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出境医 / 临床实验 / Neuromodulation of Inflammation and Vascular Function in Systolic Heart Failure (TECO-HF)

Neuromodulation of Inflammation and Vascular Function in Systolic Heart Failure (TECO-HF)

Study Description
Brief Summary:

Heart failure (HF) is the leading cause of death in US. It is associated with abnormal vascular function termed endothelial dysfunction. It is also associated with increased stress on the blood vessels and high levels of inflammation. Vagus nerve stimulation can help improve inflammation, vascular function and vascular stress. The investigator has recently completed a study showing that 1 hour of noninvasive vagus stimulation can improve vascular health. However, it is unknown if 4 weeks of stimulation will be beneficial in systolic heart failure.

The purpose of this study is to determine if transcutaneous vagal stimulation (TVS) will lead to improvement in the function of the inner lining of participants' arteries, memory, and in the levels of certain chemical markers of arterial function in the blood.

Participants will be randomized to receive either TVS or a sham stimulation and undergo 4 weeks of stimulation. Vascular function will be assessed by several non-invasive measurements, including Flow Mediate Dilation (FMD), Pulse Wave Analysis (PWA), EndoPAT, and Laser Speckle Contrast Imaging (LSCI). Participants' memory will also be measured through electronic assessments and blood will be collected and analyzed for arterial function chemical markers.


Condition or disease Intervention/treatment Phase
Heart Failure With Reduced Ejection Fraction Device: TVS Device: SHAM Not Applicable

Detailed Description:

Visit 1: Following tests(to assess vascular function) will be done: 1. FMD 2) LSCI 3) EndoPAT and 4) Pulse wave analysis (PWA). Patients will rest for 10 minutes between each test. They will be trained to use PARASYMTM unit for TVS. Blood collected, serum/plasma will be stored at -80F. Whole blood will be collected in PAXgene tubes. Patients will be instructed to apply TVS to either ear lobule (SHAM) or Tragus(experimental arm). Baseline characteristics will be collected including data on ventricular function(LVEF and left ventricular volumes).

Visit 2 (4 weeks): Follow up tests(FMD,LSCI,EndoPAT,PWA) and repeat blood collection.

Inflammatory cytokines and vascular function assays will be performed.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effect of Neuromodulation on Inflammation, Endothelial Function and Cognitive Dysfunction in Patients With Heart Failure With Reduced Ejection Fraction
Actual Study Start Date : February 4, 2020
Estimated Primary Completion Date : May 1, 2021
Estimated Study Completion Date : May 1, 2021
Arms and Interventions
Arm Intervention/treatment
Experimental: Experimental
Active TVS will be performed by use of a Tragus stimulator device with electrodes attached to the tragus of the ear. Stimulator will be applied continuously for 1 hour daily for 4 weeks.
Device: TVS
Active TVS will be performed by use of a Tragus stimulator device with electrodes attached to the tragus of the ear. Stimulator will be applied continuously for 1 hour daily for 4 weeks

Device: SHAM
Active TVS will be performed by use of a Tragus stimulator device with electrodes attached to the earl lobule. Stimulator will be applied continuously for 1 hour daily for 4 weeks.

Sham Comparator: CONTROL
Sham TVS will be performed by use of a Tragus stimulator device with electrodes attached to the ear lobule. Stimulator will be applied continuously for 1 hour daily for 4weeks.
Device: TVS
Active TVS will be performed by use of a Tragus stimulator device with electrodes attached to the tragus of the ear. Stimulator will be applied continuously for 1 hour daily for 4 weeks

Device: SHAM
Active TVS will be performed by use of a Tragus stimulator device with electrodes attached to the earl lobule. Stimulator will be applied continuously for 1 hour daily for 4 weeks.

Outcome Measures
Primary Outcome Measures :
  1. Flow Mediated Dilation (FMD) [ Time Frame: Change in the brachial artery diameter will be compared to baseline change after 4 weeks of TVS or sham. ]
    FMD is a change in the maximal diameter of the brachial artery. Brachial artery diameter (in millimeters) will be assessed before and after 4 weeks of stimulation using standard ultrasound.

