Efficacy and Safety Study of Dupilumab in Patients With Persistent Asthma

Study Overview
=================
Brief Summary
-----------------
Primary Objective: To evaluate the efficacy of dupilumab in patients with persistent asthma Secondary Objectives: To evaluate the safety and tolerability of dupilumab To evaluate the effect of dupilumab on improving patient reported outcomes including health related quality of life To evaluate dupilumab systemic exposure and immunogenicity

Detailed Description
-----------------
The total duration of study per patient is approximately 40 weeks, including 3 to 5 weeks of screening period, 24 weeks of treatment period and 12 weeks of post-treatment period.

Official Title
-----------------
A Randomized, Double Blind, Placebo-controlled, Parallel-group Phase 3 Study to Evaluate the Efficacy and Safety of Dupilumab in Patients With Persistent Asthma

Conditions
-----------------
Asthma

Intervention / Treatment
-----------------
* Drug: Dupilumab SAR231893
* Drug: Placebo
* Drug: Asthma Controller Therapies (include prednisone/prednisolone)
* Drug: Asthma Reliever Therapies


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria : Adults and adolescent patients (≥12 years of age) with a physician diagnosis of asthma for ≥12 months, based on the Global Initiative for Asthma 2017 Guidelines and the following criteria: Patients requiring a third controller for their asthma will be considered eligible for this study, and it should also be used for at least 3 months with a stable dose ≥1 month prior to the screening visit (Visit 1). Patients requiring maintenance oral corticosteroids (OCS) with a stable dose ≤10 mg/day prednisone or equivalent will be allowed; OCS should be used for at least 3 months with a stable dose ≥1 month prior to the screening visit (Visit 1). Pre-bronchodilator FEV1 ≤ 80% of predicted normal for adults and ≤90% of predicted normal for adolescents at the screening visit and the randomization visit (Visits 1 and 2), prior to randomization. Asthma Control Questionnaire 5-question version (ACQ-5) score ≥1.5 at the screening visit and the randomization visit (Visits 1 and 2), prior to randomization. For patients not requiring maintenance OCS, screening blood eosinophil count ≥150 cells/μL or Fractional Exhaled Nitric Oxide (FENO) ≥25 parts per billion (ppb); for patients requiring maintenance OCS, there is no minimum requirement for blood eosinophil count and FENO level. Exclusion criteria: Patients <12 years of age or the minimum legal age for adolescents in the country of the investigative site, whichever is higher (for those countries where local regulations permit enrollment of adults only, patient recruitment will be restricted to those who are ≥18 years of age). Weight is less than 30 kg at the screening visit (Visit 1) or the randomization visit (Visit 2). Chronic obstructive pulmonary disease or other lung diseases (eg, idiopathic pulmonary fibrosis) which may impair lung function. A patient who experiences a severe asthma exacerbation (defined as deterioration of asthma that results in emergency treatment, hospitalization due to asthma, treatment with systemic steroids, or treatment with systemic steroid at least twice the previous dose for patients on OCS maintenance) at any time from 1 month prior to the screening visit (Visit 1) up to and including the randomization visit (Visit 2). Evidence of lung disease(s) other than asthma, either clinical or imaging evidence (eg, chest X-ray, computed tomography, and magnetic resonance imaging) within 3 months prior to the screening visit (Visit 1) as per local standard of care. Current smoker or cessation of smoking within 6 months prior to the screening visit (Visit 1). Previous smoker with a smoking history >10 pack-years. Comorbid disease that might interfere with the evaluation of investigational medicinal product (IMP). The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
-----------------
Minimum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dupilumab<br>For patients without oral corticosteroids (OCS) maintenance therapy, dose 1 of dupilumab administered once in 2 weeks (q2w) with loading dose of dupilumab, two times dose 1; for patients on OCS maintenance therapy, the dose will be dupilumab dose 2 q2w with loading dose 2 times dose 2 | Drug: Dupilumab SAR231893<br>* Pharmaceutical form: Solution Route of administration: Subcutaneous<br>Drug: Asthma Controller Therapies (include prednisone/prednisolone)<br>* Pharmaceutical form: Aerosol, capsules, tablets, oral solution Route of administration: Inhalation, oral<br>Drug: Asthma Reliever Therapies<br>* Pharmaceutical form: Nebulized, aerosol Route of administration: Inhaled<br>|
| Placebo Comparator: Placebo for dupilumab<br>For patients without OCS maintenance therapy, the patients will take placebo matching to dupilumab dose 1 q2w with loading dose; for patients on OCS maintenance therapy, the patients will take placebo matching to dupilumab dose 2 q2w with loading dose | Drug: Placebo<br>* Pharmaceutical form: Solution Route of administration: Subcutaneous<br>Drug: Asthma Controller Therapies (include prednisone/prednisolone)<br>* Pharmaceutical form: Aerosol, capsules, tablets, oral solution Route of administration: Inhalation, oral<br>Drug: Asthma Reliever Therapies<br>* Pharmaceutical form: Nebulized, aerosol Route of administration: Inhaled<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in pre-bronchodilator forced expiratory volume (FEV1) | Absolute change from baseline in pre-bronchodilator FEV1 at Week 12 | Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized rate of severe exacerbation events | Annualized rate of severe exacerbation events during the 24-week placebo-controlled treatment period | During the 24-week placebo-controlled treatment period | 
| Percent change from baseline in pre-bronchodilator FEV1 | Percent change from baseline in pre-bronchodilator FEV1 at Week 12 | Baseline to Week 12 | 
| Annualized rate of loss of asthma control (LOAC) event | Annualized rate of LOAC event during the 24-week placebo-controlled treatment period | During the 24-week placebo-controlled treatment period | 
| Annualized rate of severe exacerbation events resulting in hospitalization or emergency room visit | Annualized rate of severe exacerbation events resulting in hospitalization or emergency room visit during the 24-week placebo-controlled treatment period | During the 24-week placebo-controlled treatment period | 
| Time to first severe exacerbation event | Time to first severe exacerbation event during the 24-week placebo-controlled treatment period | During the 24-week placebo-controlled treatment period | 
| Time to first LOAC | Time to first LOAC during the 24-week placebo-controlled treatment period | During the 24-week placebo-controlled treatment period | 
| Change from baseline in Asthma Control Questionnaire (ACQ)-5 score | Change from baseline in ACQ-5 score at Week 24 | Baseline to Week 24 | 
| Change from baseline in ACQ-7 score | Change from baseline in ACQ-7 score at Week 24 | Baseline to Week 24 | 
| Morning/evening asthma symptom score (e-diary) | Change from baseline at Week 24 in morning/evening asthma symptom score (e-diary) | Baseline to Week 24 | 
| Nocturnal awakenings (e-diary) | Change from baseline at Week 24 in nocturnal awakenings (e-diary) | Baseline to week 24 | 
| Use of daily puffs of rescue medication | Change from baseline at Week 24 in use of daily puffs of rescue medication | Baseline to Week 24 | 
| Change from baseline in Asthma Quality of Life Questionnaire (AQLQ) with Standardized Activities (≥12 years) (AQLQ+12) | Change from baseline in AQLQ with Standardized Activities (≥12 years) (AQLQ+12) at Week 24 | Baseline to Week 24 | 
| Change from baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels (EQ-5D-5L) | Change from baseline in EQ-5D-5L at Week 24 | Baseline to Week 24 | 
| Assessment of adverse events (AEs) | Number of participants with adverse events (AEs) | Baseline to week 36 |