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

NCT02840799 | Completed Phase 2 Results DMC

• 1 other identifier: 824290
• Study Type: interventional
• Target: 84
• Locations: 1 country
• Sites: 3

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).

Conditions

Heart Failure

Keywords

Heart Failure; Exercise Intolerance; Ejection Fraction

Outcome Measures

Primary Outcomes (2)

• Difference in Peak Oxygen Consumption (Vo2) Between KNO3 and KCl Phases

  Subjects will perform a maximal-effort peak oxygen consumption test using a supine bicycle exercise test with expired gas analysis.

  6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)

• Change in Total Work Performed During a Maximal-effort Exercise Test From Phase 1 to Phase 2

  Subjects will perform a maximal-effort supine bicycle exercise test.

  6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)

Secondary Outcomes (11)

• Effect of Potassium Nitrate (KNO3) on Quality of Life (QOL)

  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 KNO3 on the Percent Change of Systemic Vasodilatory Response to Exercise: The Change in Systemic Vascular Resistance Reserve During Exercise During a Maximal Effort Exercise Test

  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 Phosphocreatine (PCr) Recovery Kinetics Following a Standardized Plantar Flexor Exercise Protocol

  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

  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

  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)

Study Arms (2)

Potassium Nitrate (KNO3)

EXPERIMENTAL

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

Drug: Potassium Nitrate (KNO3)

Potassium Chloride (KCl)

PLACEBO COMPARATOR

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.

Drug: Potassium Chloride (KCl)

Interventions

Potassium Nitrate (KNO3) DRUG

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

Potassium Nitrate (KNO3)

Potassium Chloride (KCl) DRUG

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

Potassium Chloride (KCl)

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults aged 18-90 years of age
• A diagnosis of heart failure with 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:
• 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)
• Mitral E/e' ratio \> 14 (either lateral or septal)
• 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)
• Acute heart failure decompensation requiring IV diuretics

You may not qualify if:

• 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
• Uncontrolled atrial fibrillation, as defined by a resting heart rate\>100 beats per minute
• 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 in the mitral position
• Hypertrophic, infiltrative, or inflammatory cardiomyopathy
• Clinically significant pericardial disease, as per investigator judgement.
• 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 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 either (1) subsequent revascularization, or; (2) a subsequent angiogram demonstrating the absence of clinically significant epicardial coronary artery disease, as per investigator judgement.
• Left ventricular ejection fraction \<45% in any prior echocardiogram or cardiac MRI, unless this was in the setting of uncontrolled atrial fibrillation.

Sponsors & Collaborators

• University of Pennsylvania: lead
• Northwestern University: collaborator

Study Sites (3)

Northwestern Medical Center

Evanston, Illinois, 60208, United States

Location

Corporal Michael J Crescenz Veterans Affairs Medical Center (VA)

Philadelphia, Pennsylvania, 19104, United States

Location

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (1)

• 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.

  PMID: 39693096 DERIVED

MeSH Terms

Conditions

Heart Failure

Interventions

potassium nitrate; Potassium, Dietary

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Potassium Compounds; Inorganic Chemicals

Limitations and Caveats

Due to dispensing errors, nine participants didn't crossover. Overall study power was maintained. MRI completion varied across sites, leading to the discontinuation of this study component. MRI endpoints have a smaller N; interpret results cautiously. Myocardial circumferential strain wasn't quantified. Instead, longitudinal LV function, crucial for LV relaxation and filling, was quantified.

Results Point of Contact

• Title: Hannah Maynard
• Organization: University of Pennsylvania

hannah.maynard@pennmedicine.upenn.edu

215-662-7580

Study Officials

• Julio A Chirinos, MD, PhD

  University of Pennsylvania

  STUDY CHAIR

• 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)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 13, 2016
• First Posted: July 21, 2016
• Study Start: August 1, 2016
• Primary Completion: August 1, 2022
• Study Completion: August 1, 2022
• Last Updated: December 18, 2023
• Results First Posted: December 18, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)