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

Aortic Valve Stenosis Clinical Trial

— PULSE-AS  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03483051
• Other study ID #: 828994
• Status: Completed
• Phase: Phase 2
• Start date: May 1, 2018
• Est. completion date: May 23, 2019

Study information

• Verified date: June 2020
• Source: University of Pennsylvania
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 5
• Est. completion date: May 23, 2019
• Est. primary completion date: March 13, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years to 90 Years

Eligibility

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.

Related Conditions & MeSH terms

• Aortic Valve Stenosis
• Constriction, Pathologic

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	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	Total Work Performed During a Maximal-effort Exercise Test	The effect of KNO3 on exercise capacity, quantified as Total work performed during a maximal-effort exercise test;	9 weeks
Primary	Peak Oxygen Uptake (VO2) During a Maximal Effort Exercise Test	The effect of KNO3 on exercise capacity, quantified as: Peak oxygen consumption (VO2) during a symptom-limited maximal effort exercise test.	9 weeks
Primary	Quality of Life Score	The effect of KNO3 on quality of life, assessed using the Kansas City Cardiomyopathy Questionnaire.	9 weeks
Secondary	Systemic Vasodilator Response to Exercise	The effect of KNO3 on systemic vasodilator response, measured by change in systemic vascular resistance, during a symptom-limited maximal exercise test,	9 weeks
Secondary	Left Ventricle Diastolic Function	The effect of KNO3 on left ventricle diastolic filling parameters (measured with echocardiography at rest and after peak exercise)	9 weeks
Secondary	Myocardial Systolic Strain	The effect of KNO3 on myocardial strain (assessed with speckle-tracking echocardiography)	9 weeks
Secondary	Late Systolic Left Ventricle Load	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)	9 weeks