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    Clinical Trial Results:
    A Randomized, Double Blind, Placebo-controlled, Parallel-group Phase 3 Study to Evaluate the Efficacy and Safety of Dupilumab in Patients with Persistent Asthma

    Summary
    EudraCT number
    		 2022-002375-11
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    21 May 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC13995
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03782532
    WHO universal trial number (UTN)
    		 U1111-1175-0772
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 Avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Jun 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of dupilumab in subjects with persistent asthma.
    Protection of trial subjects
    The study was conducted by investigators experienced in the treatment of adult and adolescent subjects. The parent(s) or guardian(s) were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimised. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anesthesia may have been used to minimise distress and discomfort. Adult subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Jan 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    China: 412
    Country: Number of subjects enrolled
    India: 74
    Worldwide total number of subjects
    486
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    419
    From 65 to 84 years
    66
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 65 active sites in China and India. A total of 1022 subjects were screened from 25 Jan 2019 to 10 August 2021, out of which 536 were screen failure. Screen failures were mainly due to not meeting the eligibility criteria.

    Pre-assignment
    Screening details
    		 Randomised subjects to dupilumab or placebo arm by interactive voice/web response system (1:1 ratio). Stratified by age (less than [<]18 years, greater than or equal to [>=]18 years), eosinophil count (<150 cells per microlitre[mcL], 150-299 cells/mcL & >=300 cells/mcL), Baseline oral corticosteroid maintenance (yes/no) & region (China & non-China)

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dupilumab
    Arm description
    		 Subjects without oral corticosteroids (OCS) maintenance therapy received dupilumab 400 milligrams (mg) loading dose (2 doses of 200 mg) subcutaneous (SC) injection on Day 1 (Week 0) followed by dupilumab 200 mg SC injection every 2 weeks (q2w) for 24 weeks. Subjects on OCS maintenance therapy received dupilumab 600 mg loading dose (2 doses of 300 mg) SC injection on Day 1 (Week 0) followed by dupilumab 300 mg SC injection q2w for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dupilumab
    Investigational medicinal product code
    SAR231893
    Other name
    Dupixent
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dupilumab 200 mg (175 mg per millilitres [mg/mL] in 1.14 mL) or Dupilumab 300 mg (150 mg/mL in 2 mL) SC injection q2w for 24 weeks. Loading dose (400 mg or 600 mg) SC injection on Day 1 of Week 0.

    Arm title
    		 Placebo
    Arm description
    		 Subjects without OCS maintenance therapy received placebo loading dose (matching dupilumab 400 mg) SC on Day 1 (Week 0) followed by placebo (matching dupilumab 200 mg) SC injection q2w for 24 weeks. Subjects on OCS maintenance therapy received placebo loading dose (matching dupilumab 600 mg) SC injection on Day 1 (Week 0) followed by placebo (matching dupilumab 300 mg) SC injection q2w for 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo, 1.14 mL (matching dupilumab 200 mg) and 2 mL (matching dupilumab 300 mg), SC injection q2w for 24 weeks with a loading dose (matching dupilumab 400 mg or 600 mg) SC injection on Day 1 of Week 0.

