Pharmacokinetics, Pharmacodynamics, and Impact of Inorganic Nitrate on Exercise in HFpEF

This study will be performed to determine the safety, tolerability, and dose-response to inorganic nitrate on exercise capacity in HFpEF. There are two primary goals for this study:

1. Determine the population-specific pharmacokinetics and dose of KNO3 that can be safely given to subjects with HFpEF.
2. Determine if there is a dose-response effect of nitrate supplementation on exercise capacity, evidenced by peak oxygen consumption (peak VO2), and physiologic adaptations to exercise.

Study Overview

• Status: Completed
• Conditions: Heart Failure; Diastolic Heart Failure
• Intervention / Treatment: Drug: KNO3; Drug: KCl

Detailed Description

This study randomized subjects to either placebo (n=3) or KNO3 (n=9) given a sequential dosing regimen: 6 mmol twice daily for 1 week followed by dose escalation to 6 mmol thrice daily for 1 week). Although a primary goal of the study was to assess the safety of KNO3 and within-group changes in various end points in KNO3-treated subjects, a small number of placebo-treated (PB, n=3) subjects were included only to assess for any potential training effect on repeated exercise and Kansas City Cardiomyopathy Questionnaire (KCCQ) measurements. Potassium chloride, given in equivalent doses, was used as the PB to account for differences in blood pressure or flow that could be attributed to potassium.

The study was initially designed to be single-blinded to allow the principal investigator to be aware of arm allocation because of potential concerns for methemoglobinemia with drug administration. One investigator, who was the primary investigator responsible for supervising all visits and measurements during the study, remained blinded to treatment allocation throughout the entirety of the study. All physiological and imaging data were analyzed in a double-blind manner.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. NYHA Class II-III symptoms.
2. LV EF > 50%.
3. Stable medical therapy for at least 1 month.
4. Evidence of significant diastolic dysfunction, meeting the European Society of Echocardiography criteria for HFpEF.

Exclusion Criteria

1. Any rhythm other than sinus with native conduction.
2. Inability to exercise.
3. Moderate or greater valvular disease.
4. Hypertrophic, infiltrative, or inflammatory cardiomyopathy.
5. Pericardial disease.
6. Current angina.
7. Acute coronary syndrome or coronary intervention within the past 2 months.
8. Primary pulmonary arteriopathy.
9. Clinically significant lung disease.
10. Ischemia on stress testing without subsequent revascularization.
11. Treatment with phosphodiesterase inhibitors that cannot be withheld.
12. Treatment with organic nitrates or allopurinol.
13. Significant liver disease impacting synthetic function or volume control.
14. Poor echocardiographic windows.
15. eGFR < 30 mL/min/m2 or Cr >2.5.
16. Current smoking.
17. Alcohol dependency.
18. History of Barret's esophagus.
19. G6PD deficiency
20. Methemoglobinemia - baseline methemoglobin level >3% prior to any study medication.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: KNO3 active comparator; KNO3 will be given at a dose of 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated	Drug: KNO3; Active Comparator; Other Names: Potassium Nitrate
Placebo Comparator: KCl placebo comparator; KCl will be used as a placebo and will be given as 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated	Drug: KCl; Placebo Comparator; Other Names: Potassium Chloride

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Peak Oxygen Uptake (VO2) From Baseline Upto 1 Week of Administration for Each Dose	Peak oxygen uptake (VO2) defined as the average value obtained during the last 30 seconds of exercise.	Baseline, end of week 1, end of week 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Vasodilatory Reserve for Each Dose	Percent change in peak vascular resistance from rest to peak exercise	Baseline, end of week 1, end of week 2
Change in Mitochondrial Oxidative Capacity for Each Dose	Percent change in oxidative capacity (oxyhemoglobin levels) before and after occlusion	Baseline, end of week 1, end of week 2
Change in Aortic Augmentation Index	Percent change in augmentation index, whereas augmentation index at each time point (visit) is defined as the amplitude of the second peak to the first peak of the aortic pulse wave form multiplied by 100: augmentation index = (P2/P1)×100.	Baseline, end of week 1, end of week 2

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Investigators: Principal Investigator: Julio A Chirinos, MD, University of Pennsylvania

Publications and helpful links

General Publications

• Zamani P, Tan V, Soto-Calderon H, Beraun M, Brandimarto JA, Trieu L, Varakantam S, Doulias PT, Townsend RR, Chittams J, Margulies KB, Cappola TP, Poole DC, Ischiropoulos H, Chirinos JA. Pharmacokinetics and Pharmacodynamics of Inorganic Nitrate in Heart Failure With Preserved Ejection Fraction. Circ Res. 2017 Mar 31;120(7):1151-1161. doi: 10.1161/CIRCRESAHA.116.309832. Epub 2016 Dec 7.

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Actual): June 1, 2016
• Study Completion (Actual): June 1, 2016

Study Registration Dates

• First Submitted: September 30, 2014
• First Submitted That Met QC Criteria: September 30, 2014
• First Posted (Estimate): October 3, 2014

Study Record Updates

• Last Update Posted (Actual): October 3, 2017
• Last Update Submitted That Met QC Criteria: August 30, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Heart Failure, Diastolic
• Other Study ID Numbers: 01340