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Targeting Pulsatile Load to Increase Exercise Capacity and Quality of Life After Aortic Valve Replacement for Severe Aortic Stenosis (PULSE AS) (PULSE-AS)

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: NCT03483051
Recruitment Status : Completed
First Posted : March 29, 2018
Results First Posted : March 11, 2020
Last Update Posted : June 17, 2020
Sponsor:
Information provided by (Responsible Party):
University of Pennsylvania

Brief Summary:
The current trial is designed to assess the safety and efficacy of sustained oral administration of inorganic nitrate in patients with severe aortic stenosis and to assess the mechanisms by which inorganic nitrate enhances oxygen uptake and exercise capacity in this population.

Condition or disease Intervention/treatment Phase
Aortic Valve Stenosis Drug: Potassium Nitrate Drug: Potassium Chloride Phase 2

Detailed Description:
This is a randomized double-blind crossover clinical trial, in which 22 subjects who underwent transcatheter aortic valve replacement (TAVR) for severe aortic stenosis (AS) three or more months prior to enrollment will receive the following 2 interventions, in randomized order: (1) Potassium nitrate (KNO3), at a dose of 12-18 mmol/d by mouth for 4 weeks, or; (2) Potassium chloride (KCl), at a dose of 12-18 mmol/d by mouth for 4 weeks. A 1-week washout period will be introduced between the 2 interventions. The purpose of the trial is to test the safety of KNO3 and its efficacy on a number of clinical and physiologic endpoints in subjects who underwent TAVR for severe AS.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: In this phase IIb, double-blind, cross-over trial, we will assign 22 subjects who are post-TAVR for severe AS to: (A) Potassium nitrate administered by mouth at a dose of 6 mEq three times daily for 4 weeks, or (B) Potassium chloride (KCl) at identical doses. The order of the interventions (AB-BA design) will be randomized, with a 1-week washout period separating each intervention. A crossover design will enable each subject to receive both treatments.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Targeting Pulsatile Load to Increase Exercise Capacity and Quality of Life After Aortic Valve Replacement for Severe Aortic Stenosis (PULSE AS)
Actual Study Start Date : May 1, 2018
Actual Primary Completion Date : March 13, 2019
Actual Study Completion Date : May 23, 2019


Arm Intervention/treatment
Experimental: Potassium Nitrate (KNO3)
Capsules containing 18 mmoles of KNO3 per day, given as one capsule (6 mmoles) three times a day for 4 weeks.
Drug: Potassium Nitrate
Potassium nitrate capsules will consist of potassium nitrate (KNO3-) crystals [610 mg, corresponding to 6.03 mmoles of NO3-] with 190mg of lactose monohydrate, spray dried, NF. The dose for this trial will be 18 mmoles of NO3-per day, given as one capsule (6 mmoles) three times a day.

Sham Comparator: Potassium Chloride
Capsules containing 18 mmoles of KCl per day, given as one capsule (6 mmoles) three times a day for 4 weeks.
Drug: Potassium Chloride
Potassium chloride capsules will consist of potassium chloride (KCl), granular, USP (450mg) plus lactose monohydrate, spray dried, NF (300mg). The dose for this trial will be 18 mmoles of KCl per day, given as one capsule (6 mmoles) three times a day.




Primary Outcome Measures :
  1. Total Work Performed During a Maximal-effort Exercise Test [ Time Frame: 9 weeks ]
    The effect of KNO3 on exercise capacity, quantified as Total work performed during a maximal-effort exercise test;

  2. Peak Oxygen Uptake (VO2) During a Maximal Effort Exercise Test [ Time Frame: 9 weeks ]
    The effect of KNO3 on exercise capacity, quantified as: Peak oxygen consumption (VO2) during a symptom-limited maximal effort exercise test.

  3. Quality of Life Score [ Time Frame: 9 weeks ]
    The effect of KNO3 on quality of life, assessed using the Kansas City Cardiomyopathy Questionnaire.


Secondary Outcome Measures :
  1. Systemic Vasodilator Response to Exercise [ Time Frame: 9 weeks ]
    The effect of KNO3 on systemic vasodilator response, measured by change in systemic vascular resistance, during a symptom-limited maximal exercise test,

  2. Left Ventricle Diastolic Function [ Time Frame: 9 weeks ]
    The effect of KNO3 on left ventricle diastolic filling parameters (measured with echocardiography at rest and after peak exercise)

  3. Myocardial Systolic Strain [ Time Frame: 9 weeks ]
    The effect of KNO3 on myocardial strain (assessed with speckle-tracking echocardiography)

  4. Late Systolic Left Ventricle Load [ Time Frame: 9 weeks ]
    The effect of KNO3 on last systolic left ventricle load from wave reflections (assessed via comprehensive aortic pressure-flow regulations, using arterial tonometry and Doppler echocardiography)



Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Adults aged 50-90 years of age
  2. Diagnosis of severe aortic stenosis prior to aortic valve repair
  3. Successful trancatheter aortic valve repair via transfemoral procedural approach or successful surgical aortic valve repair at least three months prior to enrollment
  4. Stable medical therapy: no addition/removal/changes in anti-hypertensive medications, or beta-blockers in the preceding 30 days.

Exclusion Criteria

  1. Supine systolic blood pressure (SBP) < 100 mmHg OR supine diastolic blood pressure (DBP) <60 mmHg
  2. Poorly controlled hypertension, as defined as SBP > 160 mmHg OR DBP > 100 mmHg
  3. Pregnancy. Women of childbearing potential will undergo a pregnancy test during the screening visit
  4. Atrial fibrillation within the prior 8 weeks before enrollment
  5. Inability/unwillingness to exercise
  6. Moderate or greater mitral regurgitation or aortic/peri-valvular regurgitation, any degree of mitral stenosis, severe right-sided valvular disease, or presence of a mitral prosthetic valve.
  7. Moderate or severe patient prosthesis mismatch, as defined by Effective Orifice Area Index < 0.85 cm2/m2
  8. Hypertrophic, infiltrative, or inflammatory cardiomyopathy
  9. Pericardial disease
  10. Current angina
  11. Acute coronary syndrome or coronary intervention within the past 2 months
  12. Primary pulmonary arteriopathy
  13. Clinically significant lung disease as defined by: Chronic Obstructive pulmonary disease meeting Stage III or greater GOLD criteria, treatment with oral steroids within the past 6 months for an exacerbation of obstructive lung disease, or the use of daytime supplemental oxygen
  14. Ischemia on stress testing without subsequent revascularization (during the screening visit)
  15. Treatment with phosphodiesterase inhibitors that cannot be withheld
  16. Treatment with organic nitrates
  17. Significant liver disease impacting synthetic function or volume control (ALT/AST > 3x ULN, Albumin <3.0 g/dL)
  18. eGFR < 30 mL/min/1.73 m2
  19. G6PD deficiency. For males of African, Asian or Mediterranean decent, this will be evaluated prior to drug administration. A qualitative test positive for deficiency or a quantitative test with clinically significant G6PD deficiency (<60% of normal activity) will prompt exclusion from the trial (prior to drug administration).
  20. History of methemoglobinemia or methemoglobin level >5% at baseline visit
  21. Serum K>5.0 mEq/L
  22. Severe right ventricular dysfunction.
  23. Any medical condition that, in the opinion of the investigator, will interfere with the safe completion of the study.

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): NCT03483051


Locations
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United States, Pennsylvania
University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
University of Pennsylvania
Investigators
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Principal Investigator: Julio Chirinos, MD University of Pennsylvania
  Study Documents (Full-Text)

Documents provided by University of Pennsylvania:
Informed Consent Form  [PDF] August 2, 2018

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Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT03483051    
Other Study ID Numbers: 828994
First Posted: March 29, 2018    Key Record Dates
Results First Posted: March 11, 2020
Last Update Posted: June 17, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Pennsylvania:
aortic stenosis, aortic valve replacement
Additional relevant MeSH terms:
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Aortic Valve Stenosis
Constriction, Pathologic
Pathological Conditions, Anatomical
Heart Valve Diseases
Heart Diseases
Cardiovascular Diseases
Ventricular Outflow Obstruction