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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Potassium Nitrate (KNO3) | Experimental | Capsules containing 18 mmoles of KNO3 per day, given as one capsule (6 mmoles) three times a day for 4 weeks. |
|
| Potassium Chloride | Sham Comparator | Capsules containing 18 mmoles of KCl per day, given as one capsule (6 mmoles) three times a day for 4 weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Potassium Nitrate | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| 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 |
| Quality of Life Score | The effect of KNO3 on quality of life, assessed using the Kansas City Cardiomyopathy Questionnaire. | 9 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Left Ventricle Diastolic Function |
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Inclusion Criteria:
Exclusion Criteria
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| Name | Affiliation | Role |
|---|---|---|
| Julio Chirinos, MD | University of Pennsylvania | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Pennsylvania | Philadelphia | Pennsylvania | 19104 | United States |
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1 subject withdrew consent prior to treatment
1 subject screen failed
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| First Treatment, Pre Crossover |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Aug 2, 2018 |
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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.
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|
| Potassium Chloride | Drug | 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. |
|
The effect of KNO3 on left ventricle diastolic filling parameters (measured with echocardiography at rest and after peak exercise)
| 9 weeks |
| Myocardial Systolic Strain | The effect of KNO3 on myocardial strain (assessed with speckle-tracking echocardiography) | 9 weeks |
| 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 |
| FG001 | 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. |
| COMPLETED |
|
| NOT COMPLETED |
|
| Second Treatment, After Crossover |
|
1 subject withdrew consent prior to enrollment
1 subject was a screen failure and never received treatment
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | 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. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
| ||||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||||
| Region of Enrollment | Number | participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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; | Efficacy data analyses cannot be reported for privacy reasons due to enrollment of only three (3) subjects. | Posted | 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. | Efficacy data analyses cannot be reported for privacy reasons due to enrollment of only three (3) subjects. | Posted | 9 weeks |
| |||||||||||||||||||||||
| Primary | Quality of Life Score | The effect of KNO3 on quality of life, assessed using the Kansas City Cardiomyopathy Questionnaire. | Efficacy data analyses cannot be reported for privacy reasons due to enrollment of only three (3) subjects. | Posted | 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, | Efficacy data analyses cannot be reported for privacy reasons due to enrollment of only three (3) subjects. | Posted | 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) | Efficacy data analyses cannot be reported for privacy reasons due to enrollment of only three (3) subjects. | Posted | 9 weeks |
| |||||||||||||||||||||||
| Secondary | Myocardial Systolic Strain | The effect of KNO3 on myocardial strain (assessed with speckle-tracking echocardiography) | Efficacy data analyses cannot be reported for privacy reasons due to enrollment of only three (3) subjects. | Posted | 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) | Efficacy data analyses cannot be reported for privacy reasons due to enrollment of only three (3) subjects. | Posted | 9 weeks |
|
1 Year
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. | 0 | 2 | 0 | 2 | 2 | 2 |
| EG001 | 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. | 0 | 1 | 0 | 1 | 0 | 1 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Lightheadedness | Cardiac disorders | Systematic Assessment |
| ||
| Stomach Ache, diarrhea, nausea or vomiting | Gastrointestinal disorders | Systematic Assessment |
| ||
| Drop in blood pressure when standing up | Vascular disorders | Systematic Assessment |
|
Efficacy data analyses will not be performed as they are not meaningful due to enrollment of only three (3) subjects.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Julio Chirinos | University of Pennsylvania | 215-200-7779 | juliochi@pennmedicine.upenn.edu |
| Feb 12, 2020 |
| Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Aug 2, 2018 | Feb 12, 2020 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D001024 | Aortic Valve Stenosis |
| ID | Term |
|---|---|
| D000082862 | Aortic Valve Disease |
| D006349 | Heart Valve Diseases |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D014694 | Ventricular Outflow Obstruction |
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| ID | Term |
|---|---|
| C023844 | potassium nitrate |
| D011189 | Potassium Chloride |
| ID | Term |
|---|---|
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017680 | Potassium Compounds |
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| >=65 years |
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| Male |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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