  2. Laser Speckle Contrast Imaging (LSCI) [ Time Frame: Change in the perfusion units will be determined at baseline and after 4 weeks of TVS or sham stimulation. ]
    LSCI based perfusion index and perfusion units will be calculated before and after 4 weeks of TVS or sham stimulation.

  3. EndoPAT [ Time Frame: Change in the reactive hyperemia index from baseline and after 4 weeks of TVS or SHAM stimulation ]
    Hyperemia index measured with ENDOPAT will be calculated before and after 4 weeks of TVS. Hyperemia index will be calculated using the standard ENDOPAT technique using probes placed on bilateral finger.

  4. Pulse Wave Analysis (PWA) [ Time Frame: Change in the augmentation index will be calculated at baseline and after 4 weeks of TVS or sham stimulation. ]
    Arterial elasticity. Augmentation pressure (AP) will be calculated which is expressed as a percentage of the aortic pulse pressure (PP) which is the difference of systolic and diastolic BP(mm Hg).

  5. Biomarkers of inflammation [ Time Frame: Change in these biomarkers(% change) over 4 weeks will be calculated. ]
    Inflammatory cytokines will assayed at baseline and after 4 weeks of stimulation. Cytokines assayed : Il1B,IL-6,IL-17,TNF-a,TGF-b,CRP etc- expressed in pg/ml units).

  6. Biomarkers of endothelial function and oxidative stress [ Time Frame: Change in these biomarkers(%) over 4 weeks will be calculated. ]
    Biomarkers of endothelial function and oxidative stress include: ORAC, HORAC scores expressed as %.


Secondary Outcome Measures :
  1. Cognition [ Time Frame: Change in the cognition score , as assessed by the CANTAB method will be compared at baseline and after 4 weeks of TVS or sham stimulation. ]
    Cognition score(%) calculated from Cambridge Neuropsychological Test Automated Battery -CANTAB method . This will be done using a hand held ipad.


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

1. Patients (18 years or older) with Heart failure with reduced ejection fraction (HFrEF), which is a history of symptomatic heart failure with left ventricular ejection fraction (LVEF) of < 40%.

Exclusion Criteria:

  1. Patients in overt congestive heart failure / recent acute myocardial infarction (< 3 months) or Unstable angina
  2. Active malignancy
  3. Pre-menopausal women and post-menopausal women on hormone supplements.
  4. Unilateral or bilateral vagotomy
  5. Patients with bilateral upper extremity amputation
  6. Pregnant patients
  7. End-stage renal disease
  8. End-stage liver disease
  9. History of recurrent vasovagal syncope, Sick sinus syndrome, 2nd- or 3rd-degree atrioventricular (AV) block.
  10. Patients with clinically documented upper extremity arterial disease
  11. Patients with a body mass index (BMI) >35
  12. Significant hypotension (blood pressure <90mmHg) secondary to autonomic dysfunction
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Tarun Dasari, MD 4052714742 ext 44754 tdasari@ouhsc.edu

