search
Back to results

Tezepelumab on Airway Structure and Function in Patients With Uncontrolled Moderate-to-severe Asthma

Primary Purpose

Asthma

Status
Recruiting
Phase
Phase 3
Locations
Canada
Study Type
Interventional
Intervention
Tezepelumab
Placebo
Sponsored by
McMaster University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Asthma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • General

    • Able and willing to provide written informed consent.
    • Able and willing to comply with the study protocol.
    • Males and females ≥ 18 years of age.
  • Asthma-related

    • Asthma diagnosed by a respiratory physician ≥12 months prior to study enrolment based on the Global Initiative for Asthma (GINA) 2021 guidelines.
    • ACQ ≥1.5 at screening.
    • Methacholine PC20 ≤ 4 mg/mL OR ≥15% decrease in FEV1 during saline inhalation for sputum induction OR ≥15% improvement in FEV1 after bronchodilator during the screening period.
    • Criteria met for moderate or severe asthma defined by GINA 2021 guidelines, i.e. treatment with low, medium or high dose ICS (<250 mcg, 251 - 500 mcg, >500 mcg of fluticasone equivalent/day respectively) plus another controller. Patients on prednisone would not be excluded, as long as they meet the rest of the inclusion criteria.
    • FeNO >25 ppb OR ≥3% sputum eosinophils (preferred) OR blood eos ≥300/µL during the screening period.
    • History of ≥1 exacerbation in the previous year.

Exclusion Criteria:

  • General

    -- Participation in any clinical trial of an investigational agent or procedure within six months prior to screening or during the study.

  • Medical conditions and treatment history

    • History of anaphylaxis to any previous biologic therapy received.
    • Receipt of live attenuated vaccine within 30 days, receipt of COVID vaccine within 28 days, known or suspected COVID infection at the time of enrollment.
    • Acute or chronic parasitic, bacterial, fungal or viral infections that required, or currently requires, hospitalization or antimicrobial treatment during the last four weeks.
    • Acute asthma exacerbation event treated with increased doses of oral, or any dose of intramuscular (IM) or intravenous (IV) corticosteroids within six weeks prior to screening.
    • Other relevant pulmonary diseases (e.g. chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis, pulmonary arterial hypertension, tuberculosis) requiring treatment within 12 months prior to screening.
    • Alcohol or substance abuse within 12 months prior to screening.
  • Current smoker defined as having smoked at least one cigarette (or pipe, cigar, or marijuana) per day for ≥ 30 days within the three months prior to screening.

    • Ex-smokers with ≥ 10 pack-year smoking history.
    • Pregnancy.
    • Treatment with anti-IgE, anti-IL-4, anti-IL-5, or anti-IL-13 targeted therapy currently or within three months prior to screening.
  • MRI-related

    • Patient has an implanted mechanically, electrically or magnetically activated device or any metal in their body which cannot be removed, including but not limited to pacemakers, neurostimulators, biostimulators, implanted insulin pumps, aneurysm clips, bioprosthesis, artificial limb, metallic fragment or foreign body, shunt, surgical staples (including clips or metallic sutures and/or ear implants) (at the discretion of the MRI Technologist).
    • In the investigator's opinion, subject suffers from any physical, psychological or other condition(s) that might prevent performance of the MRI, such as severe claustrophobia.

Sites / Locations

  • Firestone Institute for Respiratory HealthRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Tezepelumab

Matched placebo

Arm Description

Tezepelumab 210 mg subcutaneous injections every 4 weeks as an investigational drug. Sterile tezepelumab will be provided 110 mg/mL pre-filled vial, with a dose of 210 mg delivered by pre-filled syringe.

Sterile placebo for tezepelumab will be provided in identically matched pre-filled syringes.

Outcomes

Primary Outcome Measures

Change in pre-bronchodilator 129Xe MRI ventilation defect percent (VDP).
Change from baseline to week 16 in the pre-bronchodilator 129Xe MRI ventilation defect percent (VDP).

Secondary Outcome Measures

Change in the post-bronchodilator 129Xe MRI ventilation defect percent (VDP).
Change in the post-bronchodilator 129Xe MRI ventilation defect percent (VDP) measured as percent of total ventilation.
Change in the CT mucus score (i.e. intraluminal plugging).
Change in the CT mucus score (i.e. intraluminal plugging) measured using a mucus score.
Change in the CT airway lumen area.
Change in the CT airway lumen area measured in mm^2.
Change in the CT airway wall area.
Change in the CT airway wall area measured in mm^2.
Change in the CT airway wall area percentage.
Change in the CT airway wall area percentage measured as a percentage of total airway area (wall area + airway lumen).
Change in the CT total airway count.
Change in the CT total airway count
Change in the CT gas trapping.
Change in the CT gas trapping
Change in the post-bronchodilator reversibility of 129Xe MRI VDP.
Change in the post-bronchodilator reversibility of 129Xe MRI VDP measured by ventilation defect percentage of total ventilation

Full Information

First Posted
February 11, 2022
Last Updated
January 18, 2023
Sponsor
McMaster University
search

1. Study Identification

Unique Protocol Identification Number
NCT05280418
Brief Title
Tezepelumab on Airway Structure and Function in Patients With Uncontrolled Moderate-to-severe Asthma
Official Title
A Two-arm, Placebo-controlled, Randomized Clinical Trial to Evaluate the Effect of Tezepelumab on Airway Structure and Function in Patients With Uncontrolled Moderate-to-severe Asthma
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Recruiting
Study Start Date
November 8, 2022 (Actual)
Primary Completion Date
September 2023 (Anticipated)
Study Completion Date
December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
McMaster University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
In adult patients with uncontrolled moderate-to-severe asthma, blocking TSLP with tezepelumab will improve ventilation heterogeneity (evaluated by hyperpolarized 129Xe MRI), and this will be associated with reduced airway inflammation (evaluated by sputum composition), luminal narrowing and plugging (evaluated by CT).
Detailed Description
The luminal obstruction in asthma that contributes to symptoms is due to inflammatory cells (usually eosinophils or neutrophils), mucus, smooth muscle constriction, airway wall thickness, or a combination of the above. This obstruction can be regionally visualized and quantified by computed tomography (CT), and its functional consequence can be assessed at high resolution using inhaled hyperpolarized 129Xe gas magnetic resonance imaging (MRI). Thymic stromal lymphopoietin (TSLP), an epithelial cell derived cytokine that is produced in response to environmental and proinflammatory stimuli, may contribute to all of these features of asthma through its downstream effects on a wide variety of immune (e.g. eosinophils, mast cells, group 2 innate lymphoid cells (ILC2s), Th2 cell, and Th17 cells) and structural cells (e.g. smooth muscle cells, and fibroblasts). Of note, TSLP is believed to upregulate multiple downstream inflammatory pathways, including IL-4, IL-5 and IL-13 signalling. It is also believed to mediate structural mechanisms that contribute to airway remodelling and smooth muscle dysfunction. The consequence of blocking TSLP with tezepelumab on airway structure and function has not been investigated. This study will use CT to quantify airway wall and lumen structure according to previously described methods. CT images will also be evaluated for intraluminal plugging and a visual mucus score will be generated. Ventilation heterogeneity in asthmatics, the functional consequence of luminal obstruction, can be regionally measured with high temporal and spatial resolution using inhaled hyperpolarized gas MRI. In asthmatics, focal ventilation defects are observed and these have been shown to be spatially related to airway abnormalities and to respond to bronchoconstriction, bronchodilation, and anti-T2 biologics. Due to the potential effect of tezepelumab on luminal inflammation, smooth muscle dysfunction and mucus hypersecretion, it is believed that MRI-detectable improvements in ventilation heterogeneity will be observed in asthmatics.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Asthma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Tezepelumab
Arm Type
Active Comparator
Arm Description
Tezepelumab 210 mg subcutaneous injections every 4 weeks as an investigational drug. Sterile tezepelumab will be provided 110 mg/mL pre-filled vial, with a dose of 210 mg delivered by pre-filled syringe.
Arm Title
Matched placebo
Arm Type
Placebo Comparator
Arm Description
Sterile placebo for tezepelumab will be provided in identically matched pre-filled syringes.
Intervention Type
Biological
Intervention Name(s)
Tezepelumab
Intervention Description
Monoclonal antibody designed for the treatment asthma.
Intervention Type
Biological
Intervention Name(s)
Placebo
Intervention Description
Matched placebo.
Primary Outcome Measure Information:
Title
Change in pre-bronchodilator 129Xe MRI ventilation defect percent (VDP).
Description
Change from baseline to week 16 in the pre-bronchodilator 129Xe MRI ventilation defect percent (VDP).
Time Frame
16 weeks from randomization (week 0) to endpoint assessment (week 16)
Secondary Outcome Measure Information:
Title
Change in the post-bronchodilator 129Xe MRI ventilation defect percent (VDP).
Description
Change in the post-bronchodilator 129Xe MRI ventilation defect percent (VDP) measured as percent of total ventilation.
Time Frame
From baseline (week 0) to endpoint (week 16)
Title
Change in the CT mucus score (i.e. intraluminal plugging).
Description
Change in the CT mucus score (i.e. intraluminal plugging) measured using a mucus score.
Time Frame
From baseline (week 0) to endpoint (week 16)
Title
Change in the CT airway lumen area.
Description
Change in the CT airway lumen area measured in mm^2.
Time Frame
From baseline (week 0) to endpoint (week 16)
Title
Change in the CT airway wall area.
Description
Change in the CT airway wall area measured in mm^2.
Time Frame
From baseline (week 0) to endpoint (week 16)
Title
Change in the CT airway wall area percentage.
Description
Change in the CT airway wall area percentage measured as a percentage of total airway area (wall area + airway lumen).
Time Frame
From baseline (week 0) to endpoint (week 16)
Title
Change in the CT total airway count.
Description
Change in the CT total airway count
Time Frame
From baseline (week 0) to endpoint (week 16)
Title
Change in the CT gas trapping.
Description
Change in the CT gas trapping
Time Frame
From baseline (week 0) to endpoint (week 16)
Title
Change in the post-bronchodilator reversibility of 129Xe MRI VDP.
Description
Change in the post-bronchodilator reversibility of 129Xe MRI VDP measured by ventilation defect percentage of total ventilation
Time Frame
From baseline (week 0) to endpoint (week 16)
Other Pre-specified Outcome Measures:
Title
Change in ACQ-5 score.
Description
Change in ACQ-5 score
Time Frame
From baseline (week 0) to endpoint (week 16)
Title
Change in AQLQ score.
Description
Change in AQLQ score
Time Frame
From baseline (week 0) to endpoint (week 16)
Title
Change in the pre-bronchodilator and post-bronchodilator FEV1.
Description
Change in the pre-bronchodilator and post-bronchodilator FEV1 measured in litres
Time Frame
From baseline (week 0) to endpoint (week 16)
Title
Change in the post-bronchodilator reversibility of FEV1.
Description
Change in the post-bronchodilator reversibility of FEV1 measured in litres
Time Frame
From baseline (week 0) to endpoint (week 16)
Title
Change in airways resistance and reactance measured by airwave oscillometry (R5, R20, R5-R20, X5, Ax).
Description
Change in airways resistance and reactance measured by airwave oscillometry (R5, R20, R5-R20, X5, Ax)
Time Frame
From baseline (week 0) to endpoint (week 16)
Title
Change in FeNO.
Description
Change in FeNO measured as parts per billion
Time Frame
From baseline (week 0) to endpoint (week 16)
Title
Change in blood eosinophil counts.
Description
Change in blood eosinophil measured as cells per litre
Time Frame
From baseline (week 0) to endpoint (week 16)
Title
Change in blood neutrophil counts.
Description
Change in blood neutrophil counts measured as cells per litre
Time Frame
From baseline (week 0) to endpoint (week 16)
Title
Change in sputum eosinophil counts.
Description
Change in sputum eosinophil counts measured as % total nucleated cells.
Time Frame
From baseline (week 0) to endpoint (week 16)
Title
Change in sputum neutrophil counts.
Description
Change in sputum neutrophil counts measured as % total nucleated cells.
Time Frame
From baseline (week 0) to endpoint (week 16)
Title
Change in eosinophil extracellular traps (including surrogate biomarkers histones, double stranded DNA and formalin fixed paraffin embedded sputum plugs).
Description
Change in absorbance values by fluorescence
Time Frame
From baseline (week 0) to endpoint (week 16)
Title
Change in galectin-10 levels
Description
Change in galectin-10 concentration in sputum supernatant.
Time Frame
From baseline (week 0) to endpoint (week 16)
Title
Change in sputum T2 cytokines.
Description
Change in sputum T2 cytokines.
Time Frame
From baseline (week 0) to endpoint (week 16)
Title
Change in markers of airway eosinophil activity
Description
Change in eosinophil peroxidase (EPX) levels (ng/uL)
Time Frame
From baseline (week 0) to endpoint (week 16)
Title
Change in markers of airway eosinophil activity
Description
Change in free eosinophil granules (FEGs) (none, few, moderate, many)
Time Frame
From baseline (week 0) to endpoint (week 16)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: General Able and willing to provide written informed consent. Able and willing to comply with the study protocol. Males and females ≥ 18 years of age. Asthma-related Asthma diagnosed by a respiratory physician ≥12 months prior to study enrolment based on the Global Initiative for Asthma (GINA) 2021 guidelines. ACQ ≥1.5 at screening. Methacholine PC20 ≤ 4 mg/mL OR ≥15% decrease in FEV1 during saline inhalation for sputum induction OR ≥15% improvement in FEV1 after bronchodilator during the screening period. Criteria met for moderate or severe asthma defined by GINA 2021 guidelines, i.e. treatment with low, medium or high dose ICS (<250 mcg, 251 - 500 mcg, >500 mcg of fluticasone equivalent/day respectively) plus another controller. Patients on prednisone would not be excluded, as long as they meet the rest of the inclusion criteria. FeNO >25 ppb OR ≥3% sputum eosinophils (preferred) OR blood eos ≥300/µL during the screening period. History of ≥1 exacerbation in the previous year. Exclusion Criteria: General -- Participation in any clinical trial of an investigational agent or procedure within six months prior to screening or during the study. Medical conditions and treatment history History of anaphylaxis to any previous biologic therapy received. Receipt of live attenuated vaccine within 30 days, receipt of COVID vaccine within 28 days, known or suspected COVID infection at the time of enrollment. Acute or chronic parasitic, bacterial, fungal or viral infections that required, or currently requires, hospitalization or antimicrobial treatment during the last four weeks. Acute asthma exacerbation event treated with increased doses of oral, or any dose of intramuscular (IM) or intravenous (IV) corticosteroids within six weeks prior to screening. Other relevant pulmonary diseases (e.g. chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis, pulmonary arterial hypertension, tuberculosis) requiring treatment within 12 months prior to screening. Alcohol or substance abuse within 12 months prior to screening. Current smoker defined as having smoked at least one cigarette (or pipe, cigar, or marijuana) per day for ≥ 30 days within the three months prior to screening. Ex-smokers with ≥ 10 pack-year smoking history. Pregnancy. Treatment with anti-IgE, anti-IL-4, anti-IL-5, or anti-IL-13 targeted therapy currently or within three months prior to screening. MRI-related Patient has an implanted mechanically, electrically or magnetically activated device or any metal in their body which cannot be removed, including but not limited to pacemakers, neurostimulators, biostimulators, implanted insulin pumps, aneurysm clips, bioprosthesis, artificial limb, metallic fragment or foreign body, shunt, surgical staples (including clips or metallic sutures and/or ear implants) (at the discretion of the MRI Technologist). In the investigator's opinion, subject suffers from any physical, psychological or other condition(s) that might prevent performance of the MRI, such as severe claustrophobia.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Melanie Kjarsgaard, BSc
Phone
905-522-1155
Ext
33024
Email
mkjarsga@stjoes.ca
First Name & Middle Initial & Last Name or Official Title & Degree
Sarah Svenningsen, PhD
Phone
905-522-1155
Ext
37313
Email
svennins@mcmaster.ca
Facility Information:
Facility Name
Firestone Institute for Respiratory Health
City
Hamilton
State/Province
Ontario
ZIP/Postal Code
L8N 4A6
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Melanie Kjarsgaard, BSc
Phone
905-522-1155
Ext
33024
Email
mkjarsga@stjosham.on.ca
First Name & Middle Initial & Last Name & Degree
Parameswaran Nair, MD, PhD
First Name & Middle Initial & Last Name & Degree
Svenningsen Sarah, PhD

12. IPD Sharing Statement

Citations:
PubMed Identifier
32567399
Citation
Gauvreau GM, Sehmi R, Ambrose CS, Griffiths JM. Thymic stromal lymphopoietin: its role and potential as a therapeutic target in asthma. Expert Opin Ther Targets. 2020 Aug;24(8):777-792. doi: 10.1080/14728222.2020.1783242. Epub 2020 Jun 27.
Results Reference
background
PubMed Identifier
29400693
Citation
Dunican EM, Elicker BM, Gierada DS, Nagle SK, Schiebler ML, Newell JD, Raymond WW, Lachowicz-Scroggins ME, Di Maio S, Hoffman EA, Castro M, Fain SB, Jarjour NN, Israel E, Levy BD, Erzurum SC, Wenzel SE, Meyers DA, Bleecker ER, Phillips BR, Mauger DT, Gordon ED, Woodruff PG, Peters MC, Fahy JV; National Heart Lung and Blood Institute (NHLBI) Severe Asthma Research Program (SARP). Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction. J Clin Invest. 2018 Mar 1;128(3):997-1009. doi: 10.1172/JCI95693. Epub 2018 Feb 5.
Results Reference
background
PubMed Identifier
30910637
Citation
Svenningsen S, Haider E, Boylan C, Mukherjee M, Eddy RL, Capaldi DPI, Parraga G, Nair P. CT and Functional MRI to Evaluate Airway Mucus in Severe Asthma. Chest. 2019 Jun;155(6):1178-1189. doi: 10.1016/j.chest.2019.02.403. Epub 2019 Mar 23.
Results Reference
background
PubMed Identifier
33979488
Citation
Menzies-Gow A, Corren J, Bourdin A, Chupp G, Israel E, Wechsler ME, Brightling CE, Griffiths JM, Hellqvist A, Bowen K, Kaur P, Almqvist G, Ponnarambil S, Colice G. Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma. N Engl J Med. 2021 May 13;384(19):1800-1809. doi: 10.1056/NEJMoa2034975.
Results Reference
background

Learn more about this trial

Tezepelumab on Airway Structure and Function in Patients With Uncontrolled Moderate-to-severe Asthma

We'll reach out to this number within 24 hrs