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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 : November 27, 2017
Sponsor:
Collaborator:
Northwestern University
Information provided by (Responsible Party):
University of Pennsylvania

June 13, 2016
July 21, 2016
November 27, 2017
August 2016
December 2019   (Final data collection date for primary outcome measure)
  • 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.
Same as current
Complete list of historical versions of study NCT02840799 on ClinicalTrials.gov Archive Site
  • 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) ]
Same as current
Not Provided
Not Provided
 
Effect of KNO3 Compared to KCl on Oxygen UpTake in Heart Failure With Preserved Ejection Fraction (KNO3CK OUT HFPEF)
Effect of KNO3 Compared to KCl on Oxygen UpTake in Heart Failure With Preserved Ejection Fraction (KNO3CK OUT HFPEF)
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).
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.
Interventional
Phase 2
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Heart Failure
  • 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.
  • 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)
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
76
Same as current
December 2019
December 2019   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • A diagnosis of heart failure with New York Heart Association (NYHA) Class II-III symptoms
  • LV ejection fraction >50% during baseline echocardiography
  • Stable medical therapy: no addition/removal/changes in antihypertensive medications, or beta-blockers in the preceding 30 days.
  • Elevated filling pressures as evidenced by at least 1 of the following within the last 12 months:
  • (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:
  • (a) Enlarged left atrium (LA volume index >34 ml/m2)
  • (b) Chronic loop diuretic use for control of symptoms
  • (c) Elevated natriuretic peptides (BNP levels >100 ng/L or N-terminal prohormone of brain natiuretic peptide (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 > 12 mmHg).
  • (4) Acute heart failure decompensation requiring IV diuretics

Exclusion Criteria:

  • Supine systolic blood pressure <100 mm Hg
  • Pregnancy. Women of childbearing potential will undergo a pregnancy test during the screening visit
  • Orthostatic hypotension defined as >20 mm Hg decrease in systolic blood pressure 3-5 minutes following the transition from the supine to standing position
  • Any rhythm other than sinus with native conduction at the time of screening, based on a 12-lead ECG. Patients with paroxysmal atrial fibrillation can be enrolled as long as their rhythm is sinus at the time of enrollment.
  • Hemoglobin < 10 g/dL
  • Inability/unwillingness to exercise
  • 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.
  • Hypertrophic, infiltrative, or inflammatory cardiomyopathy
  • Pericardial disease
  • Current angina
  • Acute coronary syndrome or coronary intervention within the past 2 months
  • Primary pulmonary arteriopathy
  • Clinically significant lung disease as defined by: Chronic Obstructive pulmonary disease meeting Stage III or greater Global initiative for Chronic Obstructive Pulmonary Disease (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
  • Ischemia on stress testing without subsequent revascularization
  • Left ventricular ejection fraction <45% in any prior echocardiogram or cardiac MRI.
  • Treatment with phosphodiesterase inhibitors that cannot be withheld
  • Treatment with organic nitrates or allopurinol
  • Significant liver disease impacting synthetic function or volume control (ALT/AST: Aspartate Aminotransferase) > 3x ULN (upper limit of normal), Albumin <3.0 g/dL)
  • Estimated Glomerular Filtration Rate (eGFR) < 30 mL/min/1.73m2
  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency. In males of African, Asian or Mediterranean decent, this will be formally excluded prior to enrollment.
  • Methemoglobinemia - baseline methemoglobin level >5%
  • Hyperkalemia (serum K>5.0 mEq/L). (note: mEq=milliequivalent)
  • Severe right ventricular dysfunction.
  • Any medical condition that, in the opinion of the investigator, will interfere with the safe completion of the study.

Participants who have contraindications for MRI but are otherwise good candidates for the study, may be enrolled. In this case, participants will undergo all study procedures except for the MRI scans.

Sexes Eligible for Study: All
19 Years and older   (Adult, Older Adult)
No
Contact: Julio A Chirinos, MD, PhD julio.chirinos@uphs.upenn.edu
United States
 
 
NCT02840799
824290
Yes
Not Provided
Plan to Share IPD: No
University of Pennsylvania
University of Pennsylvania
Northwestern University
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)
University of Pennsylvania
June 2017

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