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.
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
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
24
a monoclonal antibody designed for the treatment asthma and atopic dermatitis.
Matched placebo
Firestone Institute for Respiratory Health, St. Joseph's Healthcare
Hamilton, Ontario, Canada
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.
Time frame: Between screening (week -4) and week 16.
Change in geometric mean PC20 methacholine.
Change in PC20 between screening and week 16.
Time frame: Between screening (week -4) and week 16.
Change in FEV1 reversibility.
Change in FEV1 % reversibility (pre/post bronchodilator) between randomization and end of treatment.
Time frame: Between randomization (week 0) and week 16.
Change in sputum eosinophil percentage (%)
Change in sputum eosinophil percentage between randomization and end of treatment
Time frame: Between randomization (week 0) and week 16.
Change in blood eosinophil count
Change in blood eosinophil count levels between randomization and end of treatment
Time frame: 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.
Time frame: 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.
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Time frame: 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.
Time frame: Between randomization (week 0) and week 16.
Change in Asthma Control Questionnaire-5 (AQLQ)
Change in AQLQ scores between randomization and end of treatment.
Time frame: Between randomization (week 0) and week 16.
Change in Asthma Control Test (ACT)
Change in ACT scores between randomization and end of treatment.
Time frame: Between randomization (week 0) and week 16.