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

McMaster University

Status and phase: Completed; Phase 3

Conditions: Asthma

Treatments: Biological: Placebo; Biological: Dupilumab/Dupixent

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT03884842

11963

Details and patient eligibility

About

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.

Full 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.

Enrollment: 24 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Single Group Assignment

Masking: Quadruple Blind

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24 participants in 2 patient groups, including a placebo group

dupilumab

Active Comparator group

Description:

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.

Treatment:

Biological: Dupilumab/Dupixent

matched placebo

Placebo Comparator group

Description:

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

Treatment:

Biological: Placebo