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

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ClinicalTrials.gov Identifier: NCT01854047
Recruitment Status : Completed
First Posted : May 15, 2013
Results First Posted : June 2, 2017
Last Update Posted : June 26, 2017
Sponsor:
Collaborator:
Regeneron Pharmaceuticals
Information provided by (Responsible Party):
Sanofi

Tracking Information
First Submitted Date  ICMJE May 10, 2013
First Posted Date  ICMJE May 15, 2013
Results First Submitted Date  ICMJE April 27, 2017
Results First Posted Date  ICMJE June 2, 2017
Last Update Posted Date June 26, 2017
Study Start Date  ICMJE June 2013
Actual Primary Completion Date November 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 27, 2017)
  • Absolute Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Week 12: High Eosinophils -Intent to Treat (HEos-ITT) Population [ Time Frame: 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 [ Time Frame: Baseline, Week 12 ]
    FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer.
Original Primary Outcome Measures  ICMJE
 (submitted: May 10, 2013)
Change from baseline in forced expiratory volume (FEV1) [ Time Frame: Week 12 ]
Change History Complete list of historical versions of study NCT01854047 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 7, 2017)
  • Percent Change From Baseline in FEV1 at Week 12: HEos-ITT Population [ Time Frame: Baseline, Week 12 ]
    FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer.
  • Percent Change From Baseline in FEV1 at Week 12: ITT Population [ Time Frame: 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: HEos-ITT Population [ Time Frame: 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.
  • Annualized Event Rate of Severe Exacerbation During The Treatment Period: ITT Population [ Time Frame: 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 Severe Exacerbation: Kaplan-Meier Estimates at Week 12 and 24: HEos-ITT Population [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
  • Annualized Event Rate of LOAC During The Treatment Period: ITT Population [ Time Frame: 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.
  • Time to First LOAC Event: Kaplan-Meier Estimates at Week 12 and Week 24: HEos-ITT Population [ Time Frame: 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.
  • Time to First LOAC Event: Kaplan-Meier Estimates at Week 12 and Week 24: ITT Population [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 Evening Asthma Symptom Score at Week 12: ITT Population [ Time Frame: 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.
  • Change From Baseline in Asthma Control Questionnaire 5-item Version (ACQ-5) Score at Week 12: HEos-ITT Population [ Time Frame: 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 ACQ-5 Score at Week 12: ITT Population [ Time Frame: 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 [ Time Frame: 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.
  • Change From Baseline in AQLQ Global Score at Week 12: ITT Population [ Time Frame: 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.
  • Change From Baseline in Number of Inhalations Per Day of Salbutamol/Albuterol or Levosalbutamol/Levalbuterol at Week 12: HEos-ITT Population [ Time Frame: 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.
  • Change From Baseline in Number of Inhalations Per Day of Salbutamol/Albuterol or Levosalbutamol/Levalbuterol at Week 12: ITT Population [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 10, 2013)
  • Relative change from baseline in FEV1 [ Time Frame: Week 12 ]
  • Annualized rate of loss of asthma control - Time Frame: Week 24 - Safety issue: No [ Time Frame: Week 24 ]
  • Time to loss of asthma control [ Time Frame: Week 24 ]
  • Change from baseline in asthma symptom scores [ Time Frame: Week 12 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE An Evaluation of Dupilumab in Patients With Moderate to Severe Uncontrolled Asthma
Official Title  ICMJE A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study to Evaluate Dupilumab in Patients With Moderate to Severe Uncontrolled Asthma
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).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Asthma
Intervention  ICMJE
  • Drug: Dupilumab
    Solution for injection, Subcutaneous injection
    Other Names:
    • SAR231893
    • REGN668
  • Drug: placebo
    Solution for injection, Subcutaneous injection
  • Drug: ICS/LABA therapy
    Oral inhalation, Prior therapy with Mometasone furoate /formoterol, budesonide / formoterol, or fluticasone propionate / salmeterol continued at stable dose
  • Drug: Salbutamol/albuterol
    Oral inhalation as needed
  • Drug: Levosalbutamol/levalbuterol
    Oral inhalation as needed
Study Arms  ICMJE
  • Experimental: Dupilumab 300 mg q2w
    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.
    Interventions:
    • Drug: Dupilumab
    • Drug: ICS/LABA therapy
    • Drug: Salbutamol/albuterol
    • Drug: Levosalbutamol/levalbuterol
  • Experimental: Dupilumab 200 mg q2w
    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.
    Interventions:
    • Drug: Dupilumab
    • Drug: ICS/LABA therapy
    • Drug: Salbutamol/albuterol
    • Drug: Levosalbutamol/levalbuterol
  • Experimental: Dupilumab 300 mg q4w
    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.
    Interventions:
    • Drug: Dupilumab
    • Drug: placebo
    • Drug: ICS/LABA therapy
    • Drug: Salbutamol/albuterol
    • Drug: Levosalbutamol/levalbuterol
  • Experimental: Dupilumab 200 mg q4w
    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.
    Interventions:
    • Drug: Dupilumab
    • Drug: placebo
    • Drug: ICS/LABA therapy
    • Drug: Salbutamol/albuterol
    • Drug: Levosalbutamol/levalbuterol
  • Placebo Comparator: Placebo q2w
    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.
    Interventions:
    • Drug: placebo
    • Drug: ICS/LABA therapy
    • Drug: Salbutamol/albuterol
    • Drug: Levosalbutamol/levalbuterol
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 27, 2015)
776
Original Estimated Enrollment  ICMJE
 (submitted: May 10, 2013)
600
Actual Study Completion Date  ICMJE April 2015
Actual Primary Completion Date November 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria:

Participants with a physician diagnosis of moderate to severe, uncontrolled asthma for >=12 months, based on the Global Initiative for Asthma (GINA) 2009 Guidelines and:

  • Existing treatment with moderate or high-dose inhaled corticosteroid / long-acting beta-2 agonist
  • Forced expiratory volume (FEV1) 40 to 80% of predicted normal
  • Asthma Control Questionnaire, 5-question version (ACQ-5) score >=1.5
  • Reversibility of at least 12% and 200 mL in forced expiratory volume (FEV1)
  • Had experienced, within prior year: hospitalization, emergency or urgent care visit or systemic corticosteroid treatment for worsening asthma

Exclusion criteria:

  • Participants <18 years
  • Chronic obstructive pulmonary disease (COPD) or other lung diseases (eg, emphysema, idiopathic pulmonary fibrosis, Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis) which impaired pulmonary function tests
  • Chest X-ray within 12 months of screening visit or at screening visit with clinically significant findings of lung disease(s) other than asthma
  • Current smoker or cessation of smoking within 6 months prior to Visit 1
  • Previous smoker with a smoking history >10 pack-years

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Chile,   Russian Federation,   Argentina,   Australia,   France,   Italy,   Japan,   Korea, Republic of,   Mexico,   New Zealand,   Poland,   South Africa,   Spain,   Turkey,   Ukraine,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01854047
Other Study ID Numbers  ICMJE DRI12544
2013-000856-16 ( EudraCT Number )
U1111-1138-3962 ( Other Identifier: UTN )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Sanofi
Study Sponsor  ICMJE Sanofi
Collaborators  ICMJE Regeneron Pharmaceuticals
Investigators  ICMJE
Study Director: Clinical Sciences & Operations Sanofi
PRS Account Sanofi
Verification Date June 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP