Matching Perfusion and Metabolic Activity in HFpEF

NCT ID: NCT04913805

Last Updated: 2025-05-23

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 53 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-10-11
• Study Completion Date: 2027-05-01

Brief Summary

This study will test whether pharmacologic agents that increase perfusion [Potassium Nitrate (KNO3)], with and without additional supplements that may improve mitochondrial function [Propionyl-L-Carnitine (PLC) and Nicotinamide Riboside (NR)], improve submaximal exercise endurance and skeletal muscle oxidative phosphorylation capacity (SkM OxPhos) in participants with Heart Failure with Preserved Ejection Fraction (HFpEF).

Detailed Description

This study will test whether Potassium Nitrate (KNO3), with and without Propionyl-L-Carnitine (PLC) and Nicotinamide Riboside (NR), improves submaximal exercise endurance and skeletal muscle oxidative phosphorylation capacity (SkM OxPhos) in participants with Heart Failure with Preserved Ejection Fraction (HFpEF). Additionally, the study will test whether the response to supplemental oxygen during a standardized MRI assessment of skeletal muscle oxidative capacity can identify HFpEF individuals who preferentially will benefit from either KNO3 alone or the combination of pharmacologic agents (KNO3 + PLC + NR)

Conditions

Heart Failure With Preserved Ejection Fraction

Study Design

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

Study Groups

Potassium Nitrate

Potassium Nitrate (KNO3) 6 mmol three times daily

Group Type: ACTIVE_COMPARATOR

Potassium Nitrate

Intervention Type: DRUG

Potassium Nitrate is the active intervention that may increase blood flow to exercising muscle

Potassium Nitrate + Propionyl-L-Carnitine + Nicotinamide Riboside

Potassium Nitrate (KNO3) 6 mmol three times daily + Propionyl-L-Carnitine (PLC) 1000 mg twice daily + Nicotinamide Riboside (NR) 300 mg three times daily

Group Type: ACTIVE_COMPARATOR

Potassium Nitrate + Propionyl-L-Carnitine + Nicotinamide Riboside

Intervention Type: DRUG

Potassium Nitrate + Propionyl-L-Carnitine + Nicotinamide Riboside will be used as a combination intervention to both increase blood flow (KNO3) and mitochondrial function (PLC + NR)

Potassium Chloride

Potassium Chloride (KCl) 6 mmol three times daily

Group Type: PLACEBO_COMPARATOR

Potassium Chloride

Intervention Type: OTHER

Active control

Interventions

Potassium Nitrate

Potassium Nitrate is the active intervention that may increase blood flow to exercising muscle

Intervention Type: DRUG

Potassium Nitrate + Propionyl-L-Carnitine + Nicotinamide Riboside

Potassium Nitrate + Propionyl-L-Carnitine + Nicotinamide Riboside will be used as a combination intervention to both increase blood flow (KNO3) and mitochondrial function (PLC + NR)

Intervention Type: DRUG

Potassium Chloride

Active control

Intervention Type: OTHER

Other Intervention Names

KNO3; KNO3 + PLC + NR; PCl

Eligibility Criteria

Inclusion Criteria

1. NYHA Class II-III symptoms

2. Left ventricular ejection fraction >= 50%

3. Stable medical condition for at least 2 weeks, as per investigator judgment

4. Prior or current evidence for elevated filling pressures as follows:

a. Mitral early (E)/mitral septal tissue annular (e') velocity ratio > 8, in the context of a septal e' velocity <=7, in addition to one of the following: i. Large left atrium (LA volume index > 34 mL/m2) ii. Chronic loop diuretic use for control of symptoms iii. Elevated natriuretic peptides within the past year (e.g. NTproBNP > 125 pg/mL in sinus rhythm or > 375 pg/mL if in atrial fibrillation) b. Mitral E/e' ratio > 14 at rest or during exercise c. Elevated invasively-determined filling pressures previously (resting left ventricular end-diastolic pressure >= 16 mm Hg or pulmonary capillary wedge pressure >= 15 mmHg; or PCWP/LVEDP >= 25 mmHg with exercise) d. Prior episode of acute heart failure requiring IV diuretics

Exclusion Criteria

1. Age <18 years old

2. Pregnancy:

3. Treatment with organic nitrates or phosphodiesterase inhibitors that cannot be interrupted

4. Uncontrolled atrial fibrillation, as defined by a resting heart rate > 100 beats per minute at the time of the baseline assessment

5. Hemoglobin < 10 g/dL

6. Subject inability/unwillingness to exercise

7. Moderate or greater left sided valvular disease (mitral regurgitation, aortic stenosis, aortic regurgitation), mild or greater mitral stenosis, severe right-sided valvular disease

8. Known hypertrophic, infiltrative, or inflammatory cardiomyopathy

9. Clinically significant pericardial disease, as per investigator judgment

10. Current angina due to clinically significant epicardial coronary disease, as per investigator judgment

11. Acute coronary syndrome or coronary intervention within the past 2 months

12. Primary pulmonary artery hypertension (WHO Group 1 Pulmonary Arterial Hypertension)

13. Clinically significant lung disease as defined by: Chronic Obstructive Pulmonary Disease meeting Stage III or greater GOLD criteria (FEV1<50%), treatment with oral steroids within the past 6 months for an exacerbation of obstructive lung disease, current use of supplemental oxygen aside from nocturnal oxygen for the treatment of obstructive sleep apnea, desaturation to <90% on the baseline maximal effort cardiopulmonary exercise test

14. Clinically-significant ischemia, as per investigator's judgement, on stress testing without either (1) subsequent revascularization, (2) an angiogram demonstrating the absence of clinically significant epicardial coronary artery disease, as per investigator judgment; (3) a follow-up 'negative' stress test, particularly when using a more specific technique (i.e., a negative perfusion imaging test following a 'positive' ECG stress test)

15. Left ventricular ejection fraction < 45% on a prior echocardiogram or cardiac MRI, unless the reduced LVEF occurred within the context of an uncontrolled supraventricular arrhythmia, with return of a normal ejection fraction following treatment of the arrhythmia

16. Significant liver disease impacting synthetic function or volume control (ALT/AST > 3x ULN, Albumin < 3.0 g/dL)

17. eGFR < 30 mL/min/1.73m^2

18. Methemoglobin > 5%

19. Serum potassium > 5.0 mEq/L

20. Severe right ventricular dysfunction

21. Baseline resting seated systolic blood pressure > 180 mmHg or < 100 mmHg

22. Persistently low (<100 mmHg) or high (>180 mmHg) seated blood pressure at the baseline visit

23. Orthostatic blood pressure response to the transition from supine to standing (>20 mmHg reduction in systolic blood pressure 2-3 minutes after standing)

24. Active participation in another study that utilizes an investigational agent (observational studies/registries allowed)

25. Any condition that, in the opinion of the investigator, will interfere with the performance and completion of the study.

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

Sponsors

University of Pennsylvania

OTHER

Sponsor Role: lead

Responsible Party

Payman Zamani, MD

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Payman Zamani, MD

Role: PRINCIPAL_INVESTIGATOR

University of Pennsylvania

Locations

University of Pennsylvania

Philadelphia, Pennsylvania, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Melissa Fernand, MPH

Role: CONTACT

fernand@pennmedicine.upenn.edu

2672536141

Cassandra Demastus, NP

Role: CONTACT

Cassandra.Demastus@Pennmedicine.upenn.edu

4432719022

Facility Contacts

Cassandra Demastus, NP

Role: primary

Cassandra.Demastus@Pennmedicine.upenn.edu

443-271-9022

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

844627

Identifier Type: -

Identifier Source: org_study_id