    Number of subjects in period 1
    		Dupilumab Placebo
    Started
    242
    244
    Safety population
    241
    243
    Received 200 mg dose/1.14 mL
    224 [1]
    225
    Received 300 mg dose/2 mL
    17 [2]
    18 [3]
    Type-2 non-OCS population
    205 [4]
    209 [5]
    Completed
    225
    222
    Not completed
    17
    22
         Other-unspecified
    7
    6
         Randomised and not exposed
    1
    1
         Adverse event
    4
    2
         Poor compliance to protocol
    3
    -
         Withdrawal by subject
    2
    12
         Lack of efficacy
    -
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Subjects without OCS maintenance therapy that received dupilumab 200 mg.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Subjects on OCS maintenance therapy that received dupilumab 300 mg.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Subjects on OCS maintenance therapy that received placebo 2 mL (matching dupilumab 300 mg).
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Type 2 inflammatory asthma phenotype without OCS maintenance population (Type-2 non-OCS population): all randomised subjects with type 2 inflammatory asthma phenotype (screening blood eosinophils count >=150 cells/mcL or screening fractional exhaled nitric oxide (FeNO) level >=25 parts per billion [ppb]) that received dupilumab 200 mg and were not on OCS maintenance therapy.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: All randomised subjects with type 2 inflammatory asthma phenotype (screening blood eosinophils count >=150 cells/mcL or screening FeNO level >=25 ppb) that received placebo (matching dupilumab 200 mg) and were not on OCS maintenance therapy.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dupilumab
    Reporting group description
    		 Subjects without oral corticosteroids (OCS) maintenance therapy received dupilumab 400 milligrams (mg) loading dose (2 doses of 200 mg) subcutaneous (SC) injection on Day 1 (Week 0) followed by dupilumab 200 mg SC injection every 2 weeks (q2w) for 24 weeks. Subjects on OCS maintenance therapy received dupilumab 600 mg loading dose (2 doses of 300 mg) SC injection on Day 1 (Week 0) followed by dupilumab 300 mg SC injection q2w for 24 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects without OCS maintenance therapy received placebo loading dose (matching dupilumab 400 mg) SC on Day 1 (Week 0) followed by placebo (matching dupilumab 200 mg) SC injection q2w for 24 weeks. Subjects on OCS maintenance therapy received placebo loading dose (matching dupilumab 600 mg) SC injection on Day 1 (Week 0) followed by placebo (matching dupilumab 300 mg) SC injection q2w for 24 weeks.

    Reporting group values
    		 Dupilumab Placebo Total
    Number of subjects
    		 242 244 486
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50.4 ± 11.4 51.5 ± 12.2 -
    Gender categorical
    Units: Subjects
        Female
    		 135 142 277
        Male
    		 107 102 209

    End points

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    End points reporting groups
    Reporting group title
    Dupilumab
    Reporting group description
    		 Subjects without oral corticosteroids (OCS) maintenance therapy received dupilumab 400 milligrams (mg) loading dose (2 doses of 200 mg) subcutaneous (SC) injection on Day 1 (Week 0) followed by dupilumab 200 mg SC injection every 2 weeks (q2w) for 24 weeks. Subjects on OCS maintenance therapy received dupilumab 600 mg loading dose (2 doses of 300 mg) SC injection on Day 1 (Week 0) followed by dupilumab 300 mg SC injection q2w for 24 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects without OCS maintenance therapy received placebo loading dose (matching dupilumab 400 mg) SC on Day 1 (Week 0) followed by placebo (matching dupilumab 200 mg) SC injection q2w for 24 weeks. Subjects on OCS maintenance therapy received placebo loading dose (matching dupilumab 600 mg) SC injection on Day 1 (Week 0) followed by placebo (matching dupilumab 300 mg) SC injection q2w for 24 weeks.

    Subject analysis set title
    Dupilumab 200 mg q2w
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects without OCS maintenance therapy received dupilumab 400 mg loading dose (2 doses of 200 mg) SC injection on Day 1 (Week 0) followed by dupilumab 200 mg SC injection q2w for 24 weeks.

    Subject analysis set title
    Dupilumab 300 mg q2w
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects on OCS maintenance therapy received dupilumab 600 mg loading dose (2 doses of 300 mg) SC injection on Day 1 (Week 0) followed by dupilumab 300 mg SC injection q2w for 24 weeks.

    Subject analysis set title
    Placebo 1.14 mL q2w
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects without OCS maintenance therapy received placebo 1.14 mL (i.e., matching to dupilumab 200 mg) SC injection q2w for 24 weeks.

    Subject analysis set title
    Placebo 2 mL q2w
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects on OCS maintenance therapy received placebo 2 mL (i.e., matching to dupilumab 300 mg) SC injection q2w for 24 weeks.

    Primary: Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in one Second (FEV1) at Week 12

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    End point title
    		 Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in one Second (FEV1) at Week 12
    End point description
    FEV1 was the volume of air (in litres) exhaled from the lungs in the first second of a forced expiration as measured by spirometer. Least square (LS) mean and standard error (SE) was obtained from mixed-effect model with repeated measures (MMRM) analysis which included subjects who had Baseline, at least one post-baseline value up to Week 12 and no missing covariates. Analysis was performed on type 2 inflammatory asthma phenotype without OCS maintenance population (Type 2 non-OCS) population which included all randomised subjects with type 2 inflammatory asthma phenotype (screening blood eosinophils count >=150 cells/mcL or screening FeNO level >=25 ppb) who were allocated in dupilumab 200 mg q2w/matching placebo groups and were not on OCS maintenance. Number of subjects analysed=subjects with available data for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Dupilumab 200 mg q2w Placebo 1.14 mL q2w
    Number of subjects analysed
    197
    204
    Units: litre
        least squares mean (standard error)
    0.37 ± 0.04
    0.06 ± 0.04
    Statistical analysis title
    		 Dupilumab 200 mg versus Placebo
    Statistical analysis description
    MMRM model with change from Baseline in pre-bronchodilator FEV1 values up to Week 12 as the response variable, and intervention, age, sex, height, region, screening blood eosinophil level, screening FeNO level, visit, intervention-by-visit interaction, Baseline pre-bronchodilator FEV1 value and Baseline value-by-visit interaction as covariates.
    Comparison groups
    Dupilumab 200 mg q2w v Placebo 1.14 mL q2w
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.0001 [2]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    0.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.23
         upper limit
    		 0.39
    Notes
    [1] - A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the endpoints are reported and continued when primary endpoint was statistically significant at two-sided 0.05 level.
    [2] - Threshold of significance at 0.05.

    Secondary: Change From Baseline in Asthma Control Questionnaire 5 Question Version (ACQ-5) Mean Score at Week 24

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    End point title
    		 Change From Baseline in Asthma Control Questionnaire 5 Question Version (ACQ-5) Mean Score at Week 24
    End point description
    ACQ-5 had 5 questions, assessed 5 symptoms: frequency in past week awoken by asthma during night, severity of asthma symptoms in morning, limitation of daily activities due to asthma, shortness of breath due to asthma and wheeze. Subjects recalled how their asthma had been during previous week and responded to each of 5 symptom questions on 7-point scale, ranged from 0 (no impairment) to 6 (maximum impairment). ACQ-5 total mean score: mean of scores of all 5 questions, ranged from 0 (totally controlled) to 6 (severely uncontrolled). Higher score = lower asthma control. LS Mean SE from MMRM model. Analysis was performed on Type 2 non-OCS population. Here, "number of subjects analysed" = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Dupilumab 200 mg q2w Placebo 1.14 mL q2w
    Number of subjects analysed
    197
    205
    Units: score on a scale
        least squares mean (standard error)
    -1.29 ± 0.07
    -1.09 ± 0.06
    Statistical analysis title
    		 Dupilumab 200 mg versus Placebo
    Statistical analysis description
    MMRM model with change from Baseline in ACQ-5 score values up to Week 24 as response variable and intervention, age, region, screening blood eosinophil level, screening FeNO level, visit, intervention by-visit interaction, Baseline ACQ-5 score value and Baseline value-by-visit interaction as covariates.
    Comparison groups
    Dupilumab 200 mg q2w v Placebo 1.14 mL q2w
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0097 [4]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.35
         upper limit
    		 -0.05
    Notes
    [3] - A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the endpoints were reported and continued when previous endpoints was statistically significant at two-sided 0.05 level.
    [4] - Threshold of significance at 0.05.

