Clinical trial NCT03483051: Targeting Pulsatile Load to Increase Exercise Capacity and Quality of Life After Aortic Valve Replacement for Severe Aortic Stenosis (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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Aortic Valve Stenosis
Keywords: aortic stenosis, aortic valve replacement
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
First posted: 2018-03-29
Enrollment: 5
Sex: ALL
Minimum age (years): 50
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
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.
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Total Work Performed During a Maximal-effort Exercise Test
timeFrame: 9 weeks
measure: Peak Oxygen Uptake (VO2) During a Maximal Effort Exercise Test
timeFrame: 9 weeks
measure: Quality of Life Score
timeFrame: 9 weeks
Secondary outcomes:
measure: Systemic Vasodilator Response to Exercise
timeFrame: 9 weeks
measure: Left Ventricle Diastolic Function
timeFrame: 9 weeks
measure: Myocardial Systolic Strain
timeFrame: 9 weeks
measure: Late Systolic Left Ventricle Load
timeFrame: 9 weeks
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
Study officials:
affiliation: University of Pennsylvania
name: Julio Chirinos, MD
role: PRINCIPAL_INVESTIGATOR
References: