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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

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.

Condition or disease Intervention/treatment Phase
Asthma Biological: Dupilumab/Dupixent Biological: Placebo Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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"
Actual Study Start Date : July 1, 2019
Estimated Primary Completion Date : April 2021
Estimated Study Completion Date : June 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Asthma
Drug Information available for: Dupilumab

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




Primary Outcome Measures :
  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. [ 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.


Secondary Outcome Measures :
  1. Change in geometric mean PC20 methacholine. [ Time Frame: Between screening (week -4) and week 16. ]
    Change in PC20 between screening and week 16.

  2. 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.

  3. 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

  4. 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

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.


Other Outcome Measures:
  1. 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.

  2. 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)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03884842


Contacts
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Contact: Melanie Kjarsgaard, RRT 905-522-1155 ext 33024 mkjarsga@stjoes.ca
Contact: Sarah Svenningsen, PhD 905-522-1155 ext 37313 svennins@mcmaster.ca

Locations
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Canada, Ontario
Firestone Institute for Respiratory Health, St. Joseph's Healthcare Recruiting
Hamilton, Ontario, Canada, L8N 4A6
Contact: Melanie Kjarsgaard    905-522-1155 ext 33024    mkjarsga@stjosham.on.ca   
Principal Investigator: Parameswaran Nair, MD, PhD         
Sub-Investigator: Sarah Svenningsen, PhD         
Sponsors and Collaborators
McMaster University
Sanofi
Investigators
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Principal Investigator: Parameswaran Nair, MD, PhD McMaster University
Publications:
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Responsible Party: McMaster University
ClinicalTrials.gov Identifier: NCT03884842    
Other Study ID Numbers: 11963
First Posted: March 21, 2019    Key Record Dates
Last Update Posted: January 6, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by McMaster University:
Airway hyperresponsivness
Ventilation heterogeneity
Hyperpolarized Xenon-129
Sputum eosinophils
Additional relevant MeSH terms:
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Asthma
Respiratory Hypersensitivity
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases