An Evaluation of Dupilumab in Patients With Moderate to Severe Uncontrolled Asthma

Phase 2

Completed

Conditions: Asthma

Interventions: Drug: Dupilumab
Drug: placebo
Drug: ICS/LABA therapy
Drug: Salbutamol/albuterol
Drug: Levosalbutamol/levalbuterol

Registration Number: NCT01854047

Lead Sponsor: Sanofi

Brief Summary: Primary Objective:

To evaluate the efficacy of different doses and regimens of dupilumab in participants with moderate to severe uncontrolled asthma.

Secondary Objective:

To evaluate different doses and regimens of dupilumab in participants with moderate to severe uncontrolled asthma, with regard to:

* Safety and tolerability

* Dupilumab systemic exposure and anti-drug antibodies

Detailed Description: Total duration per participant of approximately 43 weeks including a screening period (14-21 days), a randomized treatment period (24 weeks), and a post-treatment period (16 weeks).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 776

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dupilumab 200 mg q2w	Dupilumab	2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1 (Week 1), followed by a single 200 mg injection q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.
Dupilumab 300 mg q4w	ICS/LABA therapy	2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1 (Week 1) followed by a Placebo alternating with single 300 mg injection of Dupilumab q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.
Dupilumab 200 mg q2w	ICS/LABA therapy	2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1 (Week 1), followed by a single 200 mg injection q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.
Dupilumab 200 mg q4w	Levosalbutamol/levalbuterol	2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1 (Week 1) followed by a Placebo alternating with single 200 mg injection of Dupilumab q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.
Dupilumab 300 mg q2w	ICS/LABA therapy	2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1 (Week 1), followed by a single 300 mg injection q2w from Week 2 to Week 22 added to stable inhaled corticosteroid/ long-acting beta-agonist (ICS/LABA) therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.
Dupilumab 300 mg q4w	Levosalbutamol/levalbuterol	2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1 (Week 1) followed by a Placebo alternating with single 300 mg injection of Dupilumab q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.
Dupilumab 200 mg q4w	placebo	2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1 (Week 1) followed by a Placebo alternating with single 200 mg injection of Dupilumab q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.
Dupilumab 200 mg q4w	Salbutamol/albuterol	2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1 (Week 1) followed by a Placebo alternating with single 200 mg injection of Dupilumab q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.
Dupilumab 200 mg q2w	Levosalbutamol/levalbuterol	2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1 (Week 1), followed by a single 200 mg injection q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.
Dupilumab 300 mg q4w	Dupilumab	2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1 (Week 1) followed by a Placebo alternating with single 300 mg injection of Dupilumab q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.
Dupilumab 300 mg q4w	placebo	2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1 (Week 1) followed by a Placebo alternating with single 300 mg injection of Dupilumab q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.
Dupilumab 200 mg q4w	ICS/LABA therapy	2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1 (Week 1) followed by a Placebo alternating with single 200 mg injection of Dupilumab q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.
Dupilumab 300 mg q2w	Salbutamol/albuterol	2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1 (Week 1), followed by a single 300 mg injection q2w from Week 2 to Week 22 added to stable inhaled corticosteroid/ long-acting beta-agonist (ICS/LABA) therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.
Dupilumab 300 mg q2w	Levosalbutamol/levalbuterol	2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1 (Week 1), followed by a single 300 mg injection q2w from Week 2 to Week 22 added to stable inhaled corticosteroid/ long-acting beta-agonist (ICS/LABA) therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.
Dupilumab 200 mg q2w	Salbutamol/albuterol	2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1 (Week 1), followed by a single 200 mg injection q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.
Dupilumab 300 mg q4w	Salbutamol/albuterol	2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1 (Week 1) followed by a Placebo alternating with single 300 mg injection of Dupilumab q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.
Placebo q2w	placebo	2 subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 (Week 1) followed by a single injection q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.
Placebo q2w	ICS/LABA therapy	2 subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 (Week 1) followed by a single injection q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.
Placebo q2w	Salbutamol/albuterol	2 subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 (Week 1) followed by a single injection q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.
Placebo q2w	Levosalbutamol/levalbuterol	2 subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 (Week 1) followed by a single injection q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.
Dupilumab 300 mg q2w	Dupilumab	2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1 (Week 1), followed by a single 300 mg injection q2w from Week 2 to Week 22 added to stable inhaled corticosteroid/ long-acting beta-agonist (ICS/LABA) therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.
Dupilumab 200 mg q4w	Dupilumab	2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1 (Week 1) followed by a Placebo alternating with single 200 mg injection of Dupilumab q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.

Primary Outcome Measures

Name	Time	Method
Absolute Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Week 12: High Eosinophils -Intent to Treat (HEos-ITT) Population	Baseline, Week 12	FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer.
Absolute Change From Baseline in FEV1 at Week 12: ITT Population	Baseline, Week 12	FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer.

Secondary Outcome Measures

Name	Time	Method
Annualized Event Rate of LOAC During The Treatment Period: ITT Population	Baseline to Week 24	LOAC was defined as any of the following: \>=6 additional reliever puffs of salbutamol/albuterol or levosalbutamol/levalbuterol in a 24-hour period (compared to baseline) on 2 consecutive days; increase in ICS \>=4 times the dose at randomization; use of systemic corticosteroids for \>=3 days; hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids. Annualized event rate was the total number of LOAC that occurred during the treatment period divided by the total number of participant-years treated.
Change From Baseline in Number of Inhalations Per Day of Salbutamol/Albuterol or Levosalbutamol/Levalbuterol at Week 12: HEos-ITT Population	Baseline, Week 12	Participants might administered salbutamol/albuterol or levosalbutamol/levalbuterol as reliever medication as needed during the study. The number of salbutamol/albuterol or levosalbutamol/levalbuterol inhalations were recorded by the participants in their electronic diary.
Time to First LOAC Event: Kaplan-Meier Estimates at Week 12 and Week 24: ITT Population	Baseline up to Week 24	The time to first LOAC event was defined as the time from the date of first dose to the date of the first LOAC event. For participants who had no LOAC event on or before last dose date + 14 days, it was censored at the date of last dose date + 14 days. The median time to first LOAC was not estimated because the number of LOAC was too low in the Dupilumab arms. Therefore, alternative Kaplan-Meier statistics, the probability of LOAC at Week 12 and 24, are presented as the descriptive measure statistics.
Change From Baseline in AQLQ Global Score at Week 12: ITT Population	Baseline, Week 12	The AQLQ is a disease-specific, self-administered quality of life questionnaire designed to measure functional impairments that are most important to participants with asthma. The AQLQ comprises of 32 items in 4 domains: symptoms (12 items), activity limitation (11 items), emotional function (5 items), environmental stimuli (4 items). Each item is scored on a 7-point Likert scale (1=maximal impairment, 7=no impairment). The 32 items of the questionnaire are averaged to produce one overall quality of life score ranging from 1 (severely impaired) to 7 (not impaired at all). Higher scores indicate better quality of life.
Percent Change From Baseline in FEV1 at Week 12: HEos-ITT Population	Baseline, Week 12	FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer.
Time to First Severe Exacerbation: Kaplan-Meier Estimates at Week 12 and 24: HEos-ITT Population	Baseline up to Week 24	The time to first severe exacerbation was defined as the time from the date of first dose to the date of the first severe exacerbation event. For participants who had no severe exacerbation on or before last dose date + 14 days, it was censored at the date of last dose date + 14 days. The median time to first severe exacerbation was not estimated because the number of severe exacerbations was too low in the Dupilumab arms. Therefore, alternative Kaplan-Meier statistics, the probability of severe exacerbation at Week 12 and 24, are presented as the descriptive measure statistics.
Time to First Severe Exacerbation: Kaplan-Meier Estimates at Week 12 and 24: ITT Population	Baseline up to Week 24	The time to first severe exacerbation was defined as the time from the date of first dose to the date of the first severe exacerbation event. For participants who had no severe exacerbation on or before last dose date + 14 days, it was censored at the date of last dose date + 14 days. The median time to first severe exacerbation was not estimated because the number of severe exacerbations was too low in the Dupilumab arms. Therefore, alternative Kaplan-Meier statistics, the probability of severe exacerbation at Week 12 and 24, are presented as the descriptive measure statistics.
Annualized Event Rate of Loss of Asthma Control (LOAC) During The Treatment Period: HEos-ITT Population	Baseline to Week 24	LOAC was defined as any of the following: \>=6 additional reliever puffs of salbutamol/albuterol or levosalbutamol/levalbuterol in a 24-hour period (compared to baseline) on 2 consecutive days; increase in inhaled corticosteroid (ICS) \>=4 times the dose at randomization; use of systemic corticosteroids for \>=3 days; hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids. Annualized event rate was the total number of LOAC that occurred during the treatment period divided by the total number of participant-years treated.
Change From Baseline in Evening Asthma Symptom Score at Week 12: ITT Population	Baseline, Week 12	Evening asthma symptom score was determined using PM symptom scoring system which evaluated participant's overall asthma symptoms experienced during the day. It ranged 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.
Annualized Event Rate of Severe Exacerbation During The Treatment Period: HEos-ITT Population	Baseline to Week 24	A severe exacerbation was defined as a deterioration of asthma requiring: use of systemic corticosteroids for \>=3 days; or hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids. Annualized event rate was the total number of exacerbations that occurred during the treatment period divided by the total number of participant-years treated.
Change From Baseline in Asthma Control Questionnaire 5-item Version (ACQ-5) Score at Week 12: HEos-ITT Population	Baseline, Week 12	The ACQ-5 has 5 questions, reflecting the top-scoring five 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 recall how their asthma had been during the previous week and to respond to each of the five symptom questions on a 7-point scale ranged from 0 (no impairment) to 6 (maximum impairment). ACQ-5 total score was mean of the scores of all 5 questions and, therefore, ranged from 0 (totally controlled) to 6 (severely uncontrolled). Higher score indicated lower asthma control.
