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

Heart Failure Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02256345
• Other study ID #: 01340
• Status: Completed
• Phase: Phase 2
• First received: September 30, 2014
• Last updated: August 30, 2017
• Start date: January 2015
• Est. completion date: June 2016

Study information

• Verified date: August 2017
• Source: University of Pennsylvania
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: June 2016
• Est. primary completion date: June 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Diastolic Heart Failure
• Heart Failure
• Heart Failure, Diastolic

Intervention

Drug:
• KNO3
Active Comparator
• KCl
Placebo Comparator

Locations

Country	Name	City	State
United States	Hospital of the 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
Primary	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	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
Secondary	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
Secondary	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