    Secondary: Annualised Rate of Severe Exacerbation Events During the 24-week Placebo-controlled Treatment Period

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    End point title
    		 Annualised Rate of Severe Exacerbation Events During the 24-week Placebo-controlled Treatment Period
    End point description
    A severe asthma exacerbation event was defined as a deterioration of asthma during the 24-week placebo-controlled treatment period requiring: use of systemic corticosteroids for >= 3 days; use of systemic corticosteroids at least double the current dose and at least 5 milligrams per day (mg/day) prednisone dose increase or equivalent and/or hospitalisation or emergency room visit because of asthma requiring systemic corticosteroid treatment. Annualised event rate was defined as the total number of severe exacerbation events with onset period from randomisation up to the Week 24 visit or last contact date (whichever came earlier) per subject-year. Analysis was performed on Type 2 non-OCS population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Dupilumab 200 mg q2w Placebo 1.14 mL q2w
    Number of subjects analysed
    205
    209
    Units: exacerbations per subject-years
        number (confidence interval 95%)
    0.177 (0.088 to 0.357)
    0.466 (0.256 to 0.849)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Pre-bronchodilator FEV1 at Week 12

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    End point title
    		 Percent Change From Baseline in Pre-bronchodilator FEV1 at Week 12
    End point description
    FEV1 was the volume of air (in litres) exhaled from the lungs in the first second of a forced expiration as measured by spirometer. LS mean and SE was derived from MMRM model with percent change from Baseline in pre-bronchodilator FEV1 values up to Week 12 as the response variable, and intervention, age, sex, height, region, screening blood eosinophil level, screening FeNO level, visit, intervention-by-visit interaction, Baseline pre-bronchodilator FEV1 value and Baseline value-by-visit interaction as covariates. Analysis was performed on Type 2 non-OCS population. Here, 'number of subjects analysed' = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Dupilumab 200 mg q2w Placebo 1.14 mL q2w
    Number of subjects analysed
    197
    204
    Units: percent change
        least squares mean (standard error)
    28.09 ± 3.25
    4.48 ± 3.15
    No statistical analyses for this end point

    Secondary: Annualised Rate of Loss of Asthma Control (LOAC) Event During the 24-week Placebo-controlled Treatment Period

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    End point title
    		 Annualised Rate of Loss of Asthma Control (LOAC) Event During the 24-week Placebo-controlled Treatment Period
    End point description
    LOAC event: any of the following: >=6 additional reliever puffs of salbutamol/albuterol or levosalbutamol/levalbuterol in 24-hour period (compared with Baseline) on 2 consecutive days, >=20% decrease in pre-bronchodilator FEV1 compared with Baseline, increase in inhaled corticosteroid (ICS) dose >=4 times than dose at randomisation, decrease in morning/evening peak expiratory flow (PEF) of 30%/more on 2 consecutive days of treatment, based on stability limit (mean morning/evening PEF obtained over last 7 days prior to Day 1) and severe exacerbation event (systemic corticosteroids [SC] use >=3 days; SC use at least double current dose and at least 5 mg/day prednisone dose increase/equivalent and/or hospitalisation/emergency visit requiring SC treatment). Annualised rate of LOAC event during 24-week treatment period: number of LOAC events with onset period from randomisation up to Week 24 visit or last contact date (whichever came earlier) per subject-year. Type 2 non-OCS population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Dupilumab 200 mg q2w Placebo 1.14 mL q2w
    Number of subjects analysed
    205
    209
    Units: LOAC per subject-year
        number (confidence interval 95%)
    0.674 (0.465 to 0.977)
    2.214 (1.649 to 2.973)
    No statistical analyses for this end point

    Secondary: Annualised Rate of Severe Exacerbation Events Resulting in Hospitalisation or Emergency Room Visit During the 24-week Placebo-controlled Treatment Period

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    End point title
    		 Annualised Rate of Severe Exacerbation Events Resulting in Hospitalisation or Emergency Room Visit During the 24-week Placebo-controlled Treatment Period
    End point description
    A severe asthma exacerbation event was defined as a deterioration of asthma during the 24-week placebo-controlled treatment period requiring: use of systemic corticosteroids for >=3 days; use of systemic corticosteroids at least double the current dose and at least 5 mg/day prednisone dose increase or equivalent and/or hospitalisation or emergency room visit because of asthma requiring systemic corticosteroid treatment. Annualised event rate was defined as the total number of severe exacerbation events with onset period from randomisation up to the Week 24 visit or last contact date (whichever came earlier) per subject-year. Annualised rate of severe exacerbation events resulting in hospitalisation or emergency room visit during the 24-week placebo-controlled treatment period was reported in this endpoint. Analysis was performed on Type 2 non-OCS population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Dupilumab 200 mg q2w Placebo 1.14 mL q2w
    Number of subjects analysed
    205
    209
    Units: exacerbations per subject-years
        number (confidence interval 95%)
    0.048 (0.015 to 0.160)
    0.114 (0.042 to 0.311)
    No statistical analyses for this end point

    Secondary: Time to First Severe Exacerbation Event During the 24-week Placebo-controlled Treatment Period

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    End point title
    		 Time to First Severe Exacerbation Event During the 24-week Placebo-controlled Treatment Period
    End point description
    The time (in days) to first severe exacerbation was defined as onset date of the first severe exacerbation event minus randomisation date +1. A severe asthma exacerbation event was defined as a deterioration of asthma during the 24-week treatment period requiring either use of systemic corticosteroids >=3 days for subjects; use of systemic corticosteroids at least double the current dose and at least 5 mg/day prednisone dose increase or equivalent or hospitalisation or emergency room visit because of asthma, requiring systemic corticosteroids treatment. Kaplan-Meier method was used for analysis. Analysis was performed on Type 2 non-OCS population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12 and Week 24
    End point values
    		 Dupilumab 200 mg q2w Placebo 1.14 mL q2w
    Number of subjects analysed
    205
    209
    Units: days
    number (confidence interval 95%)
        12 Weeks
    0.049 (0.025 to 0.085)
    0.154 (0.109 to 0.206)
        24 Weeks
    0.079 (0.047 to 0.121)
    0.189 (0.139 to 0.245)
    No statistical analyses for this end point

    Secondary: Time to First LOAC During the 24-week Placebo Controlled Treatment Period

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    End point title
    		 Time to First LOAC During the 24-week Placebo Controlled Treatment Period
    End point description
    Time (in days) to first LOAC event was date of first LOAC event minus first dose date +1. LOAC event was defined as deterioration of asthma during 24-week treatment period that resulted in any of the following: 1) >=6 additional reliever puffs of salbutamol/albuterol or levosalbutamol/levalbuterol in a 24-hour period (compared with Baseline) on 2 consecutive days, 2) >=20% decrease in pre-bronchodilator FEV1 compared with Baseline, 3) increase in ICS dose >=4 times than the dose at randomisation, 4) a decrease in morning or evening PEF of 30% or more on 2 consecutive days of treatment, based on defined stability limit (mean morning/evening PEF obtained over last 7 days prior to Day 1), 5) severe exacerbation event (SC use >=3 days; SC use at least double current dose and at least 5 mg/day prednisone dose increase/equivalent and/or hospitalisation/emergency visit requiring SC treatment). Kaplan-Meier method was used for analysis. Type 2 non-OCS population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12 and Week 24
    End point values
    		 Dupilumab 200 mg q2w Placebo 1.14 mL q2w
    Number of subjects analysed
    205
    209
    Units: days
    number (confidence interval 95%)
        12 Weeks
    0.152 (0.107 to 0.205)
    0.432 (0.364 to 0.498)
        24 Weeks
    0.212 (0.158 to 0.270)
    0.550 (0.479 to 0.614)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Asthma Control Questionnaire 7 Question Version (ACQ-7) Score at Week 24

