Matching Perfusion and Metabolic Activity in HFpEF

Heart Failure With Preserved Ejection Fraction Clinical Trial

— MPMA  

Official title:

Matching Perfusion and Metabolic Activity in HFpEF

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04913805
• Other study ID #: 844627
• Status: Recruiting
• Phase: Phase 2
• Start date: October 11, 2021
• Est. completion date: January 31, 2026

Study information

• Verified date: June 2023
• Source: University of Pennsylvania
• Contact: Payman Zamani, MD
• Phone: ?(215) 615-0800?
• Email: payman.zamani[@]pennmedicine.upenn.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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)

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 53
• Est. completion date: January 31, 2026
• Est. primary completion date: January 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure With Preserved Ejection Fraction

Intervention

Drug:
• Potassium Nitrate
Potassium Nitrate is the active intervention that may increase blood flow to exercising muscle
• 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:
• Potassium Chloride
Active control

Locations

Country	Name	City	State
United States	University of Pennsylvania	Philadelphia	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
University of Pennsylvania

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Primary	Submaximal Exercise Endurance	Time to exhaustion while exercising at 75% of peak workload	week 6
Secondary	Skeletal muscle oxidative capacity	MRI assessment of skeletal muscle oxidative phosphorylation capacity	week 6
Secondary	Vasodilatory Reserve	Percent change in systemic vascular resistance at baseline vs exhaustion	week 6
Secondary	Kansas City Cardiomyopathy Questionnaire Overall Summary Score	Assess the impact of our interventions on quality of life	week 6
Secondary	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
Secondary	Peak VO2	maximal rate of oxygen consumption determined during the last 30s of exercise.	week 6
Secondary	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
Secondary	Skeletal muscle perfusion	MRI assessment of skeletal muscle oxidative phosphorylation capacity	week 6