The RECONSTRUCT Study - Reconstructing Disease Mechanisms in Asthma (RECONSTRUCT)

February 9, 2023 updated by: Celeste Porsbjerg, Bispebjerg Hospital
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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
60

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • Denmark
      • Kobenhavn, Denmark, 2400
        • Lungemedicinsk forskningsenhed, Bispebjerg Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 64 years (ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Asthma as defined by GINA (www.ginasthma.org) Eosinophilic asthma: Fractional exhaled nitric oxide (FeNO) > 25 ppb (marker of eosinophilic airway inflammation) Non-eosinophilic asthma: Fractional exhaled nitric oxide (FeNO) < 25 ppb
  • An FEV1 value of ≥70% of expected
  • Airway hyperresponsiveness to mannitol (PD15 ≤ 315 mg)
  • Not treated with oral or inhaled steroids (past 3 months)

Exclusion Criteria:

  • Smoking (current smokers or a maximum of 10 pack years)
  • Competing respiratory diseases
  • Lower respiratory tract infection within the past 4 weeks
  • Medical history with significant comorbidity (ASA>2)
  • Pregnant or breastfeeding
  • Hypersensitivity to study medication including Spirocort, Osmohale, Midazolam or Fentanyl
  • Uncontrolled hypertension
  • Acute myocardial infarction within past 6 months
  • Aorta- or cerebral aneurism
  • Recent abdominal operation
  • Failure to comply with study protocol

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NON_RANDOMIZED
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
EXPERIMENTAL: Patients with asthma
6 weeks treatment with 1600 ug budesonide
Drug: Budesonide
1600 ug inhaled daily for 6 weeks
Other Names:
  • Pulmicort
NO_INTERVENTION: Healthy Controls
Healthy controls to establish baseline level of Na/K pumps.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Change in airway hyperresponsiveness (mannitol challenge) per change in Na+, K+ pumps content in airway smooth muscle.
Time Frame: 6 weeks
Change in PD15 per chhange in NA/K ATP'ase content
6 weeks

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
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
Change in Na+, K+ pump content in airway smooth muscle and in skeletal muscle (ρmol ouabain per g wet weight) in NEA vs. EA.
6 weeks
Change in airway hyperresponsiveness (PD15 to mannitol) in NEA vs. EA
Time Frame: 6 weeks
Change in airway hyperresponsiveness (PD15 to mannitol) in NEA vs. EA
6 weeks

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Change in asthma control score vs in Na+, K+ pumps content in airway smooth muscle.
Time Frame: 6 weeks
Change in asthma control score vs in Na+, K+ pumps content in airway smooth muscle.
6 weeks
Change in lung function (FEV1) vs in Na+, K+ pumps content in airway smooth muscle
Time Frame: 6 weeks
Change in lung function (FEV1) vs in Na+, K+ pumps content in airway smooth muscle
6 weeks
Change in asthma control score in NEA vs. EA
Time Frame: 6 weeks
Change in asthma control score in NEA vs. EA
6 weeks
Change in lung function (FEV1) in NEA vs. EA
Time Frame: 6 weeks
Change in lung function (FEV1) in NEA vs. EA
6 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Bispebjerg Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
March 27, 2017

Primary Completion (ACTUAL)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
February 28, 2019

Study Completion (ACTUAL)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
February 28, 2019

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
January 25, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 26, 2017

First Posted (ESTIMATE)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 27, 2017

Study Record Updates

Last Update Posted (ACTUAL)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
February 10, 2023

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 9, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
February 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 2016-003509-33

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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