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Dupilumab on Airway Hyper-responsiveness and Ventilation Heterogeneity in Patients With Asthma.

Primary Purpose

Asthma

Status

Completed

Phase

Phase 3

Locations

Canada

Study Type

Interventional

Intervention

Dupilumab/Dupixent

Placebo

About this trial

This is an interventional treatment trial for Asthma focused on measuring Airway hyperresponsivness, Ventilation heterogeneity, Hyperpolarized Xenon-129, Sputum eosinophils

Eligibility Criteria

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

Inclusion Criteria:

General
1. Able and willing to provide written informed consent.
2. Able and willing to comply with the study protocol.
3. Males and females ≥ 18 years of age.
  Asthma-related
4. Asthma diagnosed by a respiratory physician ≥ 12 months prior to study enrolment based on the Global Initiative for Asthma (GINA) 2014 guidelines.
5. ACQ > 1 during the screening period.
6. Airway hyperresponsiveness (methacholine PC20 ≤ 4 mg/mL OR ≥15% decreased in FEV1 during saline inhalation for sputum induction OR ≥25% improvement in FEV1 after bronchodilator) during the screening period.
7. Fraction of exhaled nitric oxide (FeNO) >25 ppb and either ≥3% sputum eosinophils (preferred) OR blood eos ≥300/µL during the screening period.
8. Inhaled corticosteroids (ICS) dose ≥500 mcg of fluticasone equivalent/day. Patients on prednisone would not be excluded as long as they meet the rest of the inclusion criteria.

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from study entry:

Prior Medical Conditions and Treatment History

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.
Treatment with anti-IgE (immunoglobulin E), anti-IL-4, anti-IL-5 (interleukin-5), or anti-IL-13 targeted therapy currently or within three months prior to screening.
ACQ > 3.0
MRI (Magnetic Resonance Imaging )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.
General
Participation in any clinical trial of an investigational agent or procedure within six months prior to screening or during the study.

Sites / Locations

Firestone Institute for Respiratory Health, St. Joseph's Healthcare

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

dupilumab

matched placebo

Arm Description

Dupilumab 300 mg subcutaneously (SC) every 2 weeks as an investigational drug. For those randomized to dupilumab, a loading dose of 600 mg will be given only at randomization/Visit 2. Sterile dupilumab of will be provided in 150 mg/mL in glass prefilled syringes (2.25 mL total volume) to deliver 300 mg in 2 mL.

Sterile placebo for dupilumab will be provided in identically matched glass prefilled syringes to deliver 2 mL.

Outcomes

Primary Outcome Measures

Proportion of patients that achieve at least one doubling dose improvement in PC20 methacholine and/or a 50% reduction in FEV1 reversibility after bronchodilator.

For patients that can undergo a methacholine challenge, one doubling dose improvement in PC20 methacholine. For those that cannot undergo a methacholine challenge a 50% reduction in FEV1 reversibility.

Secondary Outcome Measures

Change in geometric mean PC20 methacholine.

Change in PC20 between screening and week 16.

Change in FEV1 reversibility.

Change in FEV1 % reversibility (pre/post bronchodilator) between randomization and end of treatment.

Change in sputum eosinophil percentage (%)

Change in sputum eosinophil percentage between randomization and end of treatment

Change in blood eosinophil count

Change in blood eosinophil count levels between randomization and end of treatment

Change in fraction of exhaled nitric oxide (FeNO)

Change in FeNO values parts per billion (ppb) from randomization and end of treatment.

Change in FEV1 (pre-bronchodilator)

Change in pre-bronchodilator FEV1 values (in litres) between randomization and end of treatment.

Change in Asthma Control Questionnaire-5 (ACQ-5)

Change in ACQ scores between randomization and end of treatment.

Change in Asthma Control Questionnaire-5 (AQLQ)

Change in AQLQ scores between randomization and end of treatment.

Change in Asthma Control Test (ACT)

Change in ACT scores between randomization and end of treatment.

Full Information

NCT ID

NCT03884842

First Posted

March 18, 2019

Last Updated

January 18, 2023

Sponsor

McMaster University

Collaborators

Sanofi

1. Study Identification

Unique Protocol Identification Number

NCT03884842

Brief Title

Dupilumab on Airway Hyper-responsiveness and Ventilation Heterogeneity in Patients With Asthma.

Official Title

A Two-arm, Placebo-controlled Randomized Clinical Trial to Evaluate the Effect of Dupilumab on Airway Hyper-responsiveness and Ventilation Heterogeneity in Patients With Asthma With a "T2 Immune Signature"

Study Type

Interventional

2. Study Status

Record Verification Date

January 2023

Overall Recruitment Status

Completed

Study Start Date

July 1, 2019 (Actual)

Primary Completion Date

October 12, 2022 (Actual)

Study Completion Date

January 17, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

McMaster University

Collaborators

Sanofi

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

In asthmatics with airway hyperresponsiveness and a "T2 immune signature" (type 2), Dupilumab will suppress airway hyperresponsiveness (assessed by methacholine PC20 ≤ 4 mg/mL (PC20: provocative concentration causing a 20% fall in FEV1) OR ≥15% decreased in forced expired volume in 1 second (FEV1) during saline inhalation for sputum induction OR ≥25% improvement in FEV1 after bronchodilator) and airway eosinophilia (assessed by sputum eosinophils) and this will be associated with greater asthma control and improved ventilation heterogeneity.

Detailed Description

Along with these features of eosinophil recruitment, degranulation and autoantibody generation, that are partly dependent on (interleukin-4) IL-4 and (interleukin-13) IL-13 signalling, two additional characteristic features of asthma ie airway hyperresponsiveness and mucus hypersecretion are also determined by IL-13 biology. Neither of these important features have been investigated in any clinical trials of anti-IL-13 molecules. Accurate endotyping to identify patients in whom IL-13 mediated biology is the dominant pathobiology of asthma (selecting patients with significant airway hyperresponsiveness and mucus secretion) may elicit greater clinical effect. Taken together, we propose to investigate the effects of Dupilumab on airway hyperresponsiveness, on airway eosinophilia and mucus biology and their relation to airway structure and function (ventilation heterogeneity), and airway autoimmune responses. To satisfy the proposed objective we will evaluate well-established outcome measures of airway hyperresponsiveness (provocation concentration of methacholine causing a 20% fall in FEV1 (PC20), type 2 inflammation (sputum eosinophils, blood eosinophils and exhaled nitric oxide (eNO)) and mucus biology.

6. Conditions and Keywords

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

Asthma

Keywords

Airway hyperresponsivness, Ventilation heterogeneity, Hyperpolarized Xenon-129, Sputum eosinophils

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Single Group Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

24 (Actual)

8. Arms, Groups, and Interventions

Arm Title

dupilumab

Arm Type

Active Comparator

Arm Description

Arm Title

matched placebo

Arm Type

Placebo Comparator

Arm Description

Sterile placebo for dupilumab will be provided in identically matched glass prefilled syringes to deliver 2 mL.

Intervention Type

Biological

Intervention Name(s)

Dupilumab/Dupixent

Intervention Description

a monoclonal antibody designed for the treatment asthma and atopic dermatitis.

Intervention Type

Biological

Intervention Name(s)

Placebo

Intervention Description

Matched placebo

Primary Outcome Measure Information:

Title

Proportion of patients that achieve at least one doubling dose improvement in PC20 methacholine and/or a 50% reduction in FEV1 reversibility after bronchodilator.

Description

Time Frame

Between screening (week -4) and week 16.

Secondary Outcome Measure Information:

Title

Change in geometric mean PC20 methacholine.

Description

Change in PC20 between screening and week 16.

Time Frame

Between screening (week -4) and week 16.

Title

Change in FEV1 reversibility.

Description

Change in FEV1 % reversibility (pre/post bronchodilator) between randomization and end of treatment.

Time Frame

Between randomization (week 0) and week 16.

Title

Change in sputum eosinophil percentage (%)

Description

Change in sputum eosinophil percentage between randomization and end of treatment

Time Frame

Between randomization (week 0) and week 16.

Title

Change in blood eosinophil count

Description

Change in blood eosinophil count levels between randomization and end of treatment

Time Frame

Between randomization (week 0) and week 16.

Title

Change in fraction of exhaled nitric oxide (FeNO)

Description

Change in FeNO values parts per billion (ppb) from randomization and end of treatment.

Time Frame

Between randomization (week 0) and week 16.

Title

Change in FEV1 (pre-bronchodilator)

Description

Change in pre-bronchodilator FEV1 values (in litres) between randomization and end of treatment.

Time Frame

Between randomization (week 0) and week 16.

Title

Change in Asthma Control Questionnaire-5 (ACQ-5)

Description

Change in ACQ scores between randomization and end of treatment.

Time Frame

Between randomization (week 0) and week 16.

Title

Change in Asthma Control Questionnaire-5 (AQLQ)

Description

Change in AQLQ scores between randomization and end of treatment.

Time Frame

Between randomization (week 0) and week 16.

Title

Change in Asthma Control Test (ACT)

Description

Change in ACT scores between randomization and end of treatment.

Time Frame

Between randomization (week 0) and week 16.

Other Pre-specified Outcome Measures:

Title

Change in MRI ventilation heterogeneity (n=12 in each arm).

Description

Change in MRI ventilation heterogeneity seen with administration of Hyperpolarized Xenon-129 inhalation.

Time Frame

Between randomization (week 0) and week 16.

Title

Change in CT airway remodeling and airway mucus scores (n=12 in each arm).

Description

Changes are evaluated via CT inspiratory/expiratory scans via quantitative software (n=12 in each arm)

Time Frame

Between randomization (week 0) and week 16.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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) 2014 guidelines. ACQ > 1 during the screening period. Airway hyperresponsiveness (methacholine PC20 ≤ 4 mg/mL OR ≥15% decreased in FEV1 during saline inhalation for sputum induction OR ≥25% improvement in FEV1 after bronchodilator) during the screening period. Fraction of exhaled nitric oxide (FeNO) >25 ppb and either ≥3% sputum eosinophils (preferred) OR blood eos ≥300/µL during the screening period. Inhaled corticosteroids (ICS) dose ≥500 mcg of fluticasone equivalent/day. Patients on prednisone would not be excluded as long as they meet the rest of the inclusion criteria. Exclusion Criteria: Patients who meet any of the following criteria will be excluded from study entry: Prior Medical Conditions and Treatment History 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. Treatment with anti-IgE (immunoglobulin E), anti-IL-4, anti-IL-5 (interleukin-5), or anti-IL-13 targeted therapy currently or within three months prior to screening. ACQ > 3.0 MRI (Magnetic Resonance Imaging )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. General Participation in any clinical trial of an investigational agent or procedure within six months prior to screening or during the study.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Parameswaran Nair, MD, PhD

Organizational Affiliation

McMaster University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Firestone Institute for Respiratory Health, St. Joseph's Healthcare

City

Hamilton

State/Province

Ontario

ZIP/Postal Code

L8N 4A6

Country

Canada

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Citations:

PubMed Identifier

9856949

Citation

Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL, Donaldson DD. Interleukin-13: central mediator of allergic asthma. Science. 1998 Dec 18;282(5397):2258-61. doi: 10.1126/science.282.5397.2258.

Results Reference

background

PubMed Identifier

23589465

Citation

Svenningsen S, Kirby M, Starr D, Leary D, Wheatley A, Maksym GN, McCormack DG, Parraga G. Hyperpolarized (3) He and (129) Xe MRI: differences in asthma before bronchodilation. J Magn Reson Imaging. 2013 Dec;38(6):1521-30. doi: 10.1002/jmri.24111. Epub 2013 Apr 15.

Results Reference

background

PubMed Identifier

10619836

Citation

Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG, MacIntyre NR, McKay RT, Wanger JS, Anderson SD, Cockcroft DW, Fish JE, Sterk PJ. Guidelines for methacholine and exercise challenge testing-1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med. 2000 Jan;161(1):309-29. doi: 10.1164/ajrccm.161.1.ats11-99. No abstract available.

Results Reference

background

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Dupilumab on Airway Hyper-responsiveness and Ventilation Heterogeneity in Patients With Asthma.

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