Evaluation of Dupilumab's Effects on Airway Inflammation in Patients With Asthma

Study Overview
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Brief Summary
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Primary Objective: To evaluate the effect of dupilumab, compared to placebo, on airway inflammation in participants with persistent asthma. Secondary Objective: To assess the safety, tolerability, and immunogenicity of dupilumab compared to placebo.

Detailed Description
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The total study duration for each participant was between approximately 29 and maximum of 30 weeks, consisting of a screening period of 5 weeks and optional up to 7 additional days, a treatment period of 12 weeks, and a post-treatment period of 12 weeks. Participants who completed the treatment period could be eligible to participate in an open-label extension study.

Official Title
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An Exploratory, Double-blind, Placebo-controlled Study of the Effects of Dupilumab on Airway Inflammation of Adults With Persistent Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: Placebo
* Drug: Dupilumab SAR231893/REGN668
* Drug: fluticasone propionate and salmeterol
* Drug: budesonide and formoterol
* Drug: mometasone furoate and formoterol


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male and female adults with a physician diagnosis of persistent asthma for ≥12 months. Existing treatment with medium to high dose inhaled corticosteroids in combination with a long-acting beta agonist for at least 3 months with a stable dose ≥1 month prior to Visit 1 (Screening Visit). Treatment with a third asthma controller for at least 3 months with a stable dose >=1 month prior to Visit 1 was allowed. Pre-bronchodilator forced expiratory volume (FEV1) 55 to 85% of predicted normal. Exclusion criteria: Participants <18 years or >65 years. Fractional exhaled nitric oxide (FeNO) <26 parts per billion (ppb) at Visit 1 (Screening Visit). Chronic obstructive pulmonary disease or other lung diseases (eg, idiopathic pulmonary fibrosis, eosinophilic granulomatosis with polyangiitis [Churg-Strauss Syndrome]) which could impair lung function. A participant who experienced an asthma exacerbation that resulted in emergency treatment, hospitalization due to asthma, or treatment with systemic steroids at any time from 1 month prior to Visit 1. A participant who had experienced an upper or lower respiratory tract infection within the 4 weeks prior to Visit 1. Evidence of lung disease(s) other than asthma. Previous smoker (smoking history >10 pack-years) or current smoker (within 6 months prior to Visit 1). Comorbid disease that might interfere with the evaluation of investigational medicinal product or conduct of study procedures (e.g., bronchoscopy). Anti-immunoglobulin E (IgE) therapy (omalizumab) or any other biologic therapy within 6 months of Visit 1. Exposure to another investigative study medication within a time period prior to Visit 1 that is less than 5 half-lives of the study medication. Treatment with systemic (oral or injectable) corticosteroids within 28 days of Visit 1. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo (for dupilumab), 2 subcutaneous injections on Day 1 (Week 1) as a loading dose followed by a single injection q2w from Week 2 to Week 14, added to stable inhaled corticosteroid/ long-acting beta-agonist (ICS/LABA) therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. | Drug: Placebo<br>* Pharmaceutical form:solution Route of administration: subcutaneous<br>Drug: fluticasone propionate and salmeterol<br>* Pharmaceutical form:inhalation aerosol, inhalation powder Route of administration: inhaled<br>* Other names: Advair;Drug: budesonide and formoterol<br>* Pharmaceutical form:inhalation aerosol Route of administration: inhaled<br>* Other names: Symbicort;Drug: mometasone furoate and formoterol<br>* Pharmaceutical form:inhalation aerosol Route of administration: inhaled<br>* Other names: Dulera;|
| Experimental: Dupilumab<br>Dupilumab, 2 subcutaneous injections on Day 1 as a loading dose for a total of 600 mg, followed by a single 300 mg injection q2w from Week 2 to Week 14, added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. | Drug: Dupilumab SAR231893/REGN668<br>* Pharmaceutical form:solution Route of administration: subcutaneous<br>Drug: fluticasone propionate and salmeterol<br>* Pharmaceutical form:inhalation aerosol, inhalation powder Route of administration: inhaled<br>* Other names: Advair;Drug: budesonide and formoterol<br>* Pharmaceutical form:inhalation aerosol Route of administration: inhaled<br>* Other names: Symbicort;Drug: mometasone furoate and formoterol<br>* Pharmaceutical form:inhalation aerosol Route of administration: inhaled<br>* Other names: Dulera;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Eosinophils Cells Count in the Bronchial Submucosa at Week 12 | Inflammatory cells i.e. eosinophils were counted in the bronchial submucosa of biopsy thin sections using quantitative immunohistochemistry and reported as the number of cells per square millimeter. | Baseline, Week 12 | 
| Change From Baseline in Mucin-Stained Area in the Bronchial Submucosa at Week 12 | Mucin was identified by staining with Alcian-blue periodic acid-Schiff and/or immunostaining for MUC5AC and then the mucin-positive area was measured and expressed per square millimeter. | Baseline, Week 12 | 
| Change From Baseline in Mast Cells Count (Chymase Positive) in the Bronchial Submucosa at Week 12 | Inflammatory cells i.e. mast cells were counted in the bronchial submucosa of biopsy thin sections using quantitative immunohistochemistry and reported as the number of cells per square millimeter. | Baseline, Week 12 | 
| Change From Baseline in Mast Cells Count (Tryptase Positive) in the Bronchial Submucosa at Week 12 | Inflammatory cells i.e. mast cells were counted in the bronchial submucosa of biopsy thin sections using quantitative immunohistochemistry and reported as the number of cells per square millimeter. | Baseline, Week 12 | 
| Change From Baseline in T-Lymphocytes Count in the Bronchial Submucosa at Week 12 | T-Lymphocytes i.e. CD3 positive cells were counted in the bronchial submucosa of biopsy thin sections using quantitative immunohistochemistry and reported as the number of cells per square millimeter. | Baseline, Week 12 | 
| Change From Baseline in T-Helper Lymphocytes Count in the Bronchial Submucosa at Week 12 | T-helper i.e. CD4 positive lymphocytes were counted in the bronchial submucosa of biopsy thin sections using quantitative immunohistochemistry and reported as the number of cells per square millimeter. | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Fractional Exhaled Nitric Oxide (FeNO) at Week 12 | FeNO is a surrogate marker for airway inflammation. FeNO was analyzed using a NIOX instrument or similar analyzer using a flow rate of 50 mL/second, and reported in ppb. | Baseline, Week 12 | 
| Average Change in Fractional Exhaled Nitric Oxide (FeNO) From Baseline to Week 6 Through Week 12 | FeNO is a surrogate marker for airway inflammation. FeNO was analyzed using a NIOX instrument or similar analyzer using a flow rate of 50 mL/s, and reported in ppb. The average change in FeNO from baseline to Week 6 through Week 12 was calculated as follows: For each participant the change in FeNO from Baseline to Week 6, Week 8, Week 10 and Week 12 was calculated (value at Week X - value at baseline). Subsequently the weekly mean of these 4 change from baseline values was determined (Weeks 6, 8, 10 and 12). Using these weekly mean values the overall arithmetic mean and standard deviation of the average change in FeNO from baseline to Week 6 through Week 12 was calculated. | From Baseline to Week 6 through Week 12 | 
| Number of Participants With Antidrug Antibodies (ADA) | Anti-drug antibodies were detected using a validated immunoassay. Incidence of ADA were classified as following: 1) Pre-existing immunoreactivity - an ADA positive response in the assay at baseline with all post treatment ADA results negative or an ADA positive response at baseline with all post treatment ADA responses less than 4-fold over baseline titer levels. 2) Treatment-emergent ADA: an ADA positive response in the assay post first dose, when baseline results were negative or missing. 3) Treatment-boosted ADA: an ADA positive response in the assay post first dose that was greater-than or equal to 4-fold over baseline titer levels, when baseline results were positive. | From Baseline up to 24 weeks | 
| Pharmacokinetics (PK) Assessment: Serum Functional Dupilumab Concentration | Serum functional dupilumab concentrations were determined using an enzyme-linked immunosorbent assay (ELISA) method. | Week 0, Week 2, 6, 8, 12, 18, End of study (Week 24) | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Adverse event (AE) was defined as any untoward medical occurrence in a participant who received investigational medicinal product (IMP) without regard to possibility of causal relationship with this treatment. TEAEs: AEs that developed or worsened or became serious during between the first administration of study medication to the end of the 12 week Post-treatment Period. Serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included both serious and non-serious AEs. | Baseline up to Week 24 |