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Secondhand Tobacco Smoke and Cardiovascular Disease

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ClinicalTrials.gov Identifier: NCT04715568
Recruitment Status : Recruiting
First Posted : January 20, 2021
Last Update Posted : April 21, 2021
Sponsor:
Collaborator:
Flight Attendant Medical Research Institute
Information provided by (Responsible Party):
University of California, San Francisco

Brief Summary:
This is a double-blind randomized placebo-controlled crossover clinical trial of efficacy and safety of an FDA-approved angiotensin receptor blocker (losartan) to improve cardiopulmonary outcomes in individuals with pre-Chronic Obstructive Pulmonary Disease (COPD) due to prolonged exposure to secondhand tobacco smoke.

Condition or disease Intervention/treatment Phase
Cardiovascular Diseases Hypertension Drug: Losartan Drug: Placebo Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Double-blind randomized placebo-controlled crossover clinical trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: All investigators, research staff, and subjects, with the exception of the San Francisco Veteran's Administration (VA) Medical Center Research Pharmacist, will be blinded to the treatment.
Primary Purpose: Treatment
Official Title: Occult Cardiovascular Disease With Chronic Exposure to Secondhand Tobacco Smoke
Actual Study Start Date : March 30, 2021
Estimated Primary Completion Date : December 31, 2025
Estimated Study Completion Date : December 31, 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Placebo then Losartan
Placebo tablets will be administered for the first 4 weeks followed by a washout period of 2 weeks. After the washout period has been completed, losartan tablets will be administered for the next 4 weeks.
Drug: Losartan
50 mg tablets taken orally
Other Names:
  • Cozaar
  • Angiotensin II Receptor Blocker
  • Antihypertensive

Drug: Placebo
Tablets taken orally
Other Name: Inactive drug

Experimental: Losartan then Placebo
Losartan tablets will be administered for the first 4 weeks followed by a washout period of 2 weeks. After the washout period has been completed, placebo tablets will be administered for the next 4 weeks.
Drug: Losartan
50 mg tablets taken orally
Other Names:
  • Cozaar
  • Angiotensin II Receptor Blocker
  • Antihypertensive

Drug: Placebo
Tablets taken orally
Other Name: Inactive drug




Primary Outcome Measures :
  1. Mean Left Ventricular Ejection Fraction (LVEF) [ Time Frame: Baseline, approximately 1 day ]
    LVEF will be measured using Magnetic Resonance Imaging (MRI) using General Electric 1.5 Tesla MRI system without gadolinium contrast. In accordance with the American College of Cardiology (ACC), results will be reported quantitatively and qualitatively as follows: Hyperdynamic = LVEF greater than 70%, Normal = LVEF 50% to 70% (midpoint 60%), Mild dysfunction = LVEF 40% to 49% (midpoint 45%), Moderate dysfunction = LVEF 30% to 39% (midpoint 35%), Severe dysfunction = LVEF less than 30%.

  2. Mean Aortic pulse wave velocity (PWV) [ Time Frame: Baseline, approximately 1 day ]
    Aortic pulse wave velocity (PWV) is a marker of aortic stiffness and will be measured (in meters/second) by regional PWV measurement in the thoracic aorta from the MRI (General Electric 1.5 Tesla MRI system without gadolinium contrast).

  3. Change in Prevalence of CD14++CD16- [ Time Frame: Up to 10 weeks ]
    CD14++CD16- are markers of pro-inflammatory phenotypes that will be measured among peripheral blood monocytes using mass cytometry.

  4. Change in Mean Peak Oxygen Consumption (VO2 Peak) Level [ Time Frame: Up to 10 weeks ]
    VO2 Peak is the peak rate of oxygen consumption in milliliters per kilogram per minute (mL/(kg·min) measured during incremental exercise on a Cardio-Pulmonary Exercise Test (CPET). Patients are encouraged to exercise to their maximum endurance or until the nurse ends exercise due to symptoms like pain, dizziness, syncope, excessive dyspnea, or leg discomfort.


Secondary Outcome Measures :
  1. Mean Left Ventricular Mass [ Time Frame: Baseline, approximately 1 day ]
    Left ventricular mass will be measured (in grams/m2) using cardiac MRI (General Electric 1.5 Tesla MRI system without gadolinium contrast).

  2. Mean Left Ventricular Volume [ Time Frame: Baseline, approximately 1 day ]
    Left ventricular volume will be measured (in mL) using cardiac MRI (General Electric 1.5 Tesla MRI system without gadolinium contrast).

  3. Change in Mean Angiotensin Converting Enzyme (ACE) Level [ Time Frame: Up to 10 weeks ]
    ACE is a central component of the renin-angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. Level of ACE will be measured in micrograms per liter from peripheral blood sample.

  4. Change in Mean C-Reactive Protein (CRP) Level [ Time Frame: At baseline assessment (V1); 4th week of V2 (placebo/losartan) treatment period; and 4th week of V3 (placebo/losartan) treatment period ]
    CRP is an acute phase reactant and will be measured (in mg/L) from peripheral blood sample.

  5. Change in Mean Endothelin-1 Level [ Time Frame: Up to 10 weeks ]
    Endothelin-1 is a potent vasoconstrictor produced by vascular endothelial cells and will be measured from peripheral blood sample.

  6. Change in Mean P-selectin Level [ Time Frame: Up to 10 weeks ]
    P-selectin is a transmembrane glycoprotein that functions as a cell adhesion molecule on the surfaces of activated endothelial cells and will be measured from peripheral blood sample.

  7. Change in Mean Fibrinogen Level [ Time Frame: Up to 10 weeks ]
    Fibrinogen is a glycoprotein that plays a pivotal role in normal homeostasis as a substrate for conversion to fibrin and a facilitator of wound healing. It will be measured in milligrams per deciliter from peripheral blood sample.

  8. Change in Mean von Willebrand Factor (VWF) [ Time Frame: Up to 10 weeks ]
    VWF is a large multimeric glycoprotein that performs critical functions in primary hemostasis. It will be measured in micrograms per deciliter from peripheral blood sample.

  9. Change in Mean Maximum Workload [ Time Frame: Up to 10 weeks ]
    The maximum amount of workload achieved (in watts) during an incremental CPET.

  10. Change in Mean Maximum Oxygen Pulse [ Time Frame: Up to 10 weeks ]
    Oxygen pulse is the ratio between Oxygen consumption (VO2) and heart rate. The maximum O2-pulse (mL/beat), a proxy for stroke volume, will be measured during incremental CPET.

  11. Change in Mean Slope of Systolic Blood Pressure (SBP) [ Time Frame: Up to 10 weeks ]
    The rate at which the SBP increases over the workload achieved in watts during an incremental CPET is the Slope of SBP.

  12. Change in Mean Slope of Diastolic Blood Pressure (DBP) [ Time Frame: Up to 10 weeks ]
    The rate at which the DBP increases over the workload achieved in watts during an incremental CPET is the Slope of DBP.

  13. Change in Mean Slope of Heart Rate (HR) [ Time Frame: Up to 10 weeks ]
    The rate at which the HR increases over the workload achieved in watts during an incremental CPET is the Slope of HR.

  14. Change in Mean Change in Borg Score [ Time Frame: Up to 10 weeks ]
    Borg Rating of perceived exertion is a widely used and reliable indicator to monitor and guide exercise intensity. The scale allows individuals to subjectively rate their level of exertion during exercise testing. The revised category-ratio scale (0 to 10 scale) will be used, where 0 indicates no perceived exertion and 10 indicates maximal perceived exertion.

  15. Change in Mean Moderate-to-Vigorous Physical Activity (MVPA) [ Time Frame: Up to 10 weeks ]
    MVPA is measured with Metabolic Equivalents (METs). A MET is the ratio of a person's working metabolic rate compared to their resting metabolic rate. MVPA is any activity over 3 METs. An Actigraph monitor will be used to measure MVPA.



Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Must be able to understand and provide informed consent.
  • Adults >= 40 years of age.
  • Must have a history of occupational exposure to secondhand tobacco smoke for at least 5 years such as flight attendants who worked for airlines before the smoking ban on aircrafts went into effect or casino workers who worked at casinos with no smoke-free policies.
  • Must have never smoked or have a remote history of light smoking defined as follows:

    • Lifetime smoking history equivalent to < 1 pack-year and
    • No smoking history for >= 20 years at the time of enrollment.

Exclusion Criteria:

  • Inability or unwillingness of a participant to give written informed consent or comply with study protocol.
  • Subject is pregnant, breast-feeding, or plans to become pregnant.
  • Current therapy with angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB).
  • Known intolerance to ACE inhibitor or ARB.
  • History of angioedema.
  • Conventional indication for ACE inhibitor or ARB (e.g., history of myocardial infarction, known cardiomyopathy).
  • Blood pressure less than 90 mm Hg systolic or 60 mm Hg diastolic while standing or sitting.
  • Known unilateral or bilateral renal artery stenosis higher than 70%.
  • Renal insufficiency (Creatinine Clearance <30 mL/min by Cockcroft-Gault calculation).
  • Current regular use of NSAIDs defined as daily use on 5 or more days of the week for more than one month.
  • Potassium supplementation or serum potassium level of 5.0 milliequivalents (mEq)/dL or higher at V1.
  • Current use of a potassium sparing diuretic.
  • History of clinically overt cardiovascular disease including: stable or unstable angina; chest discomfort and dyspnea with baseline exertion; symptomatic coronary artery disease (as defined by history of abnormal stress test; cardiac catheterization showing >70% coronary artery stenosis; history of revascularization; pathologic Q waves on EKG); poorly controlled resting hypertension (SBP>160/ DBP>95); congestive heart failure (CHF) (as defined by left ventricular ejection fraction (LVEF) <55%; physical exam findings of CHF; symptomatic pulmonary edema); significant (>mild) valvular heart disease; congenital heart disease; cardiac arrhythmias including frequent premature atrial or ventricular contractions (>5 per minute).
  • History of clinically overt pulmonary disease that may interfere with study procedures, including: greater than mild asthma, COPD, emphysema, chronic interstitial lung disease, and pulmonary hypertension.
  • Neuromuscular disorders or physical disability to perform exercise testing using an ergometer.
  • Significant history of recreational drug use other than marijuana as defined by: recreational drug use within the last 30 years of recruitment (or) recreational drug use at a frequency of more than once a month before 30 years.
  • Marijuana use more than once a week.
  • Other uncontrolled chronic illnesses which in the judgment of the study physician would interfere with completing study procedures.
  • Failure to keep screening appointments or other indicators of non-adherence.
  • Concomitant participation in another interventional study.
  • Subjects with BMI <15 or >40 kg/m2.
  • MRI Scan Participation Exclusion Criteria - The participants will be excluded from the MRI portion of the study if they have a metallic object embedded or implanted in their body that is incompatible with Magnetic Resonance (MR) scanning, including MR incompatible pacemaker or defibrillator.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04715568


Contacts
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Contact: Mehrdad Arjomandi, MD (415)221-4810 ext 24393 mehrdad.arjomandi@ucsf.edu

Locations
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United States, California
San Francisco Veterans' Affairs Medical Center Recruiting
San Francisco, California, United States, 94121
Contact: Mehrdad Arjomandi, MD    415-221-4810 ext 24393    mehrdad.arjomandi@ucsf.edu   
Sponsors and Collaborators
University of California, San Francisco
Flight Attendant Medical Research Institute
Investigators
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Principal Investigator: Mehrdad Arjomandi, MD University of California, San Francisco
Additional Information:
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Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT04715568    
Other Study ID Numbers: 20-30189
First Posted: January 20, 2021    Key Record Dates
Last Update Posted: April 21, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by University of California, San Francisco:
Second Hand Tobacco Smoke
Additional relevant MeSH terms:
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Cardiovascular Diseases
Losartan
Antihypertensive Agents
Angiotensin II
Angiotensin Receptor Antagonists
Anti-Arrhythmia Agents
Angiotensin II Type 1 Receptor Blockers
Molecular Mechanisms of Pharmacological Action
Vasoconstrictor Agents