Impulse Oscillometry Measurements in Severe Eosinophilic Asthmatics Before and After Anti-IL-5 Factor Initiation

NCT05147155 | Completed Results DMC

• 1 other identifier: 15745/19-04-2021
• Study Type: observational
• Target: 130
• Locations: 1 country
• Sites: 1

Brief Summary

Eosinophilic inflammation in the small airways of patients with severe asthma is considered to be an important marker of disease severity. In clinical trials, treatment with mepolizumab reduces exacerbation rates by almost a half along with modest improvements in symptom scores and forced expiratory volume in 1 s (FEV1) early after the first month of commencing mepolizumab treatment. However, there is an apparent discrepancy between major patient-reported outcomes and lung function that should be explored. It has recently been reported that mepolizumab improves small airway function in severe eosinophilic asthma as detected by multiple-breath nitrogen washout test. The improvement in small airway function was seen rapidly after the first mepolizumab injection and was associated with a sustained response in the majority of patients. However, gaps in knowledge about the choice of device, gas, and standardization across systems are key issues leading the committee to conclude that multiple-breath nitrogen washout test is not ready for use as a clinical trial endpoint in asthmatics. The investigators hypothesize that early improvement in small airway function may be a significant contributor to the therapeutic response of anti-IL-5 monoclonal antibody therapy in patients with severe uncontrolled eosinophilic asthma. The investigators speculate that SAD could be effectively evaluated using IOS. Consequently, this study could lead to novel SAD subtypes with possible clinical relevance in the context of treatment with anti-IL-5 factor. The investigators hypothesize that healthy individuals and patients with severe controlled asthma would disclose a lesser extent of SAD than patients with severe uncontrolled eosinophilic asthma with or without fixed airway obstruction.

Conditions

Severe Asthma

Outcome Measures

Primary Outcomes (24)

• Airway Resistance at 5 Hz (R5) at Baseline (Pre-mepolizumab Initiation)

  Measurements of R5 at baseline (pre-mepolizumab initiation). R5 was assessed using impulse oscillometry. The values are reported in kPa/L/s and were analyzed following the guidelines of the European Respiratory Society

  0 months

• Airway Resistance at 20 Hz (R20) at Baseline

  Measurement of R20 at baseline - mepolizumab initiation. R20 was measured using impulse oscillometry, representing airway resistance at 20 Hz. Values are reported in kPa/L/s, and assessments were conducted according to the standards outlined by the European Respiratory Society.

  0 months

• Difference Between Airway Resistance at 5 Hz (R5) and 20 Hz (R20) at Baseline / (R5-R20) at Baseline

  Measurement of R5-R20 at baseline. R5-R20 represents the difference between airway resistance at 5 Hz (R5) and 20 Hz (R20), measured using impulse oscillometry. This measure reflects peripheral airway resistance. Assessments were conducted at baseline, and values are reported in kPa/L/s following guidelines from the European Respiratory Society

  0 months

• Reactance Area (AX) at Baseline

  Measurement of AX at baseline. AX, the area of reactance derived from impulse oscillometry, represents the elastic and inertial properties of the lungs. Measurements were taken at baseline using standard protocols. Values are reported in kPa/L and analyzed following guidelines from the European Respiratory Society.

  0 months

• Resonant Frequency (Fres) at Baseline

  Measurement of Fres at Baseline. Fres, the resonant frequency, is the point where the reactance of the respiratory system equals zero, indicating the balance between elastic and inertial forces in the lungs. Measurements were taken at baseline using impulse oscillometry. Values are reported in Hz and analyzed following guidelines from the European Respiratory Society

  0 months

• Respiratory Reactance at 5 Hz (X5) at Baseline

  Measurement of X5 at Baseline. X5, the respiratory reactance at 5 Hz, is a measure of the elastic properties of the lungs and the peripheral airways. It indicates how easily the lungs expand and contract during breathing. Measurements were taken at baseline using impulse oscillometry, with values expressed in kPa/L. Assessments followed European Respiratory Society guidelines. X5 is negative because the lungs store energy due to their elasticity, which results in a delayed response of airflow relative to pressure changes. This behavior is characteristic of a capacitive system, where elastic forces dominate at low frequencies. A less negative X5 means that the lung's elastic recoil is reduced, leading to decreased resistance to expansion.

