using the flow-sensitive alternating inversion recovery (FAIR) technique will be used to image muscle perfusion with high temporal resolution.
  • Effect of potassium nitrate (KNO3) on muscle phosphocreatine (PCr) recovery kinetics following a standardized plantar flexor exercise protocol [ Time Frame: 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control) ]
  • Effect of potassium nitrate (KNO3) on left ventricle (LV) diastolic function: E/e' ratio [ Time Frame: All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control) ]
  • Effect of potassium nitrate (KNO3) on left ventricle (LV) diastolic function: left atrial volume index [ Time Frame: All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control) ]
  • Effect of potassium nitrate (KNO3) on myocardial systolic strain: peak global systolic myocardial longitudinal strain [ Time Frame: All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control) ]
  • Effect of potassium nitrate (KNO3) on myocardial systolic strain: peak global systolic myocardial circumferential strain [ Time Frame: All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control) ]
  • Effect of potassium nitrate (KNO3) on late systolic wall stress as assessed by the Arts formula using echocardiographic and tonometry recordings [ Time Frame: All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control) ]
  • Effect of potassium nitrate (KNO3) on arterial wave reflections as assessed by wave separation analysis using tonometry and Doppler flow data [ Time Frame: All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control) ]
  • Effect of potassium nitrate (KNO3) on augmentation index [ Time Frame: All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control) ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effect of KNO3 Compared to KCl on Oxygen UpTake in Heart Failure With Preserved Ejection Fraction (KNO3CK OUT HFPEF)
Official Title  ICMJE Effect of KNO3 Compared to KCl on Oxygen UpTake in Heart Failure With Preserved Ejection Fraction (KNO3CK OUT HFPEF)
Brief Summary This trial seeks to assess if potassium nitrate (KNO3) therapy improves exercise capacity and oxygen uptake in heart failure patients with preserved ejection fraction (HFpEF).
Detailed Description Approximately 50% of heart failure patients exhibit preserved left ventricular (LV) ejection fraction (EF), and therefore have HF with preserved EF (HFpEF). There are currently no proven effective pharmacologic interventions. Exercise intolerance with reduced aerobic capacity is the hallmark of HFpEF and greatly impairs quality of life (QOL). During exercise, blood vessels within active muscle vasodilator, increasing perfusion to the muscle bed. Nitric oxide is a chief mediator of this process. Inorganic nitrate can ultimately be converted to nitric oxide. This conversion occurs preferentially at the site of exercising muscle, allowing for vasodilation to occur, hence increasing blood flow to the working muscle. Preliminary data suggest that inorganic nitrate improves exercise tolerance in HFpEF. The investigator will aim to test this hypothesis in a larger group.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Heart Failure
Intervention  ICMJE
  • Drug: Potassium Nitrate (KNO3)
    The effect of potassium nitrate (KNO3) supplementation on exercise capacity and peak oxygen consumption in HFpEF will be assessed.
  • Drug: Potassium Chloride (KCl)
    Potassium Chloride (KCl) is the matching placebo control drug in this trial.
Study Arms  ICMJE
  • Experimental: Potassium Nitrate (KNO3)
    Potassium nitrate (KNO3) capsules, providing 6 millimoles of inorganic nitrate per capsule, to be taken three times daily for 6 weeks.
    Intervention: Drug: Potassium Nitrate (KNO3)
  • Placebo Comparator: Potassium Chloride (KCl)

    Potassium Chloride (KCl) is the placebo (control drug) in this trial.

    Potassium Chloride (KCl) capsules administered at a dose of 6 millimoles (1 capsule) three times daily for 6 weeks.

    Intervention: Drug: Potassium Chloride (KCl)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 18, 2016)
76
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 2022
Estimated Primary Completion Date November 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Adults aged 18-90 years of age
  2. A diagnosis of heart failure with NYHA Class II-III symptoms
  3. LV ejection fraction >50% during baseline echocardiography
  4. Stable medical therapy: no addition/removal/changes in antihypertensive medications, or beta-blockers in the preceding 30 days
  5. Elevated filling pressures as evidenced by at least 1 of the following:

    1. Mitral E/e' ratio > 8 (either lateral or septal), with low e' velocity (septal e'<7 cm/sec or lateral e'< 10 cm/sec), in addition to one of the following:

      i Enlarged left atrium (LA volume index >34 ml/m2) ii Chronic loop diuretic use for control of symptoms iii Elevated natriuretic peptides (BNP levels >100 ng/L or NT-proBNP levels >300 ng/L)

    2. Mitral E/e' ratio > 14 (either lateral or septal)
    3. Elevated invasively-determined filling pressures previously (resting LVEDP>16 mmHg or mean pulmonary capillary wedge pressure [PCWP] > 12 mmHg; or PCWP/LVEDP≥25 mmHg with exercise)
    4. Acute heart failure decompensation requiring IV diuretics

Exclusion Criteria:

  1. Supine systolic blood pressure <100 mm Hg
  2. Pregnancy: Women of childbearing potential will undergo a pregnancy test during the screening visit
  3. Orthostatic hypotension defined as >20 mm Hg decrease in systolic blood pressure 3-5 minutes following the transition from the supine to standing position
  4. Uncontrolled atrial fibrillation, as defined by a resting heart rate>100 beats per minute
  5. Hemoglobin < 10 g/dL
  6. Inability/unwillingness to exercise
  7. Moderate or greater left sided valvular disease (mitral regurgitation, aortic stenosis, aortic regurgitation), any degree of mitral stenosis, severe right-sided valvular disease, or presence of a prosthetic valve in the mitral position
  8. Hypertrophic, infiltrative, or inflammatory cardiomyopathy
  9. Clinically significant pericardial disease, as per investigator judgement.
  10. Current angina
  11. Acute coronary syndrome or coronary intervention within the past 2 months
  12. Primary pulmonary arteriopathy
  13. Clinically significant lung disease as defined by: Chronic Obstructive Pulmonary Disease meeting Stage III or greater GOLD criteria, treatment with oral steroids within the past 6 months for an exacerbation of obstructive lung disease, or the use of daytime supplemental oxygen
  14. Ischemia on stress testing without either (1) subsequent revascularization, or; (2) a subsequent angiogram demonstrating the absence of clinically significant epicardial coronary artery disease, as per investigator judgement.
  15. Left ventricular ejection fraction <45% in any prior echocardiogram or cardiac MRI, unless this was in the setting of uncontrolled atrial fibrillation.
  16. Treatment with phosphodiesterase inhibitors that cannot be withheld
  17. Treatment with organic nitrates
  18. Significant liver disease impacting synthetic function or volume control (ALT/AST > 3x ULN, Albumin <3.0 g/dL)
  19. eGFR < 30 mL/min/1.73m2
  20. G6PD deficiency. In males of African, Asian or Mediterranean decent, this will be formally evaluated by enzyme testing prior to drug administration. A negative screening test for G6PD will be required in these subjects for inclusion in the study. If a quantitative test is being performed, a clinically significant reduction in G6PD activity (<60% of normal) will exclude subjects.
  21. Methemoglobinemia - baseline methemoglobin level >5%
  22. Serum K>5.0 mEq/L
  23. Severe right ventricular dysfunction
  24. Any medical condition that, in the opinion of the investigator, will interfere with the safe completion of the study.
  25. Contraindications to MRI (except as noted below), including the presence of a pacemaker, metal implants, claustrophobia, or that have known medical conditions which can be exacerbated by stress such as anxiety or panic attacks. Inability to lie flat in the MRI scanner for 90 minutes is also an exclusion criterion.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 90 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Julio A Chirinos, MD, PhD julio.chirinos@uphs.upenn.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02840799
Other Study ID Numbers  ICMJE 824290
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University of Pennsylvania
Study Sponsor  ICMJE University of Pennsylvania
Collaborators  ICMJE Northwestern University
Investigators  ICMJE
Study Chair: Julio A Chirinos, MD, PhD University of Pennsylvania
Principal Investigator: Payman Zamani, MD University of Pennsylvania
Principal Investigator: Sanjiv Shah, MD Northwestern University
Principal Investigator: Sujith Kuruvilla, MD Corporal Michael J Crescenz Veterans Affairs Medical Center (VA)
PRS Account University of Pennsylvania
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP