Evaluation of Dupilumab in Patients With Severe Steroid Dependent Asthma

Study Overview
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Brief Summary
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Primary Objective: To evaluate the efficacy of dupilumab, compared with placebo, for reducing the use of maintenance oral corticosteroids (OCS) in participants with severe steroid-dependent asthma. Secondary Objectives: To evaluate the safety and tolerability of dupilumab. To evaluate the effect of dupilumab in improving participants-reported outcomes. To evaluate dupilumab systemic exposure and the incidence of treatment-emergent antidrug antibodies.

Detailed Description
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The total study duration per participant was up to 46 weeks, consisting of a screening period of 3 to up to 8 weeks (up to 10 weeks for participants who experienced a clinically significant asthma exacerbation during the screening period), a randomized treatment period of up to 24 weeks, and a post-treatment period of 12 weeks. Participants who completed treatment were considered for eligibility into the long term extension study LTS12551 (NCT02134028).

Official Title
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A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Dupilumab in Patients With Severe Steroid Dependent Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: Dupilumab
* Drug: Placebo
* Drug: Oral corticosteroid therapy (prednisone/prednisolone)
* Drug: Inhaled corticosteroid (ICS) therapy
* Drug: Albuterol/Salbutamol
* Drug: Levalbuterol/Levosalbutamol


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Adult and adolescent (12 years of age or older) participants with a physician diagnosis of asthma for >=12 months, based on the Global Initiative for Asthma (GINA) 2014 guidelines and the following criteria: Participants with severe asthma and a well-documented, regular prescribed treatment of maintenance corticosteroids in the 6 months prior to Visit 1 and using a stable OCS dose (ie, no change of OCS dose) for 4 weeks prior to Visit 1. Participants must be taking 5 to 35 mg/day of prednisone/prednisolone, or the equivalent, at Visit 1 and at the randomization visit. In addition, the participants must agree to switch to study-required prednisone/prednisolone as their OCS and use it per protocol for the duration of the study. Existing treatment with high-dose inhaled corticosteroid (ICS; >500 mcg total daily dose of fluticasone propionate or equivalent) in combination with a second controller (ie, long-acting beta agonist [LABA], leukotriene receptor antagonist [LTRA]) for at least 3 months with a stable dose of ICS for >=1 month prior to Visit 1. In addition, participants requiring a third controller for their asthma are considered eligible for this study, and it should also be used for at least 3 months with a stable dose >= 1 month prior to Visit 1. A forced expiratory volume in 1 second (FEV1) <80% of predicted normal for adults and <=90% of predicted normal for adolescents at Visit 1. Evidence of asthma as documented by either: reversibility of at least 12% and 200 mL in FEV1 after the administration of 200 to 400 mcg (2 to 4 inhalations of albuterol/salbutamol or levalbuterol/levosalbutamol, or of a nebulized solution of albuterol/salbutamol or levalbuterol/levosalbutamol, if considered as a standard office practice) before randomization or documented in the 12 months prior to Visit 1 OR airway hyperresponsiveness (methacholine: provocative concentration that causes a positive reaction [PC20] of <8 mg/mL) documented in the 12 months prior to Visit 1. Exclusion criteria: Participants <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, participant recruitment will be restricted to those who were >=18 years of age). Participants who weighed <30.0 kg. Chronic obstructive pulmonary disease (COPD) or other lung diseases (eg, idiopathic pulmonary fibrosis, Churg-Strauss Syndrome, allergic bronchopulmonary aspergillosis, cystic fibrosis) which may impair lung function. Clinical evidence or imaging (eg, chest X-ray, computed tomography, magnetic resonance imaging) within 12 months of Visit 1 with clinically significant findings of lung disease(s) other than asthma, as per local standard of care. A participant who experiences a deterioration of asthma that results in emergency treatment or hospitalization within 4 weeks of Screening Visit 1. A participant who requires 12 puffs or more of rescue medication on any 1 day in the week prior to Visit 1. A participant who has experienced an upper or lower respiratory tract infection within the 4 weeks prior to screening. Current smoker or cessation of smoking within 6 months prior to Visit 1. Previous smoker with a smoking history >10 pack-years. Comorbid disease that might interfere with the evaluation of the investigational medicinal product. The above information is 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: 12 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo q2w<br>2 subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1, followed by a single injection every 2 weeks (q2w) for 24 weeks in combination with OCS - (prednisone or prednisolone) and stable inhaled corticosteroid (ICS). OCS dose was reduced according to a predetermined titration schedule every 4 weeks until Week 20. Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication. | Drug: Placebo<br>* Solution for injection, Subcutaneous injection in the abdomen, upper thigh or upper arm.<br>Drug: Oral corticosteroid therapy (prednisone/prednisolone)<br>* Oral administration.<br>Drug: Inhaled corticosteroid (ICS) therapy<br>* Oral inhalation, stable dose (high dose) of ICS in combination with up to 2 other controller medicines (second or third controller therapy).<br>Drug: Albuterol/Salbutamol<br>* Oral inhalation as needed.<br>Drug: Levalbuterol/Levosalbutamol<br>* Oral inhalation as needed.<br>|
| Experimental: Dupilumab 300 mg q2w<br>2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection q2w for 24 weeks in combination with OCS - (prednisone or prednisolone) and stable ICS. OCS dose was reduced according to a predetermined titration schedule every 4 weeks until Week 20. Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication. | Drug: Dupilumab<br>* Solution for injection, Subcutaneous injection in the abdomen, upper thigh or upper arm.<br>* Other names: SAR231893;Drug: Oral corticosteroid therapy (prednisone/prednisolone)<br>* Oral administration.<br>Drug: Inhaled corticosteroid (ICS) therapy<br>* Oral inhalation, stable dose (high dose) of ICS in combination with up to 2 other controller medicines (second or third controller therapy).<br>Drug: Albuterol/Salbutamol<br>* Oral inhalation as needed.<br>Drug: Levalbuterol/Levosalbutamol<br>* Oral inhalation as needed.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Reduction From Baseline in Oral Corticosteroids (OCS) Dose at Week 24 While Maintaining Asthma Control | Percentage reduction of OCS dose was calculated as (optimized OCS dose [mg/day] at baseline - final OCS dose at Week 24)/optimized OCS dose at baseline x 100. Result is presented as Least Squares Mean (Standard Error) percentage reduction from baseline derived from ANCOVA model with missing data multiply imputed. | Baseline, Week 24 | 
| Supplementary Presentation of Primary Outcome Measure Data: Median Percentage Reduction From Baseline in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control | The Primary Outcome Measure (Percentage Reduction From Baseline in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control) is summarized above, as LS Mean (SE). Table below provides a supplementary presentation of the Primary Outcome Measure data; result is presented as median (inter-quartile range). Percentage reduction of OCS dose was calculated as (optimized OCS dose [mg/day] at baseline - final OCS dose at Week 24)/optimized OCS dose at baseline x 100. | Baseline, Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving >= 50% Reduction in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control | Participants were classified according to the binary status of whether or not the 50% OCS dose reduction criterion was achieved at week 24. | Week 24 | 
| Percentage of Participants Achieving a Reduction in Oral Corticosteroids Dose to <5 mg/Day at Week 24 While Maintaining Asthma Control | Participants were classified according to the binary status of whether or not the reduction of OCS dose to <5 mg/day was achieved at Week 24. | Week 24 | 
| Percentage of Participants Achieving Maximum Possible Reduction in Oral Corticosteroids Dose Per Protocol at Week 24 While Maintaining Asthma Control | For all participants except those with baseline OCS dose at 35 mg/day, the maximum possible reduction corresponds to reduction to 0 mg/day (no longer requiring OCS). For participants starting with 35 mg/day at baseline, the maximum possible reduction is 32.5 mg/day (i.e. minimum dose per protocol is 2.5 mg). | Week 24 | 
| Percentage of Participants Who No Longer Required Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control | Participants were classified according to the binary status of whether or not the participant still required OCS at Week 24 while maintaining asthma control. | Week 24 | 
| Absolute Reduction From Baseline in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control | Absolute reduction was calculated by subtracting Week 24 value from baseline value. | Baseline and Week 24 |