  0 months

• Airway Resistance at 5 Hz (R5) at Week 4.

  Estimate the airway resistance measured at the 5 Hz frequency (R5) after four weeks from mepolizumab initiation (only severe uncontrolled asthma patients received mepolizumab). R5 was assessed using impulse oscillometry. The values are reported in kPa/L/s and were analyzed following the guidelines of the European Respiratory Society.

  4 weeks

• Airway Resistance at 20 Hz (R20) at Week 4.

  Estimate the airway resistance measured at the 20 Hz frequency (R20) after four weeks from mepolizumab initiation. R20 was measured using impulse oscillometry, representing airway resistance at 20 Hz. Values are reported in kPa/L/s, and assessments were conducted according to the standards outlined by the European Respiratory Society

  4 weeks

• Difference Between Airway Resistance at 5 Hz (R5) and 20 Hz (R20) at Week 4/ R5-R20 at Week 4.

  After four weeks of mepolizumab initiation, estimate the small airway resistance (R5- R20). R5-R20 represents the difference between airway resistance at 5 Hz (R5) and 20 Hz (R20), measured using impulse oscillometry. This measure reflects peripheral airway resistance. Assessments were conducted after 4 weeks from mepolizumab initiation, and values are reported in kPa/L/s following guidelines from the European Respiratory Society

  4 weeks

• Reactance Area (AX) at Week 4

  Estimate the AX after four weeks from mepolizumab initiation. AX, the area of reactance derived from impulse oscillometry, represents the elastic and inertial properties of the lungs. Measurements were taken at Week 4 using standard protocols. Values are reported in kPa/L and analyzed following guidelines from the European Respiratory Society.

  4 weeks

• Resonant Frequency (Fres) at Week 4.

  Estimate Fres after four weeks from mepolizumab initiation. Fres, the resonant frequency, is the point at which the reactance of the respiratory system equals zero, reflecting the balance between the elastic and inertial forces of the lungs. Measurements were taken at Week 4 using impulse oscillometry. Values are expressed in Hz and analyzed in accordance with European Respiratory Society guidelines.

  4 weeks

• Respiratory Reactance at 5 Hz (X5) at Week 4.

  Estimate X5 after four weeks from mepolizumab initiation. X5, the respiratory reactance at 5 Hz, is a measure of the elastic properties of the lungs and peripheral airways, reflecting the ability of the respiratory system to expand and contract. Measurements were taken at Week 4 using impulse oscillometry. Values are reported in kPa/L and were analyzed according to European Respiratory Society guidelines. X5 is negative because the lungs store energy due to their elasticity, which results in a delayed response of airflow relative to pressure changes. This behavior is characteristic of a capacitive system, where elastic forces dominate at low frequencies. A less negative X5 means that the lung's elastic recoil is reduced, leading to decreased resistance to expansion.

  4 weeks

• Airway Resistance at 5 Hz (R5) at Week 12

  Estimate the airway resistance measured at the 5 Hz frequency (R5) after 12 weeks from the mepolizumab initiation. R5 was assessed using spirometry with impulse oscillometry. The values are reported in kPa/L/s and were analyzed following the guidelines of the European Respiratory Society.

  12 weeks

• Airway Resistance at 20 Hz (R20) at Week 12

  Estimate the airway resistance measured at the 20 Hz frequency (R20) after 12 weeks from mepolizumab initiation. R20 was measured using impulse oscillometry, representing airway resistance at 20 Hz. Values are reported in kPa/L/s, and assessments were conducted according to the standards outlined by the European Respiratory Society.

  12 weeks

• Difference Between Airway Resistance at 5 Hz (R5) and 20 Hz (R20) at Week 12 / R5-R20 at Week 12

  Estimate small airway resistance (R5-R20) after 12 weeks from mepolizumab initiation. R5-R20 represents the difference between airway resistance at 5 Hz (R5) and 20 Hz (R20), measured using impulse oscillometry. This measure reflects peripheral airway resistance. Assessments were conducted at week 12 after mepolizuamb initiation, and values are reported in kPa/L/s following guidelines from the European Respiratory Society.

  12 weeks

• Reactance Area (AX) at Week 12

  Estimate the AX after 12 weeks from mepolizumab initiation. AX, the area of reactance derived from impulse oscillometry, represents the elastic and inertial properties of the lungs. Measurements were taken at Week 12 using standard protocols. Values are reported in kPa/L and analyzed following guidelines from the European Respiratory Society.

  12 weeks

• Resonant Frequency (Fres) at Week 12

  Estimate Fres after12 weeks from mepolizumab initiation. Fres, the resonant frequency, is the point at which the reactance of the respiratory system equals zero, reflecting the balance between the elastic and inertial forces of the lungs. Measurements were taken at Week 4 using impulse oscillometry. Values are expressed in Hz and analyzed in accordance with European Respiratory Society guidelines.

  12 weeks

• Respiratory Reactance at 5 Hz (X5) at Week 12

  Estimate X5 after 12 weeks from mepolizumab initiation. X5, the respiratory reactance at 5 Hz, measures the elastic properties of the lungs and peripheral airways, reflecting the ability of the respiratory system to expand and contract. Measurements were taken at Week 12 using impulse oscillometry. Values are reported in kPa/L and analyzed according to European Respiratory Society guidelines. X5 is negative because the lungs store energy due to their elasticity, which results in a delayed response of airflow relative to pressure changes. This behavior is characteristic of a capacitive system, where elastic forces dominate at low frequencies. A less negative X5 means that the lung's elastic recoil is reduced, leading to decreased resistance to expansion.

  12 weeks

• Airway Resistance at 5 Hz (R5) at Week 26.

  Estimate the airway resistance measured at the 5 Hz frequency (R5) after 26 weeks from the initiation of mepolizumab. R5 was assessed using spirometry with impulse oscillometry. The values are reported in kPa/L/s and were analyzed following the guidelines of the European Respiratory Society.

  26 weeks

• Airway Resistance at 20 Hz (R20) at Week 26.

  Estimate the airway resistance measured at the 20 Hz frequency (R20) after 26 weeks from mepolizumab initiation. R20 was measured using impulse oscillometry, representing airway resistance at 20 Hz. Values are reported in kPa/L/s, and assessments were conducted according to the standards outlined by the European Respiratory Society.

  26 weeks

• Difference Between Airway Resistance at 5 Hz (R5) and 20 Hz (R20) at Week 26 / R5-R20 at Week 26.

  Estimate the small airway resistance (R5-R20) after 26 weeks from mepolizumab initiation. R5-R20 represents the difference between airway resistance at 5 Hz (R5) and 20 Hz (R20), measured using impulse oscillometry. This measure reflects peripheral airway resistance. Assessments were conducted at Week 26 after mepolizumab initiation, and values are reported in kPa/L/s following guidelines from the European Respiratory Society

  26 weeks

• Reactance Area (AX) at Week 26.

  Estimate AX after 26 weeks from mepolizumab initiation. AX, the area of reactance derived from impulse oscillometry, represents the elastic and inertial properties of the lungs. Measurements were taken at Week 26 using standard protocols. Values are reported in kPa/L and analyzed following guidelines from the European Respiratory Society.

  26 weeks

• Resonant Frequency (Fres) at Week 26.

  Estimate Fres after 26 weeks from mepolizumab initiation. Fres, the resonant frequency, is the point at which the reactance of the respiratory system equals zero, reflecting the balance between the elastic and inertial forces of the lungs. Measurements were taken at Week 26 using impulse oscillometry. Values are expressed in Hz and analyzed in accordance with European Respiratory Society guidelines.

  26 weeks

• Respiratory Reactance at 5 Hz (X5) at Week 26.

  Estimate X5 after 26 weeks from mepolizumab initiation. X5, the respiratory reactance at 5 Hz, reflects the elastic properties of the lungs and peripheral airways, indicating the ability of the respiratory system to expand and contract. Measurements were taken at Week 26 using impulse oscillometry. Values are reported in kPa/L and were analyzed following European Respiratory Society guidelines. X5 is negative because the lungs store energy due to their elasticity, which results in a delayed response of airflow relative to pressure changes. This behavior is characteristic of a capacitive system, where elastic forces dominate at low frequencies. A less negative X5 means that the lung's elastic recoil is reduced, leading to decreased resistance to expansion.

  26 weeks

Study Arms (3)

Severe asthma patients

The sample will consist of 40 patients between 18 and 82 years of age with uncontrolled severe eosinophilic asthma despite receiving high dose ICS/LABA combination therapy who will receive mepolizumab, which will be administered as a 100-mg subcutaneous dose every four weeks

Biological: Mepolizumab

Control group 1

Control group 1 will be a set of 50 healthy individuals matched for age and gender

Control group 2

Control group 2 will be a set of 40 patients with severe well-controlled asthma requiring high dose ICS/LABA combination therapy from becoming uncontrolled, as previously defined, matched for age and gender.

Interventions

Mepolizumab BIOLOGICAL

This will be a 2-year prospective study. Patients with uncontrolled severe asthma will receive mepolizumab according to standard of care and best clinical practice, which will be administered as a 100-mg subcutaneous dose every four weeks.

Also known as: Nucala

Severe asthma patients

Eligibility Criteria

• Age: 18 Years - 82 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

The sample will consist of 40 patients between 18 and 82 years of age with uncontrolled severe eosinophilic asthma despite receiving high-dose ICS/LABA combination therapy.

You may qualify if:

• Written informed consent
• Male or female outpatient aged 18 to 82 years inclusive
• History of bronchial asthma for at least six months as defined by ATS criteria.
• The patients will be required to have one or more of the following objective physiological criteria: positive results on methacholine or mannitol challenge during the previous year, bronchodilator reversibility to 400 mg of inhaled Salbutamol of FEV1 ≥12% and 200ml or peak flow variability of ≥20% over two weeks.
• Diagnosis of severe asthma, defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming uncontrolled or that remains uncontrolled despite this therapy.
• All patients will be medicated with at least 880 μg of fluticasone propionate or the equivalent by inhalation per day and at least three months of treatment with an additional controller. Patients will be allowed to continue their anti-asthma therapy throughout the study.
• Patients should have uncontrolled asthma commencing mepolizumab treatment, based on investigator assessment, including one or both of the following:
• Poor symptom control (frequent symptoms or reliever use, activity limited by asthma, night waking due to asthma), defined as ACQ consistently ⩾1.5 or ACT\<20.
• Frequent exacerbations (≥2/year) requiring oral corticosteroids, or severe exacerbations (≥1/year) requiring hospitalization or burst of systemic corticosteroids (≥3 days).
• All patients will have an eosinophil count of at least 150 cells per microliter in the peripheral blood at screening or at least 300 cells per microliter at some time during the previous year.

You may not qualify if:

• Diseases and health status: clinically relevant abnormal laboratory values suggesting an unknown disease and requiring further clinical evaluation suffering from COPD (i.e., chronic bronchitis or emphysema) and/or other relevant lung diseases causing alternating impairment in lung function
• Asthmatic patients and healthy controls currently smoking or with a smoking pack history greater than 10 will be excluded.
• pregnancy
• intention to become pregnant during the course of the study
• breastfeeding
• participation in another study within the 30 days preceding and during the present study
• known or suspected non-compliance, alcohol or drug abuse
• inability to follow the procedures of the study, e.g., due to language problems, psychological disorders

Sponsors & Collaborators

• University of Thessaly: lead

Study Sites (1)

External Unit of Asthma of Respiratory Medicine Department of the University of Thessaly in Greece

Larissa, Thessaly, 41110, Greece

Location

Related Publications (1)

• Kotsiou OS, Kirgou P, Siachpazidou D, Bartziokas K, Tourlakopoulos K, Malli F, Pinaka M, Daniil Z, Gourgoulianis KI. Early benefit of mepolizumab on small airways in severe asthma: insights from the IMPOSE study. ERJ Open Res. 2025 Jun 23;11(3):00939-2024. doi: 10.1183/23120541.00939-2024. eCollection 2025 May.

  PMID: 40551802 DERIVED

MeSH Terms

Conditions

Asthma

Interventions

mepolizumab

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Results Point of Contact

• Title: Research Committee - Special Account for Research Grants University of Thessaly
• Organization: University of Thessaly

raniakotsiou@gmail.com

+306971894688

Study Officials

• Konstantinos I Gourgoulianis, Professor

  University of Thessaly

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 26 Weeks
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: June 25, 2021
• First Posted: December 7, 2021
• Study Start: April 19, 2021
• Primary Completion: October 23, 2023
• Study Completion: October 23, 2023
• Last Updated: February 24, 2025
• Results First Posted: February 24, 2025

Record last verified: 2025-02

Locations

GR (1)