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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

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.

Condition or disease Intervention/treatment Phase
Heart Failure Diastolic Heart Failure Drug: KNO3 Drug: KCl Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: Pharmacokinetics, Pharmacodynamics, and Impact of Inorganic Nitrate on Exercise in HFpEF
Study Start Date : January 2015
Actual Primary Completion Date : June 2016
Actual Study Completion Date : June 2016

Resource links provided by the National Library of Medicine


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 Name: 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 Name: Potassium Chloride




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02256345


Locations
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United States, Pennsylvania
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
University of Pennsylvania
Investigators
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Principal Investigator: Julio A Chirinos, MD University of Pennsylvania
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT02256345    
Other Study ID Numbers: 01340
First Posted: October 3, 2014    Key Record Dates
Results First Posted: October 3, 2017
Last Update Posted: October 3, 2017
Last Verified: August 2017
Additional relevant MeSH terms:
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Heart Failure
Heart Failure, Diastolic
Heart Diseases
Cardiovascular Diseases