Locations
Layout table for location information
United States, Oklahoma
University of Oklahoma Health Sciences Center Recruiting
Oklahoma City, Oklahoma, United States, 73104
Contact: Tarun Dasari, MD    405-271-8001 ext 44754    tarun-dasari@ouhsc.edu   
Principal Investigator: Tarun Dasari, MD         
Sponsors and Collaborators
University of Oklahoma
Investigators
Layout table for investigator information
Principal Investigator: Taun Dasari, MD OUHSC
Tracking Information
First Submitted Date  ICMJE March 15, 2019
First Posted Date  ICMJE May 10, 2019
Last Update Posted Date December 21, 2020
Actual Study Start Date  ICMJE February 4, 2020
Estimated Primary Completion Date May 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 26, 2019)
  • Flow Mediated Dilation (FMD) [ Time Frame: Change in the brachial artery diameter will be compared to baseline change after 4 weeks of TVS or sham. ]
    FMD is a change in the maximal diameter of the brachial artery. Brachial artery diameter (in millimeters) will be assessed before and after 4 weeks of stimulation using standard ultrasound.
  • Laser Speckle Contrast Imaging (LSCI) [ Time Frame: Change in the perfusion units will be determined at baseline and after 4 weeks of TVS or sham stimulation. ]
    LSCI based perfusion index and perfusion units will be calculated before and after 4 weeks of TVS or sham stimulation.
  • EndoPAT [ Time Frame: Change in the reactive hyperemia index from baseline and after 4 weeks of TVS or SHAM stimulation ]
    Hyperemia index measured with ENDOPAT will be calculated before and after 4 weeks of TVS. Hyperemia index will be calculated using the standard ENDOPAT technique using probes placed on bilateral finger.
  • Pulse Wave Analysis (PWA) [ Time Frame: Change in the augmentation index will be calculated at baseline and after 4 weeks of TVS or sham stimulation. ]
    Arterial elasticity. Augmentation pressure (AP) will be calculated which is expressed as a percentage of the aortic pulse pressure (PP) which is the difference of systolic and diastolic BP(mm Hg).
  • Biomarkers of inflammation [ Time Frame: Change in these biomarkers(% change) over 4 weeks will be calculated. ]
    Inflammatory cytokines will assayed at baseline and after 4 weeks of stimulation. Cytokines assayed : Il1B,IL-6,IL-17,TNF-a,TGF-b,CRP etc- expressed in pg/ml units).
  • Biomarkers of endothelial function and oxidative stress [ Time Frame: Change in these biomarkers(%) over 4 weeks will be calculated. ]
    Biomarkers of endothelial function and oxidative stress include: ORAC, HORAC scores expressed as %.
Original Primary Outcome Measures  ICMJE
 (submitted: May 7, 2019)
  • Flow Mediated Dilation (FMD) [ Time Frame: Change in the brachial artery diameter will be compared to baseline change after 8 weeks of TVS or sham. ]
    FMD is a change in the maximal diameter of the brachial artery. Brachial artery diameter (in millimeters) will be assessed before and after 8 weeks of stimulation using standard ultrasound.
  • Laser Speckle Contrast Imaging (LSCI) [ Time Frame: Change in the perfusion units will be determined at baseline and after 8 weeks of TVS or sham stimulation. ]
    LSCI based perfusion index and perfusion units will be calculated before and after 8 weeks of TVS or sham stimulation.
  • EndoPAT [ Time Frame: Change in the reactive hyperemia index from baseline and after 8 weeks of TVS or SHAM stimulation ]
    Hyperemia index measured with ENDOPAT will be calculated before and after 8 weeks of TVS. Hyperemia index will be calculated using the standard ENDOPAT technique using probes placed on bilateral finger.
  • Pulse Wave Analysis (PWA) [ Time Frame: Change in the augmentation index will be calculated at baseline and after 8 weeks of TVS or sham stimulation. ]
    Arterial elasticity. Augmentation pressure (AP) will be calculated which is expressed as a percentage of the aortic pulse pressure (PP) which is the difference of systolic and diastolic BP(mm Hg).
  • Biomarkers of inflammation [ Time Frame: Change in these biomarkers(% change) over 8 weeks will be calculated. ]
    Inflammatory cytokines will assayed at baseline and after 8 weeks of stimulation. Cytokines assayed : Il1B,IL-6,IL-17,TNF-a,TGF-b,CRP etc- expressed in pg/ml units).
  • Biomarkers of endothelial function and oxidative stress [ Time Frame: Change in these biomarkers(%) over 8 weeks will be calculated. ]
    Biomarkers of endothelial function and oxidative stress include: ORAC, HORAC scores expressed as %.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 26, 2019)
Cognition [ Time Frame: Change in the cognition score , as assessed by the CANTAB method will be compared at baseline and after 4 weeks of TVS or sham stimulation. ]
Cognition score(%) calculated from Cambridge Neuropsychological Test Automated Battery -CANTAB method . This will be done using a hand held ipad.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 7, 2019)
Cognition [ Time Frame: Change in the cognition score , as assessed by the CANTAB method will be compared at baseline and after 8 weeks of TVS or sham stimulation. ]
Cognition score(%) calculated from Cambridge Neuropsychological Test Automated Battery -CANTAB method . This will be done using a hand held ipad.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Neuromodulation of Inflammation and Vascular Function in Systolic Heart Failure
Official Title  ICMJE Effect of Neuromodulation on Inflammation, Endothelial Function and Cognitive Dysfunction in Patients With Heart Failure With Reduced Ejection Fraction
Brief Summary

Heart failure (HF) is the leading cause of death in US. It is associated with abnormal vascular function termed endothelial dysfunction. It is also associated with increased stress on the blood vessels and high levels of inflammation. Vagus nerve stimulation can help improve inflammation, vascular function and vascular stress. The investigator has recently completed a study showing that 1 hour of noninvasive vagus stimulation can improve vascular health. However, it is unknown if 4 weeks of stimulation will be beneficial in systolic heart failure.

The purpose of this study is to determine if transcutaneous vagal stimulation (TVS) will lead to improvement in the function of the inner lining of participants' arteries, memory, and in the levels of certain chemical markers of arterial function in the blood.

Participants will be randomized to receive either TVS or a sham stimulation and undergo 4 weeks of stimulation. Vascular function will be assessed by several non-invasive measurements, including Flow Mediate Dilation (FMD), Pulse Wave Analysis (PWA), EndoPAT, and Laser Speckle Contrast Imaging (LSCI). Participants' memory will also be measured through electronic assessments and blood will be collected and analyzed for arterial function chemical markers.

Detailed Description

Visit 1: Following tests(to assess vascular function) will be done: 1. FMD 2) LSCI 3) EndoPAT and 4) Pulse wave analysis (PWA). Patients will rest for 10 minutes between each test. They will be trained to use PARASYMTM unit for TVS. Blood collected, serum/plasma will be stored at -80F. Whole blood will be collected in PAXgene tubes. Patients will be instructed to apply TVS to either ear lobule (SHAM) or Tragus(experimental arm). Baseline characteristics will be collected including data on ventricular function(LVEF and left ventricular volumes).

Visit 2 (4 weeks): Follow up tests(FMD,LSCI,EndoPAT,PWA) and repeat blood collection.

Inflammatory cytokines and vascular function assays will be performed.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Heart Failure With Reduced Ejection Fraction
Intervention  ICMJE
  • Device: TVS
    Active TVS will be performed by use of a Tragus stimulator device with electrodes attached to the tragus of the ear. Stimulator will be applied continuously for 1 hour daily for 4 weeks
  • Device: SHAM
    Active TVS will be performed by use of a Tragus stimulator device with electrodes attached to the earl lobule. Stimulator will be applied continuously for 1 hour daily for 4 weeks.
Study Arms  ICMJE
  • Experimental: Experimental
    Active TVS will be performed by use of a Tragus stimulator device with electrodes attached to the tragus of the ear. Stimulator will be applied continuously for 1 hour daily for 4 weeks.
    Interventions:
    • Device: TVS
    • Device: SHAM
  • Sham Comparator: CONTROL
    Sham TVS will be performed by use of a Tragus stimulator device with electrodes attached to the ear lobule. Stimulator will be applied continuously for 1 hour daily for 4weeks.
    Interventions:
    • Device: TVS
    • Device: SHAM
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 7, 2019)
50
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 1, 2021
Estimated Primary Completion Date May 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

1. Patients (18 years or older) with Heart failure with reduced ejection fraction (HFrEF), which is a history of symptomatic heart failure with left ventricular ejection fraction (LVEF) of < 40%.

Exclusion Criteria:

  1. Patients in overt congestive heart failure / recent acute myocardial infarction (< 3 months) or Unstable angina
  2. Active malignancy
  3. Pre-menopausal women and post-menopausal women on hormone supplements.
  4. Unilateral or bilateral vagotomy
  5. Patients with bilateral upper extremity amputation
  6. Pregnant patients
  7. End-stage renal disease
  8. End-stage liver disease
  9. History of recurrent vasovagal syncope, Sick sinus syndrome, 2nd- or 3rd-degree atrioventricular (AV) block.
  10. Patients with clinically documented upper extremity arterial disease
  11. Patients with a body mass index (BMI) >35
  12. Significant hypotension (blood pressure <90mmHg) secondary to autonomic dysfunction
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Tarun Dasari, MD 4052714742 ext 44754 tdasari@ouhsc.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03945058
Other Study ID Numbers  ICMJE 10410
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University of Oklahoma
Study Sponsor  ICMJE University of Oklahoma
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Taun Dasari, MD OUHSC
PRS Account University of Oklahoma
Verification Date December 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP