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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)

Primary Purpose

Aortic Valve Stenosis

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Potassium Nitrate

Potassium Chloride

About this trial

This is an interventional treatment trial for Aortic Valve Stenosis focused on measuring aortic stenosis, aortic valve replacement

Eligibility Criteria

50 Years - 90 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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

Exclusion Criteria

Supine systolic blood pressure (SBP) < 100 mmHg OR supine diastolic blood pressure (DBP) <60 mmHg
Poorly controlled hypertension, as defined as SBP > 160 mmHg OR DBP > 100 mmHg
Pregnancy. Women of childbearing potential will undergo a pregnancy test during the screening visit
Atrial fibrillation within the prior 8 weeks before enrollment
Inability/unwillingness to exercise
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.
Moderate or severe patient prosthesis mismatch, as defined by Effective Orifice Area Index < 0.85 cm2/m2
Hypertrophic, infiltrative, or inflammatory cardiomyopathy
Pericardial disease
Current angina
Acute coronary syndrome or coronary intervention within the past 2 months
Primary pulmonary arteriopathy
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
Ischemia on stress testing without subsequent revascularization (during the screening visit)
Treatment with phosphodiesterase inhibitors that cannot be withheld
Treatment with organic nitrates
Significant liver disease impacting synthetic function or volume control (ALT/AST > 3x ULN, Albumin <3.0 g/dL)
eGFR < 30 mL/min/1.73 m2
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).
History of methemoglobinemia or methemoglobin level >5% at baseline visit
Serum K>5.0 mEq/L
Severe right ventricular dysfunction.
Any medical condition that, in the opinion of the investigator, will interfere with the safe completion of the study.

Sites / Locations

University of Pennsylvania

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Sham Comparator

Arm Label

Potassium Nitrate (KNO3)

Potassium Chloride

Arm Description

Capsules containing 18 mmoles of KNO3 per day, given as one capsule (6 mmoles) three times a day for 4 weeks.

Capsules containing 18 mmoles of KCl per day, given as one capsule (6 mmoles) three times a day for 4 weeks.

Outcomes

Primary Outcome Measures

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;

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.

Quality of Life Score

The effect of KNO3 on quality of life, assessed using the Kansas City Cardiomyopathy Questionnaire.

Secondary Outcome Measures

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,

Left Ventricle Diastolic Function

The effect of KNO3 on left ventricle diastolic filling parameters (measured with echocardiography at rest and after peak exercise)

Myocardial Systolic Strain

The effect of KNO3 on myocardial strain (assessed with speckle-tracking echocardiography)

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)

Full Information

NCT ID

NCT03483051

First Posted

February 15, 2018

Last Updated

June 3, 2020

Sponsor

University of Pennsylvania

1. Study Identification

Unique Protocol Identification Number

NCT03483051

Brief Title

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

Acronym

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

2. Study Status

Record Verification Date

June 2020

Overall Recruitment Status

Completed

Study Start Date

May 1, 2018 (Actual)

Primary Completion Date

March 13, 2019 (Actual)

Study Completion Date

May 23, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Pennsylvania

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Aortic Valve Stenosis

Keywords

aortic stenosis, aortic valve replacement

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Crossover Assignment

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

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

5 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Potassium Nitrate (KNO3)

Arm Type

Experimental

Arm Description

Capsules containing 18 mmoles of KNO3 per day, given as one capsule (6 mmoles) three times a day for 4 weeks.

Arm Title

Potassium Chloride

Arm Type

Sham Comparator

Arm Description

Capsules containing 18 mmoles of KCl per day, given as one capsule (6 mmoles) three times a day for 4 weeks.

Intervention Type

Drug

Intervention Name(s)

Potassium Nitrate

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Potassium Chloride

Intervention Description

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 Measure Information:

Title

Total Work Performed During a Maximal-effort Exercise Test

Description

The effect of KNO3 on exercise capacity, quantified as Total work performed during a maximal-effort exercise test;

Time Frame

9 weeks

Title

Peak Oxygen Uptake (VO2) During a Maximal Effort Exercise Test

Description

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

Title

Quality of Life Score

Description

The effect of KNO3 on quality of life, assessed using the Kansas City Cardiomyopathy Questionnaire.

Time Frame

9 weeks

Secondary Outcome Measure Information:

Title

Systemic Vasodilator Response to Exercise

Description

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

Title

Left Ventricle Diastolic Function

Description

The effect of KNO3 on left ventricle diastolic filling parameters (measured with echocardiography at rest and after peak exercise)

Time Frame

9 weeks

Title

Myocardial Systolic Strain

Description

The effect of KNO3 on myocardial strain (assessed with speckle-tracking echocardiography)

Time Frame

9 weeks

Title

Late Systolic Left Ventricle Load

Description

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

50 Years

Maximum Age & Unit of Time

90 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Adults aged 50-90 years of age Diagnosis of severe aortic stenosis prior to aortic valve repair Successful trancatheter aortic valve repair via transfemoral procedural approach or successful surgical aortic valve repair at least three months prior to enrollment Stable medical therapy: no addition/removal/changes in anti-hypertensive medications, or beta-blockers in the preceding 30 days. Exclusion Criteria Supine systolic blood pressure (SBP) < 100 mmHg OR supine diastolic blood pressure (DBP) <60 mmHg Poorly controlled hypertension, as defined as SBP > 160 mmHg OR DBP > 100 mmHg Pregnancy. Women of childbearing potential will undergo a pregnancy test during the screening visit Atrial fibrillation within the prior 8 weeks before enrollment Inability/unwillingness to exercise 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. Moderate or severe patient prosthesis mismatch, as defined by Effective Orifice Area Index < 0.85 cm2/m2 Hypertrophic, infiltrative, or inflammatory cardiomyopathy Pericardial disease Current angina Acute coronary syndrome or coronary intervention within the past 2 months Primary pulmonary arteriopathy 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 Ischemia on stress testing without subsequent revascularization (during the screening visit) Treatment with phosphodiesterase inhibitors that cannot be withheld Treatment with organic nitrates Significant liver disease impacting synthetic function or volume control (ALT/AST > 3x ULN, Albumin <3.0 g/dL) eGFR < 30 mL/min/1.73 m2 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). History of methemoglobinemia or methemoglobin level >5% at baseline visit Serum K>5.0 mEq/L Severe right ventricular dysfunction. Any medical condition that, in the opinion of the investigator, will interfere with the safe completion of the study.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Julio Chirinos, MD

Organizational Affiliation

University of Pennsylvania

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Pennsylvania

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

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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)

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