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

NCT03884842 | Completed Phase 3

• 1 other identifier: 11963
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

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.

Conditions

Asthma

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (9)

• Change in geometric mean PC20 methacholine.

  Between screening (week -4) and week 16.

• Change in FEV1 reversibility.

  Between randomization (week 0) and week 16.

• Change in sputum eosinophil percentage (%)

  Between randomization (week 0) and week 16.

• Change in blood eosinophil count

  Between randomization (week 0) and week 16.

• Change in fraction of exhaled nitric oxide (FeNO)

  Between randomization (week 0) and week 16.

Other Outcomes (2)

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

  Between randomization (week 0) and week 16.

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

  Between randomization (week 0) and week 16.

Study Arms (2)

dupilumab

ACTIVE COMPARATOR

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

matched placebo

PLACEBO COMPARATOR

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

Biological: Placebo

Interventions

Dupilumab/Dupixent BIOLOGICAL

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

dupilumab

Placebo BIOLOGICAL

Matched placebo

matched placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• McMaster University: lead
• Sanofi: collaborator

Study Sites (1)

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

Hamilton, Ontario, L8N 4A6, Canada

Location

Related Publications (4)

• 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.

  PMID: 9856949 BACKGROUND

• 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.

  PMID: 23589465 BACKGROUND

• 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.

  PMID: 10619836 BACKGROUND

• Svenningsen S, Kjarsgaard M, Haider E, Venegas C, Konyer N, Friedlander Y, Nasir N, Boylan C, Kirby M, Nair P. Effects of Dupilumab on Mucus Plugging and Ventilation Defects in Patients with Moderate-to-Severe Asthma: A Randomized, Double-Blind, Placebo-Controlled Trial. Am J Respir Crit Care Med. 2023 Nov 1;208(9):995-997. doi: 10.1164/rccm.202306-1102LE. No abstract available.

  PMID: 37603097 DERIVED

MeSH Terms

Conditions

Asthma

Interventions

dupilumab

Condition Hierarchy (Ancestors)

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

Study Officials

• Parameswaran Nair, MD, PhD

  McMaster University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 18, 2019
• First Posted: March 21, 2019
• Study Start: July 1, 2019
• Primary Completion: October 12, 2022
• Study Completion: January 17, 2023
• Last Updated: January 20, 2023

Record last verified: 2023-01

Locations

CA (1)