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

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"

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.

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Biological: Placebo; Biological: Dupilumab/Dupixent

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.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 4A6
      • Firestone Institute for Respiratory Health, St. Joseph's Healthcare

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

1. Acute or chronic parasitic, bacterial, fungal or viral infections that required, or currently requires, hospitalization or antimicrobial treatment during the last four weeks.
2. 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.
3. 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.
4. Alcohol or substance abuse within 12 months prior to screening.
5. 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.
6. Ex-smokers with ≥ 10 pack-year smoking history.
7. 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.

8. ACQ > 3.0

   MRI (Magnetic Resonance Imaging )Related

9. 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).

10. 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

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: dupilumab; 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.	Biological: Dupilumab/Dupixent; a monoclonal antibody designed for the treatment asthma and atopic dermatitis.
Placebo Comparator: matched placebo; Sterile placebo for dupilumab will be provided in identically matched glass prefilled syringes to deliver 2 mL.	Biological: Placebo; Matched placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Between screening (week -4) and week 16.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in geometric mean PC20 methacholine.	Change in PC20 between screening and week 16.	Between screening (week -4) and week 16.
Change in FEV1 reversibility.	Change in FEV1 % reversibility (pre/post bronchodilator) between randomization and end of treatment.	Between randomization (week 0) and week 16.
Change in sputum eosinophil percentage (%)	Change in sputum eosinophil percentage between randomization and end of treatment	Between randomization (week 0) and week 16.
Change in blood eosinophil count	Change in blood eosinophil count levels between randomization and end of treatment	Between randomization (week 0) and week 16.
Change in fraction of exhaled nitric oxide (FeNO)	Change in FeNO values parts per billion (ppb) from randomization and end of treatment.	Between randomization (week 0) and week 16.
Change in FEV1 (pre-bronchodilator)	Change in pre-bronchodilator FEV1 values (in litres) between randomization and end of treatment.	Between randomization (week 0) and week 16.
Change in Asthma Control Questionnaire-5 (ACQ-5)	Change in ACQ scores between randomization and end of treatment.	Between randomization (week 0) and week 16.
Change in Asthma Control Questionnaire-5 (AQLQ)	Change in AQLQ scores between randomization and end of treatment.	Between randomization (week 0) and week 16.
Change in Asthma Control Test (ACT)	Change in ACT scores between randomization and end of treatment.	Between randomization (week 0) and week 16.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in MRI ventilation heterogeneity (n=12 in each arm).	Change in MRI ventilation heterogeneity seen with administration of Hyperpolarized Xenon-129 inhalation.	Between randomization (week 0) and week 16.
Change in CT airway remodeling and airway mucus scores (n=12 in each arm).	Changes are evaluated via CT inspiratory/expiratory scans via quantitative software (n=12 in each arm)	Between randomization (week 0) and week 16.

Collaborators and Investigators

• Sponsor: McMaster University
• Collaborators: Sanofi
• Investigators: Principal Investigator: Parameswaran Nair, MD, PhD, McMaster University

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2019
• Primary Completion (Actual): October 12, 2022
• Study Completion (Actual): January 17, 2023

Study Registration Dates

• First Submitted: March 18, 2019
• First Submitted That Met QC Criteria: March 19, 2019
• First Posted (Actual): March 21, 2019

Study Record Updates

• Last Update Posted (Actual): January 20, 2023
• Last Update Submitted That Met QC Criteria: January 18, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Airway hyperresponsivness; Ventilation heterogeneity; Hyperpolarized Xenon-129; Sputum eosinophils
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Hypersensitivity; Asthma; Respiratory Hypersensitivity
• Other Study ID Numbers: 11963

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No