Change From Baseline in Number of Inhalations Per Day of Salbutamol/Albuterol or Levosalbutamol/Levalbuterol at Week 12: ITT Population	Baseline, Week 12	Participants might administered salbutamol/albuterol or levosalbutamol/levalbuterol as reliever medication as needed during the study. The number of salbutamol/albuterol or levosalbutamol/levalbuterol inhalations were recorded by the participants in their electronic diary.
Percent Change From Baseline in FEV1 at Week 12: ITT Population	Baseline, Week 12	FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer.
Annualized Event Rate of Severe Exacerbation During The Treatment Period: ITT Population	Baseline to Week 24	A severe exacerbation was defined as a deterioration of asthma requiring: use of systemic corticosteroids for \>=3 days; or hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids. Annualized event rate was the total number of exacerbations that occurred during the treatment period divided by the total number of participant-years treated.
Time to First LOAC Event: Kaplan-Meier Estimates at Week 12 and Week 24: HEos-ITT Population	Baseline up to Week 24	The time to first LOAC event was defined as the time from the date of first dose to the date of the first LOAC event. For participants who had no LOAC event on or before last dose date + 14 days, it was censored at the date of last dose date + 14 days. The median time to first LOAC was not estimated because the number of LOAC was too low in the Dupilumab arms. Therefore, alternative Kaplan-Meier statistics, the probability of LOAC at Week 12 and 24, are presented as the descriptive measure statistics.
Change From Baseline in Morning Asthma Symptom Score at Week 12: HEos-ITT Population	Baseline, Week 12	Morning asthma symptom score was determined using AM (ante meridiem) symptom scoring system which evaluated participant's overall asthma symptoms experienced during the night. It ranged from 0 to 4 as: 0 = No asthma symptoms, slept through the night, 1= Slept well, but some complaints in the morning, no night-time 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.
Change From Baseline in Morning Asthma Symptom Score at Week 12: ITT Population	Baseline, Week 12	Morning asthma symptom score was determined using AM symptom scoring system which evaluated participant's overall asthma symptoms experienced during the night. It ranged from 0 to 4 as: 0 = No asthma symptoms, slept through the night, 1= Slept well, but some complaints in the morning, no night-time 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.
Change From Baseline in Evening Asthma Symptom Score at Week 12: HEos-ITT Population	Baseline, Week 12	Evening asthma symptom score was determined using PM (post meridiem) symptom scoring system which evaluated participant's overall asthma symptoms experienced during the day. It ranged 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.
Change From Baseline in ACQ-5 Score at Week 12: ITT Population	Baseline, Week 12	The ACQ-5 has 5 questions, reflecting the top-scoring five 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 recall how their asthma had been during the previous week and to respond to each of the five symptom questions on a 7-point scale ranged from 0 (no impairment) to 6 (maximum impairment). ACQ-5 total score was mean of the scores of all 5 questions and, therefore, ranged from 0 (totally controlled) to 6 (severely uncontrolled). Higher score indicated lower asthma control.
Change From Baseline in Asthma Quality of Life Questionnaire (AQLQ) Global Score at Week 12: HEos-ITT Population	Baseline, Week 12	The AQLQ is a disease-specific, self-administered quality of life questionnaire designed to measure functional impairments that are most important to participants with asthma. The AQLQ comprises of 32 items in 4 domains: symptoms (12 items), activity limitation (11 items), emotional function (5 items), environmental stimuli (4 items). Each item is scored on a 7-point Likert scale (1=maximal impairment, 7=no impairment). The 32 items of the questionnaire are averaged to produce one overall quality of life score ranging from 1 (severely impaired) to 7 (not impaired at all). Higher scores indicate better quality of life.

Trial Locations

Locations (201): Investigational Site Number 840050
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Fullerton, California, United States
Investigational Site Number 840041
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Huntington Beach, California, United States
Investigational Site Number 840019
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Los Angeles, California, United States
Investigational Site Number 840029
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Los Angeles, California, United States
Investigational Site Number 840022
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Los Angeles, California, United States
Investigational Site Number 840013
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Mission Viejo, California, United States
Investigational Site Number 840044
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Newport Beach, California, United States
Investigational Site Number 840007
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Riverside, California, United States
Investigational Site Number 840014
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Rolling Hills Estates, California, United States
Investigational Site Number 840036
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San Jose, California, United States
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Investigational Site Number 840050
🇺🇸Fullerton, California, United States