Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02256345
Recruitment Status : Completed
First Posted : October 3, 2014
Results First Posted : October 3, 2017
Last Update Posted : October 3, 2017
Sponsor:
Information provided by (Responsible Party):
University of Pennsylvania

Tracking Information
First Submitted Date  ICMJE September 30, 2014
First Posted Date  ICMJE October 3, 2014
Results First Submitted Date  ICMJE June 14, 2017
Results First Posted Date  ICMJE October 3, 2017
Last Update Posted Date October 3, 2017
Study Start Date  ICMJE January 2015
Actual Primary Completion Date June 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 30, 2017)
Change in Peak Oxygen Uptake (VO2) From Baseline Upto 1 Week of Administration for Each Dose [ Time Frame: Baseline, end of week 1, end of week 2 ]
Peak oxygen uptake (VO2) defined as the average value obtained during the last 30 seconds of exercise.
Original Primary Outcome Measures  ICMJE
 (submitted: September 30, 2014)
Change in peak VO2 from baseline to the end of 1 week of administration for each dose [ Time Frame: 1 week ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 30, 2017)
  • Change in Vasodilatory Reserve for Each Dose [ Time Frame: Baseline, end of week 1, end of week 2 ]
    Percent change in peak vascular resistance from rest to peak exercise
  • Change in Mitochondrial Oxidative Capacity for Each Dose [ Time Frame: Baseline, end of week 1, end of week 2 ]
    Percent change in oxidative capacity (oxyhemoglobin levels) before and after occlusion
  • Change in Aortic Augmentation Index [ Time Frame: Baseline, end of week 1, end of week 2 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 30, 2014)
  • Change in Vasodilatory Reserve for Each Dose [ Time Frame: 1 week ]
  • Change in Mitochondrial Oxidative Capacity for Each Dose [ Time Frame: 1 week ]
  • Change in Aortic Augmentation Index [ Time Frame: 1 week ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pharmacokinetics, Pharmacodynamics, and Impact of Inorganic Nitrate on Exercise in HFpEF
Official Title  ICMJE Pharmacokinetics, Pharmacodynamics, and Impact of Inorganic Nitrate on Exercise in HFpEF
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:

  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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Condition  ICMJE
  • Heart Failure
  • Diastolic Heart Failure
Intervention  ICMJE
  • Drug: KNO3
    Active Comparator
    Other Name: Potassium Nitrate
  • Drug: KCl
    Placebo Comparator
    Other Name: Potassium Chloride
Study Arms  ICMJE
  • 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
    Intervention: Drug: KNO3
  • 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
    Intervention: Drug: KCl
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 30, 2014)
12
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE June 2016
Actual Primary Completion Date June 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02256345
Other Study ID Numbers  ICMJE 01340
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University of Pennsylvania
Study Sponsor  ICMJE University of Pennsylvania
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Julio A Chirinos, MD University of Pennsylvania
PRS Account University of Pennsylvania
Verification Date August 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP