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

Study Overview
=================
Brief 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: Determine the population-specific pharmacokinetics and dose of KNO3 that can be safely given to subjects with HFpEF. 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.

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.

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

Conditions
-----------------
Heart Failure, Diastolic Heart Failure

Intervention / Treatment
-----------------
* Drug: KNO3
* Drug: KCl


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: NYHA Class II-III symptoms. LV EF > 50%. Stable medical therapy for at least 1 month. Evidence of significant diastolic dysfunction, meeting the European Society of Echocardiography criteria for HFpEF. Exclusion Criteria Any rhythm other than sinus with native conduction. Inability to exercise. Moderate or greater valvular disease. Hypertrophic, infiltrative, or inflammatory cardiomyopathy. Pericardial disease. Current angina. Acute coronary syndrome or coronary intervention within the past 2 months. Primary pulmonary arteriopathy. Clinically significant lung disease. Ischemia on stress testing without subsequent revascularization. Treatment with phosphodiesterase inhibitors that cannot be withheld. Treatment with organic nitrates or allopurinol. Significant liver disease impacting synthetic function or volume control. Poor echocardiographic windows. eGFR < 30 mL/min/m2 or Cr >2.5. Current smoking. Alcohol dependency. History of Barret's esophagus. G6PD deficiency Methemoglobinemia - baseline methemoglobin level >3% prior to any study medication.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: KNO3 active comparator<br>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<br>* Active Comparator<br>* Other names: Potassium Nitrate;|
| Placebo Comparator: KCl placebo comparator<br>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<br>* Placebo Comparator<br>* 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 |