<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/NCT03034005</url>
  </required_header>
  <id_info>
    <org_study_id>2016-003509-33</org_study_id>
    <nct_id>NCT03034005</nct_id>
  </id_info>
  <brief_title>The RECONSTRUCT Study - Reconstructing Disease Mechanisms in Asthma</brief_title>
  <acronym>RECONSTRUCT</acronym>
  <official_title>The RECONSTRUCT Study - Reconstructing Disease Mechanisms in Asthma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Bispebjerg Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Bispebjerg Hospital</source>
  <oversight_info>
    <has_dmc>Yes</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>
      This study aims to assess the effect of inhaled corticosteroids (ICS) on airway smooth muscle&#xD;
      (ASM) Na+, K+ pumps in patients with asthma.We wish to investigate differences in Na+, K+&#xD;
      pump content in healthy versus asthmatic patients, whether a reduction in airway&#xD;
      hyper-responsiveness observed in asthmatic patients treated with ICS is attributable to an&#xD;
      increase in Na+, K+ pump content in ASM cells and compare this in patients with&#xD;
      non-eosinophilic asthma versus eosinophilic asthma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Purpose and background&#xD;
&#xD;
      Inhaled corticosteroids and asthma phenotypes Inhaled corticosteroid (ICS) is a cornerstone&#xD;
      in the treatment of asthma. ICS acts locally in the airways through several pathways to limit&#xD;
      inflammation, primarily through reduction of eosinophilic inflammation.&#xD;
&#xD;
      In clinical practice however a substantial part of adult patients with asthma have no&#xD;
      eosinophilic inflammation in the airways despite reduced lung function and increased&#xD;
      contractility of the smooth muscles in the airways i.e., airway hyperresponsiveness(AHR).&#xD;
      This group of patients with non-eosinophilic asthma (NEA) represents up to 50 % of adult&#xD;
      asthmatics with even higher occurrence among patients referred to a specialist.&#xD;
&#xD;
      The effect of ICS in NEA is debated but despite lack of eosinophilic inflammation, ICS has&#xD;
      been shown to significantly reduce AHR in patients with NEA, suggesting mechanistic pathways&#xD;
      different from reduction in eosinophilic inflammation.&#xD;
&#xD;
      Airway smooth muscle and inhaled corticosteroids Airway smooth muscle (ASM) is the most&#xD;
      abundant tissue type in the airways. It plays a crucial part in the pathogenesis of asthma&#xD;
      and serves as an important target for therapy especially with β-adrenergic agents and to some&#xD;
      extent anti-muscarinic agents, counteracting bronchoconstriction. However also ICS has been&#xD;
      proposed to have direct action on ASM cells affecting contractility through reduction of&#xD;
      intracellular Ca2+ or down regulation of membrane bound receptors as well as through limiting&#xD;
      cellular proliferation and secretory function. The bronchodilating effect of β-adrenergic&#xD;
      agents has in animal models shown to be potentiated by administration of corticosteroids.&#xD;
&#xD;
      Inhaled corticosteroids and the Na+, K+ pump Both ICS and systemically administered&#xD;
      prednisone has been shown to increase Na+, K+ pump activity in leucocytes from patients with&#xD;
      asthma and in both rats and humans systemically administered corticosteroid increases the&#xD;
      amount of Na+, K+ pumps in striated muscle by 20-40 % and 30-60 % respectively. We have&#xD;
      recently demonstrated a similar effect with ICS where a therapeutically relevant daily dose&#xD;
      of 1600 μg budesonide, administered in the respiratory tract by inhalation, increased the&#xD;
      amount of Na+, K+ pumps in striated muscle by 17 %.&#xD;
&#xD;
      1.1.4 The Na+, K+ pump and airway smooth muscle The Na+, K+ pump creates an inward Na+&#xD;
      current by removing Na+ from the intracellular lumen of cells. This may drive extrusion of&#xD;
      Ca2+ from the lumen of the ASM cells through the Na+, Ca2+ exchanger lowering intracellular&#xD;
      Ca2+ concentration. Since Ca2+ plays a central role in smooth muscle contraction, lower&#xD;
      intracellular concentrations may protect against bronchoconstriction as well as the contrary&#xD;
      might reinforce AHR.&#xD;
&#xD;
      In vitro studies have demonstrated disturbances in leucocyte Na+, K+ pump activity and&#xD;
      increased intracellular Na+ in patients with hyperreactivity and asthma. Likewise in vitro&#xD;
      studies of human bronchial muscle have shown increased AHR and concentrations of&#xD;
      intracellular Ca2+ as well as decreased β-adrenergic induced relaxation of human bronchial&#xD;
      muscle when Na+, K+ pumps are blocked.&#xD;
&#xD;
      Bronchoconstriction and airway remodeling are universal features of asthma and especially&#xD;
      bronchoconstriction can to some extent be related to proposed disturbances in Na+, K+ pump&#xD;
      activity and positive effects of ICS besides being anti-inflammatory is therefore suspected&#xD;
      to be beneficial independent of cellular patterns. However the non-inflammatory effect might&#xD;
      be more evident in patients with NEA since it is not blurred by the anti-inflammatory effect&#xD;
      seen in patients with EA.&#xD;
&#xD;
      No studies have assessed the effect of ICS on ASM Na+, K+ pumps in patients with asthma. In&#xD;
      the present study the investigators wish to study differences in Na+, K+ pump content in&#xD;
      healthy versus asthmatic patients, whether a reduction in AHR observed in asthmatic patients&#xD;
      treated with ICS is attributable to an increase in Na+, K+ pump content in ASM cells and&#xD;
      compare this in patients with NEA versus EA.&#xD;
&#xD;
      This results in a study in two parts:&#xD;
&#xD;
      I. A comparison of the level of Na+, K+ pumps in ASM in patients with asthma vs healthy&#xD;
      subjects.&#xD;
&#xD;
      II. A description of the association between changes in Na+, K+ pump content in ASM and&#xD;
      change in AHR after ICS in patients with asthma.&#xD;
&#xD;
      Hypothesis Study part I: The amount of ASM Na+, K+ pumps are lower in adult patients with&#xD;
      asthma compared to healthy subjects.&#xD;
&#xD;
      Study part II: The reduction in airway hyperresponsiveness in adult patients with asthma&#xD;
      after treatment with ICS is related to an increase in the content of Na+, K+ pumps in ASM.&#xD;
&#xD;
      We further hypothesize that the association between the increase in Na+, K+ pumps in ASM and&#xD;
      the change in AHR after ICS treatment is strongest in NEA versus EA.&#xD;
&#xD;
      Aim Study part I: To describe differences in ASM content of Na+, K+ pumps among healthy&#xD;
      subjects and patients with NEA or EA respectively.&#xD;
&#xD;
      Study part II: To describe the correlation between increase in ASM content of Na+, K+ pumps&#xD;
      and reduction in airway hyperresponsiveness to mannitol after six weeks of daily inhalation&#xD;
      of glucocorticoid, in patients with asthma.&#xD;
&#xD;
      Perspectives Asthma is common and may be difficult to treat, especially the non-eosinophilic&#xD;
      phenotype. This study aims to increase our understanding of pathogenic mechanisms in asthma,&#xD;
      unrelated to inflammatory pathways. This may lead towards a shift from the current paradigm&#xD;
      of asthma as a purely inflammatory condition, creating novel understanding of the role of ion&#xD;
      transport regulation in the pathogenesis and treatment of asthma, ultimately revealing&#xD;
      targets for novel treatments.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 27, 2017</start_date>
  <completion_date type="Actual">February 28, 2019</completion_date>
  <primary_completion_date type="Actual">February 28, 2019</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in airway hyperresponsiveness (mannitol challenge) per change in Na+, K+ pumps content in airway smooth muscle.</measure>
    <time_frame>6 weeks</time_frame>
    <description>Change in PD15 per chhange in NA/K ATP'ase content</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Na+, K+ pump content in airway smooth muscle and in skeletal muscle (ρmol ouabain per g wet weight) in NEA vs. EA.</measure>
    <time_frame>6 weeks</time_frame>
    <description>Change in Na+, K+ pump content in airway smooth muscle and in skeletal muscle (ρmol ouabain per g wet weight) in NEA vs. EA.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in airway hyperresponsiveness (PD15 to mannitol) in NEA vs. EA</measure>
    <time_frame>6 weeks</time_frame>
    <description>Change in airway hyperresponsiveness (PD15 to mannitol) in NEA vs. EA</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Change in asthma control score vs in Na+, K+ pumps content in airway smooth muscle.</measure>
    <time_frame>6 weeks</time_frame>
    <description>Change in asthma control score vs in Na+, K+ pumps content in airway smooth muscle.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in lung function (FEV1) vs in Na+, K+ pumps content in airway smooth muscle</measure>
    <time_frame>6 weeks</time_frame>
    <description>Change in lung function (FEV1) vs in Na+, K+ pumps content in airway smooth muscle</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in asthma control score in NEA vs. EA</measure>
    <time_frame>6 weeks</time_frame>
    <description>Change in asthma control score in NEA vs. EA</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in lung function (FEV1) in NEA vs. EA</measure>
    <time_frame>6 weeks</time_frame>
    <description>Change in lung function (FEV1) in NEA vs. EA</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">60</enrollment>
  <condition>Asthma</condition>
  <arm_group>
    <arm_group_label>Patients with asthma</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>6 weeks treatment with 1600 ug budesonide</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy Controls</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Healthy controls to establish baseline level of Na/K pumps.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Budesonide</intervention_name>
    <description>1600 ug inhaled daily for 6 weeks</description>
    <arm_group_label>Patients with asthma</arm_group_label>
    <other_name>Pulmicort</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Asthma as defined by GINA (www.ginasthma.org) Eosinophilic asthma: Fractional exhaled&#xD;
             nitric oxide (FeNO) &gt; 25 ppb (marker of eosinophilic airway inflammation)&#xD;
             Non-eosinophilic asthma: Fractional exhaled nitric oxide (FeNO) &lt; 25 ppb&#xD;
&#xD;
          -  An FEV1 value of ≥70% of expected&#xD;
&#xD;
          -  Airway hyperresponsiveness to mannitol (PD15 ≤ 315 mg)&#xD;
&#xD;
          -  Not treated with oral or inhaled steroids (past 3 months)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Smoking (current smokers or a maximum of 10 pack years)&#xD;
&#xD;
          -  Competing respiratory diseases&#xD;
&#xD;
          -  Lower respiratory tract infection within the past 4 weeks&#xD;
&#xD;
          -  Medical history with significant comorbidity (ASA&gt;2)&#xD;
&#xD;
          -  Pregnant or breastfeeding&#xD;
&#xD;
          -  Hypersensitivity to study medication including Spirocort, Osmohale, Midazolam or&#xD;
             Fentanyl&#xD;
&#xD;
          -  Uncontrolled hypertension&#xD;
&#xD;
          -  Acute myocardial infarction within past 6 months&#xD;
&#xD;
          -  Aorta- or cerebral aneurism&#xD;
&#xD;
          -  Recent abdominal operation&#xD;
&#xD;
          -  Failure to comply with study protocol&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>64 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Celeste Porsbjerg</last_name>
    <role>Principal Investigator</role>
    <affiliation>Assistant Professor</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Lungemedicinsk forskningsenhed, Bispebjerg Hospital</name>
      <address>
        <city>Kobenhavn</city>
        <zip>2400</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>January 25, 2017</study_first_submitted>
  <study_first_submitted_qc>January 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 27, 2017</study_first_posted>
  <last_update_submitted>February 9, 2023</last_update_submitted>
  <last_update_submitted_qc>February 9, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 10, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Bispebjerg Hospital</investigator_affiliation>
    <investigator_full_name>Celeste Porsbjerg</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>Inhaled corticosteroids</keyword>
  <keyword>Airway hyper-responsiveness</keyword>
  <keyword>Airway smooth muscle</keyword>
  <keyword>sodium-potassium pump</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Asthma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Budesonide</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


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/NCT03034005
org study id: 2016-003509-33
nct id: NCT03034005
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
This study aims to assess the effect of inhaled corticosteroids (ICS) on airway smooth muscle
      (ASM) Na+, K+ pumps in patients with asthma.We wish to investigate differences in Na+, K+
      pump content in healthy versus asthmatic patients, whether a reduction in airway
      hyper-responsiveness observed in asthmatic patients treated with ICS is attributable to an
      increase in Na+, K+ pump content in ASM cells and compare this in patients with
      non-eosinophilic asthma versus eosinophilic asthma.
Purpose and background

      Inhaled corticosteroids and asthma phenotypes Inhaled corticosteroid (ICS) is a cornerstone
      in the treatment of asthma. ICS acts locally in the airways through several pathways to limit
      inflammation, primarily through reduction of eosinophilic inflammation.

      In clinical practice however a substantial part of adult patients with asthma have no
      eosinophilic inflammation in the airways despite reduced lung function and increased
      contractility of the smooth muscles in the airways i.e., airway hyperresponsiveness(AHR).
      This group of patients with non-eosinophilic asthma (NEA) represents up to 50 % of adult
      asthmatics with even higher occurrence among patients referred to a specialist.

      The effect of ICS in NEA is debated but despite lack of eosinophilic inflammation, ICS has
      been shown to significantly reduce AHR in patients with NEA, suggesting mechanistic pathways
      different from reduction in eosinophilic inflammation.

      Airway smooth muscle and inhaled corticosteroids Airway smooth muscle (ASM) is the most
      abundant tissue type in the airways. It plays a crucial part in the pathogenesis of asthma
      and serves as an important target for therapy especially with β-adrenergic agents and to some
      extent anti-muscarinic agents, counteracting bronchoconstriction. However also ICS has been
      proposed to have direct action on ASM cells affecting contractility through reduction of
      intracellular Ca2+ or down regulation of membrane bound receptors as well as through limiting
      cellular proliferation and secretory function. The bronchodilating effect of β-adrenergic
      agents has in animal models shown to be potentiated by administration of corticosteroids.

      Inhaled corticosteroids and the Na+, K+ pump Both ICS and systemically administered
      prednisone has been shown to increase Na+, K+ pump activity in leucocytes from patients with
      asthma and in both rats and humans systemically administered corticosteroid increases the
      amount of Na+, K+ pumps in striated muscle by 20-40 % and 30-60 % respectively. We have
      recently demonstrated a similar effect with ICS where a therapeutically relevant daily dose
      of 1600 μg budesonide, administered in the respiratory tract by inhalation, increased the
      amount of Na+, K+ pumps in striated muscle by 17 %.

      1.1.4 The Na+, K+ pump and airway smooth muscle The Na+, K+ pump creates an inward Na+
      current by removing Na+ from the intracellular lumen of cells. This may drive extrusion of
      Ca2+ from the lumen of the ASM cells through the Na+, Ca2+ exchanger lowering intracellular
      Ca2+ concentration. Since Ca2+ plays a central role in smooth muscle contraction, lower
      intracellular concentrations may protect against bronchoconstriction as well as the contrary
      might reinforce AHR.

      In vitro studies have demonstrated disturbances in leucocyte Na+, K+ pump activity and
      increased intracellular Na+ in patients with hyperreactivity and asthma. Likewise in vitro
      studies of human bronchial muscle have shown increased AHR and concentrations of
      intracellular Ca2+ as well as decreased β-adrenergic induced relaxation of human bronchial
      muscle when Na+, K+ pumps are blocked.

      Bronchoconstriction and airway remodeling are universal features of asthma and especially
      bronchoconstriction can to some extent be related to proposed disturbances in Na+, K+ pump
      activity and positive effects of ICS besides being anti-inflammatory is therefore suspected
      to be beneficial independent of cellular patterns. However the non-inflammatory effect might
      be more evident in patients with NEA since it is not blurred by the anti-inflammatory effect
      seen in patients with EA.

      No studies have assessed the effect of ICS on ASM Na+, K+ pumps in patients with asthma. In
      the present study the investigators wish to study differences in Na+, K+ pump content in
      healthy versus asthmatic patients, whether a reduction in AHR observed in asthmatic patients
      treated with ICS is attributable to an increase in Na+, K+ pump content in ASM cells and
      compare this in patients with NEA versus EA.

      This results in a study in two parts:

      I. A comparison of the level of Na+, K+ pumps in ASM in patients with asthma vs healthy
      subjects.

      II. A description of the association between changes in Na+, K+ pump content in ASM and
      change in AHR after ICS in patients with asthma.

      Hypothesis Study part I: The amount of ASM Na+, K+ pumps are lower in adult patients with
      asthma compared to healthy subjects.

      Study part II: The reduction in airway hyperresponsiveness in adult patients with asthma
      after treatment with ICS is related to an increase in the content of Na+, K+ pumps in ASM.

      We further hypothesize that the association between the increase in Na+, K+ pumps in ASM and
      the change in AHR after ICS treatment is strongest in NEA versus EA.

      Aim Study part I: To describe differences in ASM content of Na+, K+ pumps among healthy
      subjects and patients with NEA or EA respectively.

      Study part II: To describe the correlation between increase in ASM content of Na+, K+ pumps
      and reduction in airway hyperresponsiveness to mannitol after six weeks of daily inhalation
      of glucocorticoid, in patients with asthma.

      Perspectives Asthma is common and may be difficult to treat, especially the non-eosinophilic
      phenotype. This study aims to increase our understanding of pathogenic mechanisms in asthma,
      unrelated to inflammatory pathways. This may lead towards a shift from the current paradigm
      of asthma as a purely inflammatory condition, creating novel understanding of the role of ion
      transport regulation in the pathogenesis and treatment of asthma, ultimately revealing
      targets for novel treatments.
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change in airway hyperresponsiveness (mannitol challenge) per change in Na+, K+ pumps content in airway smooth muscle.
time frame: 6 weeks
description: Change in PD15 per chhange in NA/K ATP'ase content
measure: Change in Na+, K+ pump content in airway smooth muscle and in skeletal muscle (ρmol ouabain per g wet weight) in NEA vs. EA.
time frame: 6 weeks
description: Change in Na+, K+ pump content in airway smooth muscle and in skeletal muscle (ρmol ouabain per g wet weight) in NEA vs. EA.
measure: Change in airway hyperresponsiveness (PD15 to mannitol) in NEA vs. EA
time frame: 6 weeks
description: Change in airway hyperresponsiveness (PD15 to mannitol) in NEA vs. EA
measure: Change in asthma control score vs in Na+, K+ pumps content in airway smooth muscle.
time frame: 6 weeks
description: Change in asthma control score vs in Na+, K+ pumps content in airway smooth muscle.
measure: Change in lung function (FEV1) vs in Na+, K+ pumps content in airway smooth muscle
time frame: 6 weeks
description: Change in lung function (FEV1) vs in Na+, K+ pumps content in airway smooth muscle
measure: Change in asthma control score in NEA vs. EA
time frame: 6 weeks
description: Change in asthma control score in NEA vs. EA
measure: Change in lung function (FEV1) in NEA vs. EA
time frame: 6 weeks
description: Change in lung function (FEV1) in NEA vs. EA
arm group label: Patients with asthma
arm group type: Experimental
description: 6 weeks treatment with 1600 ug budesonide
arm group label: Healthy Controls
arm group type: No Intervention
description: Healthy controls to establish baseline level of Na/K pumps.
intervention type: Drug
intervention name: Budesonide
description: 1600 ug inhaled daily for 6 weeks
arm group label: Patients with asthma
other name: Pulmicort
criteria: 
gender: All
minimum age: 18 Years
maximum age: 64 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Celeste Porsbjerg
role: Principal Investigator
affiliation: Assistant Professor
facility: 
country: Denmark
responsible party type: Principal Investigator
investigator affiliation: Bispebjerg Hospital
investigator full name: Celeste Porsbjerg
investigator title: Associate Professor
mesh term: Asthma
mesh term: Budesonide
sharing ipd: No