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

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ClinicalTrials.gov Identifier: NCT03884842
Recruitment Status : Recruiting
First Posted : March 21, 2019
Last Update Posted : January 6, 2021
Sponsor:
Collaborator:
Sanofi
Information provided by (Responsible Party):
McMaster University

Tracking Information
First Submitted Date  ICMJE March 18, 2019
First Posted Date  ICMJE March 21, 2019
Last Update Posted Date January 6, 2021
Actual Study Start Date  ICMJE July 1, 2019
Estimated Primary Completion Date April 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 19, 2019)
Proportion of patients that achieve at least one doubling dose improvement in PC20 methacholine and/or a 50% reduction in FEV1 reversibility after bronchodilator. [ Time Frame: Between screening (week -4) and week 16. ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 19, 2019)
  • Change in geometric mean PC20 methacholine. [ Time Frame: Between screening (week -4) and week 16. ]
    Change in PC20 between screening and week 16.
  • Change in FEV1 reversibility. [ Time Frame: Between randomization (week 0) and week 16. ]
    Change in FEV1 % reversibility (pre/post bronchodilator) between randomization and end of treatment.
  • Change in sputum eosinophil percentage (%) [ Time Frame: Between randomization (week 0) and week 16. ]
    Change in sputum eosinophil percentage between randomization and end of treatment
  • Change in blood eosinophil count [ Time Frame: Between randomization (week 0) and week 16. ]
    Change in blood eosinophil count levels between randomization and end of treatment
  • Change in fraction of exhaled nitric oxide (FeNO) [ Time Frame: Between randomization (week 0) and week 16. ]
    Change in FeNO values parts per billion (ppb) from randomization and end of treatment.
  • Change in FEV1 (pre-bronchodilator) [ Time Frame: Between randomization (week 0) and week 16. ]
    Change in pre-bronchodilator FEV1 values (in litres) between randomization and end of treatment.
  • Change in Asthma Control Questionnaire-5 (ACQ-5) [ Time Frame: Between randomization (week 0) and week 16. ]
    Change in ACQ scores between randomization and end of treatment.
  • Change in Asthma Control Questionnaire-5 (AQLQ) [ Time Frame: Between randomization (week 0) and week 16. ]
    Change in AQLQ scores between randomization and end of treatment.
  • Change in Asthma Control Test (ACT) [ Time Frame: Between randomization (week 0) and week 16. ]
    Change in ACT scores between randomization and end of treatment.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: March 19, 2019)
  • Change in MRI ventilation heterogeneity (n=12 in each arm). [ Time Frame: Between randomization (week 0) and week 16. ]
    Change in MRI ventilation heterogeneity seen with administration of Hyperpolarized Xenon-129 inhalation.
  • Change in CT airway remodeling and airway mucus scores (n=12 in each arm). [ Time Frame: Between randomization (week 0) and week 16. ]
    Changes are evaluated via CT inspiratory/expiratory scans via quantitative software (n=12 in each arm)
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Dupilumab on Airway Hyper-responsiveness and Ventilation Heterogeneity in Patients With Asthma.
Official Title  ICMJE 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"
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Asthma
Intervention  ICMJE
  • Biological: Dupilumab/Dupixent
    a monoclonal antibody designed for the treatment asthma and atopic dermatitis.
  • Biological: Placebo
    Matched placebo
Study Arms  ICMJE
  • 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.

    Intervention: Biological: Dupilumab/Dupixent
  • Placebo Comparator: matched placebo
    Sterile placebo for dupilumab will be provided in identically matched glass prefilled syringes to deliver 2 mL.
    Intervention: Biological: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 19, 2019)
32
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2021
Estimated Primary Completion Date April 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Melanie Kjarsgaard, RRT 905-522-1155 ext 33024 mkjarsga@stjoes.ca
Contact: Sarah Svenningsen, PhD 905-522-1155 ext 37313 svennins@mcmaster.ca
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03884842
Other Study ID Numbers  ICMJE 11963
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party McMaster University
Study Sponsor  ICMJE McMaster University
Collaborators  ICMJE Sanofi
Investigators  ICMJE
Principal Investigator: Parameswaran Nair, MD, PhD McMaster University
PRS Account McMaster University
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP