Aortic Valve Stenosis
Conditions
Keywords
aortic stenosis, aortic valve replacement
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.
Interventions
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.
DRUGPotassium 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.
Sponsors
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
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.
Eligibility
Sex/Gender
ALL
Age
50 Years to 90 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Work Performed During a Maximal-effort Exercise Test | 9 weeks | The effect of KNO3 on exercise capacity, quantified as Total work performed during a maximal-effort exercise test; |
| Peak Oxygen Uptake (VO2) During a Maximal Effort Exercise Test | 9 weeks | The effect of KNO3 on exercise capacity, quantified as: Peak oxygen consumption (VO2) during a symptom-limited maximal effort exercise test. |
| Quality of Life Score | 9 weeks | The effect of KNO3 on quality of life, assessed using the Kansas City Cardiomyopathy Questionnaire. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Late Systolic Left Ventricle Load | 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) |
| Myocardial Systolic Strain | 9 weeks | The effect of KNO3 on myocardial strain (assessed with speckle-tracking echocardiography) |
| Systemic Vasodilator Response to Exercise | 9 weeks | The effect of KNO3 on systemic vasodilator response, measured by change in systemic vascular resistance, during a symptom-limited maximal exercise test, |
| Left Ventricle Diastolic Function | 9 weeks | The effect of KNO3 on left ventricle diastolic filling parameters (measured with echocardiography at rest and after peak exercise) |
Countries
United States
Participant flow
Pre-assignment details
1 subject withdrew consent prior to treatment 1 subject screen failed
Participants by arm
| Arm | Count |
|---|---|
| ARM A Potassium Nitrate Then Potassium Chloride Capsules containing 18 mmoles of KNO3 per day, given as one capsule (6 mmoles) three times a day for 4 weeks.
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. | 2 |
| ARM B Potassium Chloride Then Potassium Nitrate Capsules containing 18 mmoles of KCl per day, given as one capsule (6 mmoles) three times a day for 4 weeks.
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. | 1 |
| Total | 3 |
Baseline characteristics
| Characteristic | ARM A Potassium Nitrate Then Potassium Chloride | ARM B Potassium Chloride Then Potassium Nitrate | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 1 Participants | 3 Participants |
| Region of Enrollment United States | 2 participants | 1 participants | 3 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 1 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 1 |
| other Total, other adverse events | 2 / 2 | 0 / 1 |
| serious Total, serious adverse events | 0 / 2 | 0 / 1 |
Outcome results
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.
Time frame: 9 weeks
Population: Efficacy data analyses cannot be reported for privacy reasons due to enrollment of only three (3) subjects.
Primary
Quality of Life Score
The effect of KNO3 on quality of life, assessed using the Kansas City Cardiomyopathy Questionnaire.
Time frame: 9 weeks
Population: Efficacy data analyses cannot be reported for privacy reasons due to enrollment of only three (3) subjects.
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;
Time frame: 9 weeks
Population: Efficacy data analyses cannot be reported for privacy reasons due to enrollment of only three (3) subjects.
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)
Time frame: 9 weeks
Population: Efficacy data analyses cannot be reported for privacy reasons due to enrollment of only three (3) subjects.
Secondary
Left Ventricle Diastolic Function
The effect of KNO3 on left ventricle diastolic filling parameters (measured with echocardiography at rest and after peak exercise)
Time frame: 9 weeks
Population: Efficacy data analyses cannot be reported for privacy reasons due to enrollment of only three (3) subjects.
Secondary
Myocardial Systolic Strain
The effect of KNO3 on myocardial strain (assessed with speckle-tracking echocardiography)
Time frame: 9 weeks
Population: Efficacy data analyses cannot be reported for privacy reasons due to enrollment of only three (3) subjects.
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,
Time frame: 9 weeks
Population: Efficacy data analyses cannot be reported for privacy reasons due to enrollment of only three (3) subjects.