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Pharmacokinetics, Pharmacodynamics, and Impact of Inorganic Nitrate on Exercise in HFpEF

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02256345
Recruitment Status : Completed
First Posted : October 3, 2014
Results First Posted : October 3, 2017
Last Update Posted : October 3, 2017
Sponsor:
Information provided by (Responsible Party):
University of Pennsylvania

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Single (Participant);   Primary Purpose: Treatment
Conditions Heart Failure
Diastolic Heart Failure
Interventions Drug: KNO3
Drug: KCl
Enrollment 12
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Randomized to KNO3 Randomized to KCl
Hide Arm/Group Description

KNO3 will be given at a dose of 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated.

Active Comparator: Potassium Nitrate (KNO3)

KCl will be used as a placebo and will be given as 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated.

Placebo Comparator: Potassium Chloride (KCl)

Period Title: Overall Study
Started 9 3
Completed 9 3
Not Completed 0 0
Arm/Group Title Randomized to KNO3 Randomized to KCl Total
Hide Arm/Group Description

KNO3 will be given at a dose of 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated

Active Comparator: Potassium Nitrate

KCl will be used as a placebo and will be given as 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if tolerating well.

Placebo Comparator: Potassium Chloride

Total of all reporting groups
Overall Number of Baseline Participants 9 3 12
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 9 participants 3 participants 12 participants
62.4  (5.5) 62.7  (8.0) 62.5  (5.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 3 participants 12 participants
Female
6
  66.7%
2
  66.7%
8
  66.7%
Male
3
  33.3%
1
  33.3%
4
  33.3%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Race, n (%) Number Analyzed 9 participants 3 participants 12 participants
White
5
  55.6%
3
 100.0%
8
  66.7%
Black
3
  33.3%
0
   0.0%
3
  25.0%
Pacific Islander
1
  11.1%
0
   0.0%
1
   8.3%
New York Heart Association Heart failure classification (NYHA Class) n (%)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 3 participants 12 participants
Class II
8
  88.9%
2
  66.7%
10
  83.3%
Class III
1
  11.1%
1
  33.3%
2
  16.7%
[1]
Measure Description:

Class II- Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea (shortness of breath).

Class III- Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, or dyspnea.

Body Mass Index, kg/m^2, mean (SD)  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 9 participants 3 participants 12 participants
33.4  (6.3) 37.4  (9.9) 34.4  (7.0)
Number of Obese Participants, n(%)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 3 participants 12 participants
5
  55.6%
3
 100.0%
8
  66.7%
Number of Hypertensive Participants, n(%)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 3 participants 12 participants
9
 100.0%
3
 100.0%
12
 100.0%
Number of Participants with Hyperlipidemia, n (%)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 3 participants 12 participants
7
  77.8%
3
 100.0%
10
  83.3%
Number of Participants with Coronary Artery Disease, n (%)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 3 participants 12 participants
3
  33.3%
1
  33.3%
4
  33.3%
Number of Participants with History of atrial fibrillation, n (%)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 3 participants 12 participants
0
   0.0%
1
  33.3%
1
   8.3%
Number of Participants with Diabetes Mellitus, n (%)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 3 participants 12 participants
5
  55.6%
2
  66.7%
7
  58.3%
Number of Participants with Obstructive sleep apnea, n (%)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 3 participants 12 participants
3
  33.3%
3
 100.0%
6
  50.0%
Number of Participants with Current Continuous Positive Airway Pressure (CPAP) use, n (%)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 3 participants 12 participants
2
  22.2%
3
 100.0%
5
  41.7%
Number of Participants with Obstructive lung disease, n (%)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 3 participants 12 participants
2
  22.2%
1
  33.3%
3
  25.0%
Number of Participants on Beta-blockers, n (%)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 3 participants 12 participants
7
  77.8%
2
  66.7%
9
  75.0%
Number of Participants onACEI/ARB, n (%)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 3 participants 12 participants
7
  77.8%
2
  66.7%
9
  75.0%
Number of Participants on Mineralocorticoid receptor antagonists, n (%)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 3 participants 12 participants
2
  22.2%
1
  33.3%
3
  25.0%
Number of Participants on Calcium-channel blockers, n (%)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 3 participants 12 participants
3
  33.3%
1
  33.3%
4
  33.3%
Number of Participants on Loop diuretics, n (%)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 3 participants 12 participants
7
  77.8%
2
  66.7%
9
  75.0%
Number of Participants on Thiazide diuretic, n (%)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 3 participants 12 participants
3
  33.3%
1
  33.3%
4
  33.3%
Number of Participants on Statin, n (%)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 3 participants 12 participants
5
  55.6%
2
  66.7%
7
  58.3%
Estimated Glomerular Filtration Rate (eGFR), mL/min per 1.73m^2, mean (SD)  
Mean (Standard Deviation)
Unit of measure:  mL/min per 1.73m^2
Number Analyzed 9 participants 3 participants 12 participants
71.0  (14.1) 64.7  (5.9) 69.4  (12.6)
Estimated Glomerular Filtration Rate (eGFR) <60 mL/min per 1.73m^2, n (%)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 3 participants 12 participants
3
  33.3%
1
  33.3%
4
  33.3%
N-terminal pro-brain natriuretic peptide (NT-proBNP), pg/ml, mean (SD)  
Mean (Standard Deviation)
Unit of measure:  Pg/ml
Number Analyzed 9 participants 3 participants 12 participants
108.3  (94.7) 119  (87.0) 111  (89.0)
Number of Participants with high N-terminal pro-brain natriuretic peptide (NT-proBNP), pg/ml, n (%)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 3 participants 12 participants
3
  33.3%
2
  66.7%
5
  41.7%
Hemoglobin, g/dL, mean (SD)  
Mean (Standard Deviation)
Unit of measure:  g/dL
Number Analyzed 9 participants 3 participants 12 participants
13.6  (0.8) 13.5  (1.0) 13.6  (0.8)
Methemoglobin, %, mean (SD)  
Mean (Standard Deviation)
Unit of measure:  Percent of total hemoglobin
Number Analyzed 9 participants 3 participants 12 participants
1.0  (0.2) 1.0  (0.5) 1.0  (0.3)
Left Ventricular (LV) mass,g, mean (SD)  
Mean (Standard Deviation)
Unit of measure:  g
Number Analyzed 9 participants 3 participants 12 participants
174.43  (77.09) 165.98  (19.27) 172.32  (66.36)
Left Ventricular (LV) mass index, g/m^2, mean (SD)  
Mean (Standard Deviation)
Unit of measure:  G/m^2
Number Analyzed 9 participants 3 participants 12 participants
79.78  (26.01) 76.18  (7.33) 78.88  (22.46)
Relative wall thickness, mean (SD)   [1] 
Mean (Standard Deviation)
Unit of measure:  Ratio
Number Analyzed 9 participants 3 participants 12 participants
0.47  (0.09) 0.46  (0.09) 0.47  (0.09)
[1]
Measure Description: The ratio of twice LV diastolic posterior wall thickness to left ventricular end-diastolic dimension
Mitral early inflow velocity (E), cm/s, mean (SD)  
Mean (Standard Deviation)
Unit of measure:  Cm/s
Number Analyzed 9 participants 3 participants 12 participants
74.53  (24.75) 85.73  (7.04) 77.33  (21.91)
Mitral atrial inflow velocity (E), cm/s, mean (SD)  
Mean (Standard Deviation)
Unit of measure:  Cm/s
Number Analyzed 9 participants 3 participants 12 participants
70.74  (20.06) 88.61  (21.28) 75.21  (20.99)
Septal tissue doppler early velocity (e'), mm/s, mean (SD)  
Mean (Standard Deviation)
Unit of measure:  Mm/s
Number Analyzed 9 participants 3 participants 12 participants
70.64  (12.45) 93.71  (28.65) 76.41  (19.26)
Septal E/e' ratio, mean (SD)  
Mean (Standard Deviation)
Unit of measure:  Ratio
Number Analyzed 9 participants 3 participants 12 participants
10.70  (3.76) 9.60  (2.39) 10.42  (3.40)
Left atrial volume index, mL/m^2, mean (SD)  
Mean (Standard Deviation)
Unit of measure:  mL/m^2
Number Analyzed 9 participants 3 participants 12 participants
27.20  (7.87) 29.38  (5.33) 27.74  (7.15)
Left ventricular ejection fraction, %, mean (SD)  
Mean (Standard Deviation)
Unit of measure:  % (stroke volume/ end-diastolic vol)x100
Number Analyzed 9 participants 3 participants 12 participants
65.84  (7.74) 59.41  (13.66) 64.23  (9.27)
1.Primary Outcome
Title Change in Peak Oxygen Uptake (VO2) From Baseline Upto 1 Week of Administration for Each Dose
Hide Description Peak oxygen uptake (VO2) defined as the average value obtained during the last 30 seconds of exercise.
Time Frame Baseline, end of week 1, end of week 2
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Randomized to KNO3 Randomized to KCl
Hide Arm/Group Description:

KNO3 will be given at a dose of 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated

Active Comparator: Potassium Nitrate

KCl will be used as a placebo and will be given as 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if tolerating well.

Placebo Comparator: Potassium Chloride

Overall Number of Participants Analyzed 9 3
Mean (95% Confidence Interval)
Unit of Measure: L/min
Baseline Viist
1.16
(1.13 to 1.19)
1.49
(1.43 to 1.54)
End of week 1 visit
1.20
(1.17 to 1.24)
1.44
(1.39 to 1.49)
End of week 2 visit
1.20
(1.17 to 1.23)
1.44
(1.39 to 1.50)
2.Secondary Outcome
Title Change in Vasodilatory Reserve for Each Dose
Hide Description Percent change in peak vascular resistance from rest to peak exercise
Time Frame Baseline, end of week 1, end of week 2
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Randomized to KNO3 Randomized to KCl
Hide Arm/Group Description:

KNO3 will be given at a dose of 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated

Active Comparator: Potassium Nitrate

KCl will be used as a placebo and will be given as 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if tolerating well.

Placebo Comparator: Potassium Chloride

Overall Number of Participants Analyzed 9 3
Mean (95% Confidence Interval)
Unit of Measure: %change in peak vascular resistance
Baseline
-25.6
(-40.9 to -10.4)
-25.8
(-31.4 to -20.3)
End of week 1 visit
-27.1
(-43.6 to -10.5)
-30.6
(-36.2 to -25.1)
End of week 2 visit
-34.2
(-49.4 to -18.9)
-20.0
(-24.2 to -15.8)
3.Secondary Outcome
Title Change in Mitochondrial Oxidative Capacity for Each Dose
Hide Description Percent change in oxidative capacity (oxyhemoglobin levels) before and after occlusion
Time Frame Baseline, end of week 1, end of week 2
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Randomized to KNO3 Randomized to KCl
Hide Arm/Group Description:

KNO3 will be given at a dose of 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated

Active Comparator: Potassium Nitrate

KCl will be used as a placebo and will be given as 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if tolerating well.

Placebo Comparator: Potassium Chloride

Overall Number of Participants Analyzed 9 3
Mean (95% Confidence Interval)
Unit of Measure: Percent change in oxidative capacity
Baseline
63.2
(47.6 to 78.8)
106.5
(59.2 to 153.7)
End of week 1 visit
59.2
(42.1 to 76.2)
110.4
(63.2 to 157.7)
End of Week 2 visit
62.2
(46.6 to 77.7)
45.4
(5.0 to 85.8)
4.Secondary Outcome
Title Change in Aortic Augmentation Index
Hide Description Percent change in augmentation index, whereas augmentation index at each time point (visit) is defined as the amplitude of the second peak to the first peak of the aortic pulse wave form multiplied by 100: augmentation index = (P2/P1)×100.
Time Frame Baseline, end of week 1, end of week 2
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Randomized to KNO3 Randomized to KCl
Hide Arm/Group Description:

KNO3 will be given at a dose of 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated

Active Comparator: Potassium Nitrate

KCl will be used as a placebo and will be given as 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if tolerating well.

Placebo Comparator: Potassium Chloride

Overall Number of Participants Analyzed 9 3
Mean (95% Confidence Interval)
Unit of Measure: Percent change in augumentation index
Baseline visit
3.0
(-5.4 to 11.4)
-2.3
(-11.5 to 6.8)
End of week 1 visit
-5.4
(-13.1 to 2.4)
-11.9
(-23.5 to -0.2)
End of week 2 visit
-7.1
(-14.9 to 0.6)
-0.2
(-9.4 to 9.0)
Time Frame Adverse events were collected at every visit. There are a total of three visits that are 1 week apart.
Adverse Event Reporting Description All adverse events were non serious so they are reported under Other Adverse Events
 
Arm/Group Title Randomized to KNO3 Randomized to KCl
Hide Arm/Group Description

KNO3 will be given at a dose of 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated

Active Comparator: Potassium Nitrate

KCl will be used as a placebo and will be given as 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if tolerating well.

Placebo Comparator: Potassium Chloride

All-Cause Mortality
Randomized to KNO3 Randomized to KCl
Affected / at Risk (%) Affected / at Risk (%)
Total   0/9 (0.00%)      0/3 (0.00%)    
Hide Serious Adverse Events
Randomized to KNO3 Randomized to KCl
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/9 (0.00%)      0/3 (0.00%)    
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Randomized to KNO3 Randomized to KCl
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   5/9 (55.56%)      1/3 (33.33%)    
Cardiac disorders     
Palpitations   1/9 (11.11%)  0/3 (0.00%) 
Mild lower extremity edema   0/9 (0.00%)  1/3 (33.33%) 
Gastrointestinal disorders     
GI symptoms  [1]  3/9 (33.33%)  1/3 (33.33%) 
General disorders     
Any side effect   4/9 (44.44%)  1/3 (33.33%)  1
Fatigue   1/9 (11.11%)  0/3 (0.00%) 
Infections and infestations     
Tooth infection   1/9 (11.11%)  0/3 (0.00%) 
Nervous system disorders     
Headache   2/9 (22.22%)  0/3 (0.00%) 
Indicates events were collected by systematic assessment
[1]
Includes GI upset, nausea, vomiting, flatulence
  • Small sample size
  • Serial blood draws, which caused a decrease in hemoglobin concentration, which may have constrained the increase in VO2,peak and reduced the magnitude of the improvement in exercise capacity and quality of life.
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Julio Chirinos
Organization: UPenn
Phone: 2158235800
EMail: julio.chirinos@uphs.upenn.edu
Layout table for additonal information
Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT02256345    
Other Study ID Numbers: 01340
First Submitted: September 30, 2014
First Posted: October 3, 2014
Results First Submitted: June 14, 2017
Results First Posted: October 3, 2017
Last Update Posted: October 3, 2017