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

NCT ID: NCT02840799

Last Updated: 2023-12-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 84 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-08-31
• Study Completion Date: 2022-08-31

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.

Conditions

Heart Failure

Keywords

Heart Failure; Exercise Intolerance; Ejection Fraction

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Potassium Nitrate (KNO3)

Potassium nitrate (KNO3) capsules, providing 6 millimoles of inorganic nitrate per capsule, to be taken three times daily for 6 weeks.

Group Type: EXPERIMENTAL

Potassium Nitrate (KNO3)

Intervention Type: DRUG

The effect of potassium nitrate (KNO3) supplementation on exercise capacity and peak oxygen consumption in HFpEF will be assessed.

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.

Group Type: PLACEBO_COMPARATOR

Potassium Chloride (KCl)

Intervention Type: DRUG

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

Interventions

Potassium Nitrate (KNO3)

The effect of potassium nitrate (KNO3) supplementation on exercise capacity and peak oxygen consumption in HFpEF will be assessed.

Intervention Type: DRUG

Potassium Chloride (KCl)

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

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 90 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Northwestern University

OTHER

Sponsor Role: collaborator

University of Pennsylvania

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Julio A Chirinos, MD, PhD

Role: STUDY_CHAIR

University of Pennsylvania

Payman Zamani, MD

Role: PRINCIPAL_INVESTIGATOR

University of Pennsylvania

Sanjiv Shah, MD

Role: PRINCIPAL_INVESTIGATOR

Northwestern University

Sujith Kuruvilla, MD

Role: PRINCIPAL_INVESTIGATOR

Corporal Michael J Crescenz Veterans Affairs Medical Center (VA)

Locations

Northwestern Medical Center

Evanston, Illinois, United States

Corporal Michael J Crescenz Veterans Affairs Medical Center (VA)

Philadelphia, Pennsylvania, United States

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, United States

Countries

United States

References

Zamani P, Shah SJ, Cohen JB, Zhao M, Yang W, Afable JL, Caturla M, Maynard H, Pourmussa B, Demastus C, Mohanty I, Miyake MM, Adusumalli S, Margulies KB, Prenner SB, Poole DC, Wilson N, Reddy R, Townsend RR, Ischiropoulos H, Cappola TP, Chirinos JA. Potassium Nitrate in Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial. JAMA Cardiol. 2025 Mar 1;10(3):284-289. doi: 10.1001/jamacardio.2024.4417.

Reference Type: DERIVED

PMID: 39693096 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

824290

Identifier Type: -

Identifier Source: org_study_id