xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT06027606</url>
    </required_header>
    <id_info>
      <org_study_id>Pro00126438</org_study_id>
      <nct_id>NCT06027606</nct_id>
    </id_info>
    <brief_title>Cardiovascular Consequences of Inhaled Short-acting Beta-agonist Use</brief_title>
    <official_title>Cardiovascular Consequences of Prolonged Inhaled Short-acting Beta-agonist Use in Healthy Participants</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>University of Alberta</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>University of Alberta</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
      <is_us_export>No</is_us_export>
    </oversight_info>
    <brief_summary>
      <textblock>
        The goal of this clinical trial is to test the impact inhalers have on blood vessels in young&#xD;
        healthy individuals. The main question it aims to answer is if long term use of asthma&#xD;
        inhalers have any effect on the blood vessels and heart. Participants will be asked to:&#xD;
  &#xD;
          -  Perform lung function and exercise tests&#xD;
  &#xD;
          -  Have ultrasound images taken of the artery in their arm&#xD;
  &#xD;
          -  Use an inhaler for 4 weeks&#xD;
  &#xD;
          -  Visit the lab for testing on 4-6 different occasions&#xD;
  &#xD;
        Researchers will compare two different inhalers (Ventolin and Symbicort) with a placebo to&#xD;
        see if the inhalers have any effect on the blood vessels over the 4 week period.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Session 1) The first visit is a screening visit where participants will be invited to our&#xD;
        Clinical Sciences Building research lab to conduct pulmonary function testing and&#xD;
        cardiopulmonary exercise testing. A small blood sample will be collected via finger prick to&#xD;
        measure hemoglobin. The cardiopulmonary screening will ensure no underlining health problems&#xD;
        are observed in the participant which would exclude them from the study. This visit will take&#xD;
        ~2 hours.&#xD;
  &#xD;
        Session 2) The second visit will occur within 1 week of the first visit. On the second visit,&#xD;
        participants will arrive fasted (12 hours) and be asked not to consume caffeine or perform&#xD;
        exercise 8 hours prior to arriving. These restrictions ensure accuracy in our measurement of&#xD;
        vascular reactivity. Measurement of cardiovascular function using heart rate, blood pressure,&#xD;
        flow-mediated dilation, and pulse wave velocity after 10 minutes of supine rest will occur.&#xD;
        Participants will be randomized to one of three study arms: 1) salbutamol (2x200mcg), 2)&#xD;
        budesonide-formoterol (1x400mcg), or 3) placebo (2x0mcg). Upon receiving their group&#xD;
        allocation, an unblinded member of the research team will help the participant in taking the&#xD;
        required dosage, and then the participant will return to 10 minutes of supine rest. Heart&#xD;
        rate, blood pressure, flow-mediated dilation, and pulse wave velocity will then be&#xD;
        re-evaluated by a blinded member of the research team. Session 2 should take approximate ~1.5&#xD;
        hours.&#xD;
  &#xD;
        Session 2A) Participants will be asked to sign a second, optional, informed consent form&#xD;
        outlining the additional measures, techniques, and risks that are associated with the&#xD;
        protocol. Participants will rest in the supine position and have an intravenous line inserted&#xD;
        into the cubital fossa of the forearm. A small amount of blood will be pulled for sex hormone&#xD;
        analysis. A 3-lead electrocardiogram will be attached, and finger blood pressure will be&#xD;
        monitored beat-by-beat. Cardiac output will be estimated using cardiac ultrasound, while&#xD;
        brachial blood flow will be estimated using doppler ultrasound. Muscle sympathetic nervous&#xD;
        activity will be measured in the peroneal nerve using microneurography. Lung diffusing&#xD;
        capacity and its components will be evaluated by standardized breath-hold techniques. In&#xD;
        short, participants inhale a very small amount of carbon monoxide and methane and hold their&#xD;
        breath for 6 seconds before rapidly exhaling . This maneuver is completed three times using&#xD;
        21%, 40%, and 60% oxygen concentration to determine diffusing capacity and pulmonary vascular&#xD;
        function. After obtaining baseline measures of all outcomes, a beta-agonist (isoproterenol)&#xD;
        will be injected through the intravenous line at a starting dosage of 0.01 μg∙kg-1∙min-1 for&#xD;
        10 minutes and increase in a stepwise manner at a rate of 0.01 μg∙kg-1∙min-1 every 10 minutes&#xD;
        to a maximal rate of 0.04 μg∙kg-1∙min-1. The incremental dosages creating a dose-response&#xD;
        curve for the variables blood pressure, heart rate, cardiac output, and brachial blood flow&#xD;
        with a reduced curve indicating less β-receptor sensitivity. All values will be obtained&#xD;
        within the last two minutes of the 10-minute dosage. Lung diffusing capacity will be&#xD;
        evaluated following the final dosage of isoproterenol. Upon completion of infusion and data&#xD;
        acquisition, participants will remain resting until blood pressure and heart rate return to&#xD;
        baseline values. This session will be completed within 2 weeks of session 1 and will take ~2&#xD;
        hours.&#xD;
  &#xD;
        Intervention: Following either session 2 or 2A if the participant consented to the additional&#xD;
        testing session, participants will then be sent home with their inhaler and dosage regimen&#xD;
        and complete the intervention for 4-weeks, filling out questionnaires to monitor symptoms&#xD;
        each week. Inhalers will be equipped with electronic trackers to calculate the number of&#xD;
        doses the participants have received.&#xD;
  &#xD;
        Session 3) Following the 4-week intervention, participants will then replicate session 1 with&#xD;
        a pulmonary function test and exercise test spanning ~2 hours. As completed during the first&#xD;
        session, a small blood sample will be collected via finger prick to measure hemoglobin. This&#xD;
        session will occur within 1-2 days of completing the 4-week intervention.&#xD;
  &#xD;
        Session 4) Participants will be asked to arrive fasted (12 hours) and be asked not to consume&#xD;
        caffeine or perform exercise 8 hours prior to arriving. The session will consist of the same&#xD;
        measurements (pulse wave velocity, blood pressure, heart rate, and flow-mediated dilation)&#xD;
        and procedure as Session 2 and spanning ~1.5 hours. This session will occur between 2-4 days&#xD;
        following the intervention.&#xD;
  &#xD;
        Session 4A) Those partaking in the additional optional visits would also then complete visit&#xD;
        4A which would be the same protocol as visit 2A and take ~2 hours to complete. This session&#xD;
        will occur 3-6 days following intervention.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">September 1, 2023</start_date>
    <completion_date type="Anticipated">December 2024</completion_date>
    <primary_completion_date type="Anticipated">August 2024</primary_completion_date>
    <phase>Phase 1</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <primary_purpose>Basic Science</primary_purpose>
      <masking>Double (Participant, Investigator)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Pulse wave velocity</measure>
      <time_frame>Up to 3 days following intervention completion</time_frame>
      <description>Velocity of blood flow between pulse points</description>
    </primary_outcome>
    <primary_outcome>
      <measure>% Increase in Brachial Artery Diameter (Flow Mediated Dilation (FMD))</measure>
      <time_frame>Up to 3 days following intervention completion</time_frame>
      <description>Brachial artery dilation following suprasystolic occlusion</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Muscle sympathetic nerve activity</measure>
      <time_frame>Up to 5 days following intervention completion</time_frame>
      <description>Burst frequency of sympathetic nerve following intervention</description>
    </secondary_outcome>
    <number_of_arms>3</number_of_arms>
    <enrollment type="Anticipated">90</enrollment>
    <condition>Healthy</condition>
    <arm_group>
      <arm_group_label>Salbutamol</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Participants are healthy and between the ages of 18-40 years old</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Budesonide-formoterol</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Participants are healthy and between the ages of 18-40 years old</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Placebo</arm_group_label>
      <arm_group_type>Sham Comparator</arm_group_type>
      <description>Participants are healthy and between the ages of 18-40 years old</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Salbutamol 400mcg</intervention_name>
      <description>Salbutamol is a short-acting beta-agonist used primarily as a rescue inhaler for respiratory disease such as asthma</description>
      <arm_group_label>Salbutamol</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Budesonide/formoterol</intervention_name>
      <description>Budesonide/formoterol is a inhaled corticosteroid with long-acting beta-agonist component primarily used as a maintenance inhaler for respiratory conditions such as asthma</description>
      <arm_group_label>Budesonide-formoterol</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Placebo</intervention_name>
      <description>Practice inhaler primarily used in training scenarios so looks identical to medical inhalers</description>
      <arm_group_label>Placebo</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Healthy participants between the ages of 18-40 years free from a medical history of&#xD;
               cardiopulmonary disease&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Absolute contraindication to exercise testing or an orthopedic condition that may&#xD;
               limit exercise testing as identified by standardized health screening tool (PAR-Q+).&#xD;
  &#xD;
            -  Abnormal findings during the pulmonary function test and/or cardiopulmonary exercise&#xD;
               test including pulmonary function values below the lower limit of normal, decrease in&#xD;
               FEV1 following exercise (&gt;10%), tachycardia (&gt;100bpm at rest), and resting&#xD;
               hypertension (&gt;140/90 mmHg).&#xD;
  &#xD;
            -  Pre-existing cardiac conditions (heart failure, congenital heart defect, valvular&#xD;
               disease) that may limit exercise testing.&#xD;
  &#xD;
            -  Comorbidities such as diabetes, dyslipidemia, liver disease, neuromuscular disease,&#xD;
               renal disease, and respiratory disease&#xD;
  &#xD;
            -  Prescription of medical inhaler&#xD;
  &#xD;
            -  History of inhalants usage for greater than 1 year including but not limited to&#xD;
               cigarettes, marijuana, and vaporizers.&#xD;
  &#xD;
            -  Pregnancy or lactation&#xD;
  &#xD;
            -  Women of childbearing potential must be willing to use an acceptable method of&#xD;
               contraception to avoid pregnancy throughout the study. Acceptable methods of&#xD;
               contraception include tubal ligation, oral contraceptive, and barrier methods.&#xD;
               Abstinence is an acceptable form of contraception, only insofar as patients agree to&#xD;
               use another acceptable method of birth control, preferably a barrier method, if they&#xD;
               become sexually active.&#xD;
  &#xD;
            -  Medication usage of monoamine oxidase inhibitors, tricyclic antidepressants,&#xD;
               beta-blockers, diuretics, digoxin, other inhaled sympathomimetric bronchodilators or&#xD;
               epinephrine, ritonavir, ketoconazole, itraconazole, cytochrome P450 sA4 inhibitors,&#xD;
               xanthine derivatives, steroids, non-potassium sparing diuretics, L-Dopa, L-thyroxine,&#xD;
               and oxytocin.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>40 Years</maximum_age>
      <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Tracey Bryan, MD</last_name>
      <role>Study Director</role>
      <affiliation>University of Alberta</affiliation>
    </overall_official>
    <overall_official>
      <last_name>Michael K Stickland, PhD</last_name>
      <role>Principal Investigator</role>
      <affiliation>University of Alberta</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Desi P Fuhr, MSc</last_name>
      <phone>7804921121</phone>
      <email>fuhr@ualberta.ca</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Andrew R Brotto, MSc</last_name>
      <phone>7804921121</phone>
      <email>abrotto@ualberta.ca</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Clinical Physiology Laboratory</name>
        <address>
          <city>Edmonton</city>
          <state>Alberta</state>
          <zip>T6G2R3</zip>
          <country>Canada</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Desi Fuhr, MSc</last_name>
        <phone>780-492-1121</phone>
        <email>fuhr@ualberta.ca</email>
      </contact>
      <contact_backup>
        <last_name>Michael K Stickland, PhD</last_name>
        <phone>780-492-3995</phone>
        <email>michael.stickland@ualberta.ca</email>
      </contact_backup>
    </location>
    <location_countries>
      <country>Canada</country>
    </location_countries>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>August 9, 2023</study_first_submitted>
    <study_first_submitted_qc>September 5, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 7, 2023</study_first_posted>
    <last_update_submitted>September 5, 2023</last_update_submitted>
    <last_update_submitted_qc>September 5, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 7, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Budesonide</mesh_term>
      <mesh_term>Albuterol</mesh_term>
      <mesh_term>Formoterol Fumarate</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT06027606
  org study id: Pro00126438
  nct id: NCT06027606
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  is us export: No
  The goal of this clinical trial is to test the impact inhalers have on blood vessels in young
        healthy individuals. The main question it aims to answer is if long term use of asthma
        inhalers have any effect on the blood vessels and heart. Participants will be asked to:
  
          -  Perform lung function and exercise tests
  
          -  Have ultrasound images taken of the artery in their arm
  
          -  Use an inhaler for 4 weeks
  
          -  Visit the lab for testing on 4-6 different occasions
  
        Researchers will compare two different inhalers (Ventolin and Symbicort) with a placebo to
        see if the inhalers have any effect on the blood vessels over the 4 week period.
  Session 1) The first visit is a screening visit where participants will be invited to our
        Clinical Sciences Building research lab to conduct pulmonary function testing and
        cardiopulmonary exercise testing. A small blood sample will be collected via finger prick to
        measure hemoglobin. The cardiopulmonary screening will ensure no underlining health problems
        are observed in the participant which would exclude them from the study. This visit will take
        ~2 hours.
  
        Session 2) The second visit will occur within 1 week of the first visit. On the second visit,
        participants will arrive fasted (12 hours) and be asked not to consume caffeine or perform
        exercise 8 hours prior to arriving. These restrictions ensure accuracy in our measurement of
        vascular reactivity. Measurement of cardiovascular function using heart rate, blood pressure,
        flow-mediated dilation, and pulse wave velocity after 10 minutes of supine rest will occur.
        Participants will be randomized to one of three study arms: 1) salbutamol (2x200mcg), 2)
        budesonide-formoterol (1x400mcg), or 3) placebo (2x0mcg). Upon receiving their group
        allocation, an unblinded member of the research team will help the participant in taking the
        required dosage, and then the participant will return to 10 minutes of supine rest. Heart
        rate, blood pressure, flow-mediated dilation, and pulse wave velocity will then be
        re-evaluated by a blinded member of the research team. Session 2 should take approximate ~1.5
        hours.
  
        Session 2A) Participants will be asked to sign a second, optional, informed consent form
        outlining the additional measures, techniques, and risks that are associated with the
        protocol. Participants will rest in the supine position and have an intravenous line inserted
        into the cubital fossa of the forearm. A small amount of blood will be pulled for sex hormone
        analysis. A 3-lead electrocardiogram will be attached, and finger blood pressure will be
        monitored beat-by-beat. Cardiac output will be estimated using cardiac ultrasound, while
        brachial blood flow will be estimated using doppler ultrasound. Muscle sympathetic nervous
        activity will be measured in the peroneal nerve using microneurography. Lung diffusing
        capacity and its components will be evaluated by standardized breath-hold techniques. In
        short, participants inhale a very small amount of carbon monoxide and methane and hold their
        breath for 6 seconds before rapidly exhaling . This maneuver is completed three times using
        21%, 40%, and 60% oxygen concentration to determine diffusing capacity and pulmonary vascular
        function. After obtaining baseline measures of all outcomes, a beta-agonist (isoproterenol)
        will be injected through the intravenous line at a starting dosage of 0.01 μg∙kg-1∙min-1 for
        10 minutes and increase in a stepwise manner at a rate of 0.01 μg∙kg-1∙min-1 every 10 minutes
        to a maximal rate of 0.04 μg∙kg-1∙min-1. The incremental dosages creating a dose-response
        curve for the variables blood pressure, heart rate, cardiac output, and brachial blood flow
        with a reduced curve indicating less β-receptor sensitivity. All values will be obtained
        within the last two minutes of the 10-minute dosage. Lung diffusing capacity will be
        evaluated following the final dosage of isoproterenol. Upon completion of infusion and data
        acquisition, participants will remain resting until blood pressure and heart rate return to
        baseline values. This session will be completed within 2 weeks of session 1 and will take ~2
        hours.
  
        Intervention: Following either session 2 or 2A if the participant consented to the additional
        testing session, participants will then be sent home with their inhaler and dosage regimen
        and complete the intervention for 4-weeks, filling out questionnaires to monitor symptoms
        each week. Inhalers will be equipped with electronic trackers to calculate the number of
        doses the participants have received.
  
        Session 3) Following the 4-week intervention, participants will then replicate session 1 with
        a pulmonary function test and exercise test spanning ~2 hours. As completed during the first
        session, a small blood sample will be collected via finger prick to measure hemoglobin. This
        session will occur within 1-2 days of completing the 4-week intervention.
  
        Session 4) Participants will be asked to arrive fasted (12 hours) and be asked not to consume
        caffeine or perform exercise 8 hours prior to arriving. The session will consist of the same
        measurements (pulse wave velocity, blood pressure, heart rate, and flow-mediated dilation)
        and procedure as Session 2 and spanning ~1.5 hours. This session will occur between 2-4 days
        following the intervention.
  
        Session 4A) Those partaking in the additional optional visits would also then complete visit
        4A which would be the same protocol as visit 2A and take ~2 hours to complete. This session
        will occur 3-6 days following intervention.
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Basic Science
  masking: Double (Participant, Investigator)
  measure: Pulse wave velocity
  time frame: Up to 3 days following intervention completion
  description: Velocity of blood flow between pulse points
  measure: % Increase in Brachial Artery Diameter (Flow Mediated Dilation (FMD))
  time frame: Up to 3 days following intervention completion
  description: Brachial artery dilation following suprasystolic occlusion
  measure: Muscle sympathetic nerve activity
  time frame: Up to 5 days following intervention completion
  description: Burst frequency of sympathetic nerve following intervention
  arm group label: Salbutamol
  arm group type: Experimental
  description: Participants are healthy and between the ages of 18-40 years old
  arm group label: Budesonide-formoterol
  arm group type: Experimental
  description: Participants are healthy and between the ages of 18-40 years old
  arm group label: Placebo
  arm group type: Sham Comparator
  description: Participants are healthy and between the ages of 18-40 years old
  intervention type: Drug
  intervention name: Salbutamol 400mcg
  description: Salbutamol is a short-acting beta-agonist used primarily as a rescue inhaler for respiratory disease such as asthma
  arm group label: Salbutamol
  intervention type: Drug
  intervention name: Budesonide/formoterol
  description: Budesonide/formoterol is a inhaled corticosteroid with long-acting beta-agonist component primarily used as a maintenance inhaler for respiratory conditions such as asthma
  arm group label: Budesonide-formoterol
  intervention type: Drug
  intervention name: Placebo
  description: Practice inhaler primarily used in training scenarios so looks identical to medical inhalers
  arm group label: Placebo
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 40 Years
  healthy volunteers: Accepts Healthy Volunteers
  last name: Tracey Bryan, MD
  role: Study Director
  affiliation: University of Alberta
  last name: Michael K Stickland, PhD
  role: Principal Investigator
  affiliation: University of Alberta
  last name: Desi P Fuhr, MSc
  phone: 7804921121
  email: fuhr@ualberta.ca
  last name: Andrew R Brotto, MSc
  phone: 7804921121
  email: abrotto@ualberta.ca
  facility: 
  status: Recruiting
  contact: 
  contact backup: 
  country: Canada
  responsible party type: Sponsor
  mesh term: Budesonide
  mesh term: Albuterol
  mesh term: Formoterol Fumarate
  sharing ipd: No