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

Sponsor
University of Pennsylvania (Other)
Overall Status
Completed
CT.gov ID
NCT02256345
Collaborator
(none)
12
Enrollment
1
Location
2
Arms
17
Duration (Months)
0.7
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study will be performed to determine the safety, tolerability, and dose-response to inorganic nitrate on exercise capacity in HFpEF. There are two primary goals for this study:

  1. Determine the population-specific pharmacokinetics and dose of KNO3 that can be safely given to subjects with HFpEF.

  2. Determine if there is a dose-response effect of nitrate supplementation on exercise capacity, evidenced by peak oxygen consumption (peak VO2), and physiologic adaptations to exercise.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

This study randomized subjects to either placebo (n=3) or KNO3 (n=9) given a sequential dosing regimen: 6 mmol twice daily for 1 week followed by dose escalation to 6 mmol thrice daily for 1 week). Although a primary goal of the study was to assess the safety of KNO3 and within-group changes in various end points in KNO3-treated subjects, a small number of placebo-treated (PB, n=3) subjects were included only to assess for any potential training effect on repeated exercise and Kansas City Cardiomyopathy Questionnaire (KCCQ) measurements. Potassium chloride, given in equivalent doses, was used as the PB to account for differences in blood pressure or flow that could be attributed to potassium.

The study was initially designed to be single-blinded to allow the principal investigator to be aware of arm allocation because of potential concerns for methemoglobinemia with drug administration. One investigator, who was the primary investigator responsible for supervising all visits and measurements during the study, remained blinded to treatment allocation throughout the entirety of the study. All physiological and imaging data were analyzed in a double-blind manner.

Study Design

Study Type:
Interventional
Actual Enrollment :
12 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Single (Participant)
Primary Purpose:
Treatment
Official Title:
Pharmacokinetics, Pharmacodynamics, and Impact of Inorganic Nitrate on Exercise in HFpEF
Study Start Date :
Jan 1, 2015
Actual Primary Completion Date :
Jun 1, 2016
Actual Study Completion Date :
Jun 1, 2016

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: KNO3 active comparator

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

Drug: KNO3
Active Comparator
Other Names:
  • Potassium Nitrate

    		•
    Placebo Comparator: KCl placebo comparator

    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

    Drug: KCl
    Placebo Comparator
    Other Names:
  • Potassium Chloride

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Change in Peak Oxygen Uptake (VO2) From Baseline Upto 1 Week of Administration for Each Dose [Baseline, end of week 1, end of week 2]

      Peak oxygen uptake (VO2) defined as the average value obtained during the last 30 seconds of exercise.

    Secondary Outcome Measures

    1. Change in Vasodilatory Reserve for Each Dose [Baseline, end of week 1, end of week 2]

      Percent change in peak vascular resistance from rest to peak exercise

    2. Change in Mitochondrial Oxidative Capacity for Each Dose [Baseline, end of week 1, end of week 2]

      Percent change in oxidative capacity (oxyhemoglobin levels) before and after occlusion

    3. Change in Aortic Augmentation Index [Baseline, end of week 1, end of week 2]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    1. NYHA Class II-III symptoms.

    2. LV EF > 50%.

    3. Stable medical therapy for at least 1 month.

    4. Evidence of significant diastolic dysfunction, meeting the European Society of Echocardiography criteria for HFpEF.

    Exclusion Criteria

    1. Any rhythm other than sinus with native conduction.

    2. Inability to exercise.

    3. Moderate or greater valvular disease.

    4. Hypertrophic, infiltrative, or inflammatory cardiomyopathy.

    5. Pericardial disease.

    6. Current angina.

    7. Acute coronary syndrome or coronary intervention within the past 2 months.

    8. Primary pulmonary arteriopathy.

    9. Clinically significant lung disease.

    10. Ischemia on stress testing without subsequent revascularization.

    11. Treatment with phosphodiesterase inhibitors that cannot be withheld.

    12. Treatment with organic nitrates or allopurinol.

    13. Significant liver disease impacting synthetic function or volume control.

    14. Poor echocardiographic windows.

    15. eGFR < 30 mL/min/m2 or Cr >2.5.

    16. Current smoking.

    17. Alcohol dependency.

    18. History of Barret's esophagus.

    19. G6PD deficiency

    20. Methemoglobinemia - baseline methemoglobin level >3% prior to any study medication.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Hospital of the University of Pennsylvania Philadelphia Pennsylvania United States 19104

    Sponsors and Collaborators

    • University of Pennsylvania

    Investigators

    • Principal Investigator: Julio A Chirinos, MD, University of Pennsylvania

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    University of Pennsylvania
    ClinicalTrials.gov Identifier:
    NCT02256345
    Other Study ID Numbers:
    • 01340
    First Posted:
    Oct 3, 2014
    Last Update Posted:
    Oct 3, 2017
    Last Verified:
    Aug 1, 2017
    Additional relevant MeSH terms:
    Heart Failure
    Heart Failure, Diastolic

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Randomized to KNO3 Randomized to KCl
    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

    Baseline Characteristics

    Arm/Group Title Randomized to KNO3 Randomized to KCl Total
    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 Participants 9 3 12
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    62.4
    (5.5)
    62.7
    (8.0)
    62.5
    (5.8)
    Sex: Female, Male (Count of Participants)
    Female
    6
    66.7%
    2
    66.7%
    8
    66.7%
    Male
    3
    33.3%
    1
    33.3%
    4
    33.3%
    Race/Ethnicity, Customized (Count of Participants)
    White
    5
    55.6%
    3
    100%
    8
    66.7%
    Black
    3
    33.3%
    0
    0%
    3
    25%
    Pacific Islander
    1
    11.1%
    0
    0%
    1
    8.3%
    New York Heart Association Heart failure classification (NYHA Class) n (%) (Count of Participants)
    Class II
    8
    88.9%
    2
    66.7%
    10
    83.3%
    Class III
    1
    11.1%
    1
    33.3%
    2
    16.7%
    Body Mass Index, kg/m^2, mean (SD) (kg/m^2) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [kg/m^2]
    33.4
    (6.3)
    37.4
    (9.9)
    34.4
    (7.0)
    Number of Obese Participants, n(%) (Count of Participants)
    Count of Participants [Participants]
    5
    55.6%
    3
    100%
    8
    66.7%
    Number of Hypertensive Participants, n(%) (Count of Participants)
    Count of Participants [Participants]
    9
    100%
    3
    100%
    12
    100%
    Number of Participants with Hyperlipidemia, n (%) (Count of Participants)
    Count of Participants [Participants]
    7
    77.8%
    3
    100%
    10
    83.3%
    Number of Participants with Coronary Artery Disease, n (%) (Count of Participants)
    Count of Participants [Participants]
    3
    33.3%
    1
    33.3%
    4
    33.3%
    Number of Participants with History of atrial fibrillation, n (%) (Count of Participants)
    Count of Participants [Participants]
    0
    0%
    1
    33.3%
    1
    8.3%
    Number of Participants with Diabetes Mellitus, n (%) (Count of Participants)
    Count of Participants [Participants]
    5
    55.6%
    2
    66.7%
    7
    58.3%
    Number of Participants with Obstructive sleep apnea, n (%) (Count of Participants)
    Count of Participants [Participants]
    3
    33.3%
    3
    100%
    6
    50%
    Number of Participants with Current Continuous Positive Airway Pressure (CPAP) use, n (%) (Count of Participants)
    Count of Participants [Participants]
    2
    22.2%
    3
    100%
    5
    41.7%
    Number of Participants with Obstructive lung disease, n (%) (Count of Participants)
    Count of Participants [Participants]
    2
    22.2%
    1
    33.3%
    3
    25%
    Number of Participants on Beta-blockers, n (%) (Count of Participants)
    Count of Participants [Participants]
    7
    77.8%
    2
    66.7%
    9
    75%
    Number of Participants onACEI/ARB, n (%) (Count of Participants)
    Count of Participants [Participants]
    7
    77.8%
    2
    66.7%
    9
    75%
    Number of Participants on Mineralocorticoid receptor antagonists, n (%) (Count of Participants)
    Count of Participants [Participants]
    2
    22.2%
    1
    33.3%
    3
    25%
    Number of Participants on Calcium-channel blockers, n (%) (Count of Participants)
    Count of Participants [Participants]
    3
    33.3%
    1
    33.3%
    4
    33.3%
    Number of Participants on Loop diuretics, n (%) (Count of Participants)
    Count of Participants [Participants]
    7
    77.8%
    2
    66.7%
    9
    75%
    Number of Participants on Thiazide diuretic, n (%) (Count of Participants)
    Count of Participants [Participants]
    3
    33.3%
    1
    33.3%
    4
    33.3%
    Number of Participants on Statin, n (%) (Count of Participants)
    Count of Participants [Participants]
    5
    55.6%
    2
    66.7%
    7
    58.3%
    Estimated Glomerular Filtration Rate (eGFR), mL/min per 1.73m^2, mean (SD) (mL/min per 1.73m^2) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mL/min per 1.73m^2]
    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 (%) (Count of Participants)
    Count of Participants [Participants]
    3
    33.3%
    1
    33.3%
    4
    33.3%
    N-terminal pro-brain natriuretic peptide (NT-proBNP), pg/ml, mean (SD) (pg/ml) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [pg/ml]
    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 (%) (Count of Participants)
    Count of Participants [Participants]
    3
    33.3%
    2
    66.7%
    5
    41.7%
    Hemoglobin, g/dL, mean (SD) (g/dL) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [g/dL]
    13.6
    (0.8)
    13.5
    (1.0)
    13.6
    (0.8)
    Methemoglobin, %, mean (SD) (percent of total hemoglobin) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [percent of total hemoglobin]
    1.0
    (0.2)
    1.0
    (0.5)
    1.0
    (0.3)
    Left Ventricular (LV) mass,g, mean (SD) (g) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [g]
    174.43
    (77.09)
    165.98
    (19.27)
    172.32
    (66.36)
    Left Ventricular (LV) mass index, g/m^2, mean (SD) (g/m^2) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [g/m^2]
    79.78
    (26.01)
    76.18
    (7.33)
    78.88
    (22.46)
    Relative wall thickness, mean (SD) (ratio) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [ratio]
    0.47
    (0.09)
    0.46
    (0.09)
    0.47
    (0.09)
    Mitral early inflow velocity (E), cm/s, mean (SD) (cm/s) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [cm/s]
    74.53
    (24.75)
    85.73
    (7.04)
    77.33
    (21.91)
    Mitral atrial inflow velocity (E), cm/s, mean (SD) (cm/s) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [cm/s]
    70.74
    (20.06)
    88.61
    (21.28)
    75.21
    (20.99)
    Septal tissue doppler early velocity (e'), mm/s, mean (SD) (mm/s) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mm/s]
    70.64
    (12.45)
    93.71
    (28.65)
    76.41
    (19.26)
    Septal E/e' ratio, mean (SD) (ratio) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [ratio]
    10.70
    (3.76)
    9.60
    (2.39)
    10.42
    (3.40)
    Left atrial volume index, mL/m^2, mean (SD) (mL/m^2) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mL/m^2]
    27.20
    (7.87)
    29.38
    (5.33)
    27.74
    (7.15)
    Left ventricular ejection fraction, %, mean (SD) (% (stroke volume/ end-diastolic vol)x100) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [% (stroke volume/ end-diastolic vol)x100]
    65.84
    (7.74)
    59.41
    (13.66)
    64.23
    (9.27)

    Outcome Measures

    1. Primary Outcome
    Title Change in Peak Oxygen Uptake (VO2) From Baseline Upto 1 Week of Administration for Each Dose
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Randomized to KNO3 Randomized to KCl
    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
    Measure Participants 9 3
    Baseline Viist
    1.16
    1.49
    End of week 1 visit
    1.20
    1.44
    End of week 2 visit
    1.20
    1.44
    2. Secondary Outcome
    Title Change in Vasodilatory Reserve for Each Dose
    Description Percent change in peak vascular resistance from rest to peak exercise
    Time Frame Baseline, end of week 1, end of week 2

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Randomized to KNO3 Randomized to KCl
    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
    Measure Participants 9 3
    Baseline
    -25.6
    -25.8
    End of week 1 visit
    -27.1
    -30.6
    End of week 2 visit
    -34.2
    -20.0
    3. Secondary Outcome
    Title Change in Mitochondrial Oxidative Capacity for Each Dose
    Description Percent change in oxidative capacity (oxyhemoglobin levels) before and after occlusion
    Time Frame Baseline, end of week 1, end of week 2

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Randomized to KNO3 Randomized to KCl
    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
    Measure Participants 9 3
    Baseline
    63.2
    106.5
    End of week 1 visit
    59.2
    110.4
    End of Week 2 visit
    62.2
    45.4
    4. Secondary Outcome
    Title Change in Aortic Augmentation Index
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Randomized to KNO3 Randomized to KCl
    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
    Measure Participants 9 3
    Baseline visit
    3.0
    -2.3
    End of week 1 visit
    -5.4
    -11.9
    End of week 2 visit
    -7.1
    -0.2

    Adverse Events

    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
    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 (%) # Events Affected / at Risk (%) # Events
    Total 0/9 (0%) 0/3 (0%)
    Serious Adverse Events
    Randomized to KNO3 Randomized to KCl
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/9 (0%) 0/3 (0%)
    Other (Not Including Serious) Adverse Events
    Randomized to KNO3 Randomized to KCl
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 5/9 (55.6%) 1/3 (33.3%)
    Cardiac disorders
    Palpitations 1/9 (11.1%) 0/3 (0%)
    Mild lower extremity edema 0/9 (0%) 1/3 (33.3%)
    Gastrointestinal disorders
    GI symptoms 3/9 (33.3%) 1/3 (33.3%)
    General disorders
    Any side effect 4/9 (44.4%) 1/3 (33.3%) 1
    Fatigue 1/9 (11.1%) 0/3 (0%)
    Infections and infestations
    Tooth infection 1/9 (11.1%) 0/3 (0%)
    Nervous system disorders
    Headache 2/9 (22.2%) 0/3 (0%)

    Limitations/Caveats

    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.

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Julio Chirinos
    Organization UPenn
    Phone 2158235800
    Email julio.chirinos@uphs.upenn.edu
    Responsible Party:
    University of Pennsylvania
    ClinicalTrials.gov Identifier:
    NCT02256345
    Other Study ID Numbers:
    • 01340
    First Posted:
    Oct 3, 2014
    Last Update Posted:
    Oct 3, 2017
    Last Verified:
    Aug 1, 2017