Efficacy, Safety, and Tolerability of Dupilumab in Patients With Persistent Moderate to Severe Eosinophilic Asthma

Study Overview
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Brief Summary
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Primary Objective: To investigate the effects of Dupilumab (SAR231893/REGN668) administered subcutaneously (SC) once weekly (qw) for 12 weeks as compared to placebo on reducing the incidence of asthma exacerbation in participants with persistent moderate to severe eosinophilic asthma. Secondary Objectives: To assess the safety and tolerability of Dupilumab administered SC qw for 12 weeks in participants with persistent moderate to severe eosinophilic asthma. To assess Dupilumab serum concentrations following qw SC dosing for 12 weeks in participants with persistent moderate to severe eosinophilic asthma.

Detailed Description
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The total duration of the study period per participant was 20-22 weeks broken down as follows: Screening period: up to 14 days, Treatment period: 12 weeks, Follow-up period: 6-8 weeks.

Official Title
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Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Assess the Efficacy, Safety, and Tolerability of SAR231893/REGN668 Administered Subcutaneously Once Weekly for 12 Weeks in Patients With Persistent Moderate to Severe Eosinophilic Asthma Who Are Partially Controlled/Uncontrolled by Inhaled Corticosteroid Plus Long-acting beta2 Agonist Therapy

Conditions
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Asthma

Intervention / Treatment
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* Drug: Dupilumab
* Drug: Placebo (for Dupilumab)
* Drug: Fluticasone/Salmeterol combination therapy
* Drug: Fluticasone monotherapy
* Drug: Albuterol
* Drug: Levalbuterol


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Medical diagnosis of persistent asthma for at least 12 months whose: airway inflammation likely to be eosinophilic, asthma partially controlled or uncontrolled on ICS plus LABA therapy. On a stable dose of either Fluticasone/Salmeterol, Budesonide/Formoterol, Mometasone/Formoterol combination therapy for at least 1 month prior to screening. Signed an Informed Consent Form and Health Insurance Portability and Accountability Act (HIPAA) Authorization Form. Exclusion criteria: Less than 18 years or greater than 65 years of age. Clinically relevant abnormal laboratory values suggesting an unknown disease and requiring further evaluation. Chronic obstructive pulmonary disease and/or other lung diseases impairing Pulmonary Function Tests. Beta-adrenergic receptor blockers required for any reason. Current smoker or cessation of smoking within the 6 months prior to screening. Previous smoking with a smoking history >10 cigarette pack/years. Participation in another study within 6 months prior to screening if the study medication was an antibody or within 30 days prior to screening for all other study medications. Known or suspected non-compliance, alcohol or drug abuse. Inability to follow the procedures of the study (e.g, due to language problems, psychological disorders). Concomitant severe diseases or diseases for which the use of ICS or LABA were contraindicated. Known allergy to doxycycline or related compounds. Pregnancy or intention to become pregnant during the course of the study, breast feeding, or unwillingness to use a highly effective method of contraception throughout the study in women of childbearing potential. Recent history of a parasitic infection or travel to a parasitic endemic area within 6 months prior to screening. 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: 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo (for Dupilumab)<br>Placebo (for Dupilumab) subcutaneous (SC) injection once weekly (qw) for 12 weeks added to background therapy of inhaled corticosteroids/long-acting beta2-adrenergic agonist (ICS/LABA) (Fluticasone/Salmeterol combination therapy at stable dose for 4 weeks followed by Fluticasone monotherapy, dose progressively decreased and discontinued at Week 9). Albuterol or Levalbuterol was given as rescue medication. | Drug: Placebo (for Dupilumab)<br>* Solution for injection, one subcutaneous injection.<br>Drug: Fluticasone/Salmeterol combination therapy<br>* Oral inhalation twice daily.<br>Drug: Fluticasone monotherapy<br>* Oral inhalation twice daily.<br>Drug: Albuterol<br>* Oral inhalation as needed.<br>Drug: Levalbuterol<br>* Oral inhalation as needed.<br>|
| Experimental: Dupilumab 300 mg qw<br>Dupilumab 300 mg SC injection qw for 12 weeks added to background therapy of ICS/LABA (Fluticasone/Salmeterol combination therapy at stable dose for 4 weeks followed by Fluticasone monotherapy, dose progressively decreased and discontinued at Week 9). Albuterol or Levalbuterol was given as rescue medication. | Drug: Dupilumab<br>* Solution for injection, one subcutaneous injection.<br>* Other names: REGN668;Drug: Fluticasone/Salmeterol combination therapy<br>* Oral inhalation twice daily.<br>Drug: Fluticasone monotherapy<br>* Oral inhalation twice daily.<br>Drug: Albuterol<br>* Oral inhalation as needed.<br>Drug: Levalbuterol<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 of Participants With Asthma Exacerbation | An asthma exacerbation was defined as the occurrence of any of the following: ≥30% reduction from baseline in morning PEF on 2 consecutive days; or ≥6 additional reliever puffs of albuterol or levalbuterol in a 24-hour period (compared to baseline) on 2 consecutive days; or deterioration of asthma, as determined by the investigator, requiring systemic steroid treatment, or an increase in inhaled corticosteroid (ICS) of ≥4 times the last dose received prior to discontinuation from the study, or hospitalization. The occurrence of asthma exacerbations by individual criteria are reported. | Baseline up to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Asthma Exacerbation: Kaplan-Meier Estimates at Week 4, Week 8 and Week 12 | The time-to-asthma exacerbation was defined as the time from the date of randomization to the date of the first asthma exacerbation event; for participants without asthma exacerbation, it was censored at the end of treatment visit date. The median time to first asthma exacerbation was not estimated because the number of asthma exacerbations was too low in the Dupilumab arm. Therefore, alternative Kaplan-Meier statistics, the probability of asthma exacerbation at Week 4, 8 and 12, are presented as the descriptive measure statistics. | Baseline up to Week 12 | 
| Percentage of Participants With Composite Asthma Events | Composite asthma event was defined as a 30% or greater reduction from baseline in morning PEF on 2 consecutive days together with 6 or more additional reliever puffs of albuterol or levalbuterol in a 24-hour period (compared to baseline) on 2 consecutive days. | Baseline up to Week 12 | 
| Change From Baseline in Forced Expiratory Flow in One Second (FEV1) to Week 12 | FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. | Baseline, Week 12 | 
| Change From Baseline in Peak Expiratory Flow (PEF) to Week 12 | The PEF is a participant's maximum speed of expiration, as measured with a peak flow meter. Peak flow testing for PEF was performed at home (morning and evening) while sitting or standing prior to using any medication (if needed) for asthma. | Baseline, Week 12 | 
| Change From Baseline in Asthma Control Questionnaire (5-question Version [ACQ-5]) to Week 12 | ACQ-5 questionnaire is a validated questionnaire comprising of 5 questions for asthma symptoms: woken at night by symptoms, wake in the mornings with symptoms, limitation of daily activities, shortness of breath, and wheeze. Participants were asked to rate their asthma symptoms during the previous week on a 7-point scale as 0=no impairment, 6=maximum impairment. ACQ-5 score is the mean of the 5 questions and range between 0 (disease totally controlled) and 6 (disease severely uncontrolled), a higher score indicated lower asthma control. | Baseline, Week 12 | 
| Change From Baseline in 22-item Sinonasal Outcome Test (SNOT-22) Score to Week 12 | The SNOT-22 is a validated measure of health related quality of life in sinonasal disease. It is a 22 item questionnaire with each item assigned a score ranging from 0-5. The total score may range from 0 (no disease) -110 (worst disease), lower scores represent better health related quality of life. | Baseline, Week 12 | 
| Change From Baseline in Morning Asthma Symptom Scores to Week 12 | AM (ante meridiem) symptom scoring system rates were participant's overall asthma symptoms experienced during the night. It ranges from 0 to 4 as: 0 = No asthma symptoms, slept through the night, 1= Slept well, but some complaints in the morning. No nighttime awakenings,2= Woke up once because of asthma (including early awakening),3= Woke up several times because of asthma (including early awakening), 4= Bad night, awake most of the night because of asthma. | Baseline, Week 12 | 
| Change From Baseline in Evening Asthma Symptom Scores to Week 12 | PM (post meridiem) symptom scoring system rates were participant's overall asthma symptoms experienced during the day. It ranges from 0 to 4 as: 0=very well, no asthma symptoms, 1=one episode of wheezing, cough, or breathlessness, 2=more than one episode of wheezing, cough, or breathlessness without interference of normal activities, 3=wheezing, cough, or breathlessness most of the day, which interfered to some extent with normal activities, 4=asthma very bad, unable to carry out daily activities as usual. | Baseline, Week 12 | 
| Change From Baseline in Number of Nocturnal Awakenings Per Day to Week 12 | Participants recorded every morning on awakening the number of asthma-related nocturnal awakenings requiring use of rescue medication that occurred during the previous night. | Baseline, Week 12 | 
| Change From Baseline in Number of Inhalations Per Day of Albuterol or Levalbuterol to Week 12 | Number of Albuterol or Levalbuterol inhalations were recorded daily by the participants in their electronic diary as Albuterol or Levalbuterol was to be used only as needed for symptoms, not on a regular basis or prophylactically. | Baseline, Week 12 |