Asthma
Conditions
Keywords
Airway hyperresponsivness, Ventilation heterogeneity, Hyperpolarized Xenon-129, Sputum eosinophils
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.
Interventions
BIOLOGICALDupilumab/Dupixent
a monoclonal antibody designed for the treatment asthma and atopic dermatitis.
BIOLOGICALPlacebo
Matched placebo
Sponsors
Sanofi
McMaster University
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of patients that achieve at least one doubling dose improvement in PC20 methacholine and/or a 50% reduction in FEV1 reversibility after bronchodilator. | 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
| Measure | Time frame | Description |
|---|---|---|
| Change in geometric mean PC20 methacholine. | Between screening (week -4) and week 16. | Change in PC20 between screening and week 16. |
| Change in FEV1 reversibility. | 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 (%) | Between randomization (week 0) and week 16. | Change in sputum eosinophil percentage between randomization and end of treatment |
| Change in blood eosinophil count | 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) | Between randomization (week 0) and week 16. | Change in FeNO values parts per billion (ppb) from randomization and end of treatment. |
| Change in Asthma Control Questionnaire-5 (AQLQ) | Between randomization (week 0) and week 16. | Change in AQLQ scores between randomization and end of treatment. |
| Change in Asthma Control Test (ACT) | Between randomization (week 0) and week 16. | Change in ACT scores between randomization and end of treatment. |
| Change in FEV1 (pre-bronchodilator) | 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) | Between randomization (week 0) and week 16. | Change in ACQ scores between randomization and end of treatment. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in MRI ventilation heterogeneity (n=12 in each arm). | 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). | Between randomization (week 0) and week 16. | Changes are evaluated via CT inspiratory/expiratory scans via quantitative software (n=12 in each arm) |
Countries
Canada
Outcome results
None listed