Matching Perfusion and Metabolic Activity in HFpEF (MPMA)

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).

Study Overview

• Status: Recruiting
• Conditions: Heart Failure With Preserved Ejection Fraction
• Intervention / Treatment: Drug: Potassium Nitrate; Drug: Potassium Nitrate + Propionyl-L-Carnitine + Nicotinamide Riboside; Other: Potassium Chloride

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)

• Study Type: Interventional
• Enrollment (Estimated): 53
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Payman Zamani, MD; Phone Number: ‭(215) 615-0800‬; Email: payman.zamani@pennmedicine.upenn.edu

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • University of Pennsylvania
      • Contact: Nicole Tafuna'i; Phone Number: 801-831-1044; Email: Nicole.Tafunai@Pennmedicine.upenn.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. NYHA Class II-III symptoms
2. Left ventricular ejection fraction >= 50%
3. Stable medical therapy for at least 1 month

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
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. Orthostatic blood pressure response to the transition from supine to standing (>20 mmHg reduction in systolic blood pressure 2-3 minutes after standing)
23. Active participation in another study that utilizes an investigational agent (observational studies/registries allowed)
24. Any condition that, in the opinion of the investigator, will interfere with the performance and completion of the study.
25. Contraindications to MRI

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Potassium Nitrate; Potassium Nitrate (KNO3) 6 mmol three times daily	Drug: Potassium Nitrate; Potassium Nitrate is the active intervention that may increase blood flow to exercising muscle; Other Names: KNO3
Active Comparator: 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	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); Other Names: KNO3 + PLC + NR
Placebo Comparator: Potassium Chloride; Potassium Chloride (KCl) 6 mmol three times daily	Other: Potassium Chloride; Active control; Other Names: PCl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Submaximal Exercise Endurance	Time to exhaustion while exercising at 75% of peak workload	week 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Skeletal muscle oxidative capacity	MRI assessment of skeletal muscle oxidative phosphorylation capacity	week 6
Vasodilatory Reserve	Percent change in systemic vascular resistance at baseline vs exhaustion	week 6
Kansas City Cardiomyopathy Questionnaire Overall Summary Score	Assess the impact of our interventions on quality of life	week 6
VO2 Kinetics	Assess the impact of our interventions on the kinetics of oxygen consumption (VO2 kinetics) during exercise and recovery "On" and "Off" kinetics will be modeled during the submaximal exercise transient	week 6
Peak VO2	maximal rate of oxygen consumption determined during the last 30s of exercise.	week 6
Steps per day	we will use actigraphy to document the average number of steps taken per day during the final week of each interventional period. Assess the impact of our interventions on ambulatory physical activity	week 6
Skeletal muscle perfusion	MRI assessment of skeletal muscle oxidative phosphorylation capacity	week 6

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Skeletal Muscle Oxidative Capacity	The change in MRI skeletal muscle oxidative phosphorylation capacity between assessments while breathing room air versus 100% inspired oxygen	<4 hours in between MRIs

Collaborators and Investigators

• Sponsor: University of Pennsylvania

Study record dates

Study Major Dates

• Study Start (Actual): October 11, 2021
• Primary Completion (Estimated): January 31, 2026
• Study Completion (Estimated): January 31, 2026

Study Registration Dates

• First Submitted: April 19, 2021
• First Submitted That Met QC Criteria: May 30, 2021
• First Posted (Actual): June 4, 2021

Study Record Updates

• Last Update Posted (Actual): June 23, 2023
• Last Update Submitted That Met QC Criteria: June 20, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Antimetabolites; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Vitamins; Vitamin B Complex; Nicotinic Acids; Niacinamide; Niacin
• Other Study ID Numbers: 844627

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No