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    End point title
    		 Change From Baseline in Asthma Control Questionnaire 7 Question Version (ACQ-7) Score at Week 24
    End point description
    ACQ-7 had 7 questions: frequency in past week awoken by asthma during night, severity of asthma symptoms in morning, limitation of daily activities due to asthma, shortness of breath due to asthma, wheeze, short-acting bronchodilator use & FEV1 (pre-bronchodilator & % predicted). Subjects recalled how their asthma was during previous week & responded to symptom questions on 7-point scale (0=no impairment, 6=maximum impairment). Total score: mean of scores of all 7 questions; ranged from 0 (totally controlled) to 6 (severely uncontrolled), higher score=lower asthma control. LS means SE: MMRM model with change from Baseline in ACQ-7 score values up to Week 24 as response variable, & intervention, age, region, screening blood eosinophil level, screening FeNO level, visit, intervention by-visit interaction, Baseline ACQ-7 score value & Baseline value-by-visit interaction as covariates. Type 2 non-OCS population. "Number of subjects analysed"=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Dupilumab 200 mg q2w Placebo 1.14 mL q2w
    Number of subjects analysed
    197
    205
    Units: score on a scale
        least squares mean (standard error)
    -1.17 ± 0.06
    -0.87 ± 0.06
    No statistical analyses for this end point

    Secondary: Change From Baseline in Morning and Evening Asthma Symptom Score at Week 24

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    End point title
    		 Change From Baseline in Morning and Evening Asthma Symptom Score at Week 24
    End point description
    Morning asthma symptom score (ASS) evaluated subject's overall asthma symptoms experienced during previous night. Score ranged from 0 (no asthma symptoms, slept through night) to 4 (bad night, awake most of night because of asthma). Evening ASS evaluated subject's overall asthma symptoms experienced during day since morning. Score ranged from 0 (very well, no asthma symptoms) to 4 (asthma very bad, unable to carry out daily activities as usual). For morning and evening ASS, lower scores=more mild symptoms. LS Mean and SE:MMRM model with change from Baseline in morning/evening symptom score values up to Week 24 as the response variable, and intervention, age, region, screening blood eosinophil level, screening FeNO level, visit, intervention by-visit interaction, Baseline morning/evening symptom score value and Baseline value-by-visit interaction as covariates. Type 2 non-OCS population. 'Number of subjects analysed' = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Dupilumab 200 mg q2w Placebo 1.14 mL q2w
    Number of subjects analysed
    198
    206
    Units: score on a scale
    least squares mean (standard error)
        Morning Symptom Score
    -0.54 ± 0.05
    -0.35 ± 0.05
        Evening Symptom Score
    -0.47 ± 0.05
    -0.30 ± 0.05
    No statistical analyses for this end point

    Secondary: Change From Baseline in Nocturnal Awakenings per Night at Week 24

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    End point title
    		 Change From Baseline in Nocturnal Awakenings per Night at Week 24
    End point description
    Subjects recorded every morning the number of asthma-related nocturnal awakenings that occurred during the previous night. LS Mean and SE derived from MMRM model with change from Baseline in number of nocturnal awakenings/night up to Week 24 as the response variable, and intervention, age, region, screening blood eosinophil level, screening FeNO level, visit, intervention by-visit interaction, Baseline number of nocturnal awakenings/night and Baseline value-by-visit interaction as covariates. Analysis was performed on Type 2 non-OCS population. Here, 'number of subjects analysed' = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Dupilumab 200 mg q2w Placebo 1.14 mL q2w
    Number of subjects analysed
    198
    206
    Units: nocturnal awakenings per night
        least squares mean (standard error)
    -0.34 ± 0.03
    -0.24 ± 0.03
    No statistical analyses for this end point

    Secondary: Change From Baseline in Number of Puffs of Daily Reliever Medication Used Per 24 Hours at Week 24

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    End point title
    		 Change From Baseline in Number of Puffs of Daily Reliever Medication Used Per 24 Hours at Week 24
    End point description
    Subjects might be administered salbutamol/albuterol or levosalbutamol/levalbuterol as reliever medication as needed. Number of reliever medication inhalations were recorded daily in electronic diary. When nebuliser solutions were used as alternative delivery method, nebuliser dose was converted to number of puffs as per conversion factor: salbutamol/albuterol nebuliser solution (2.5 mg) and levosalbutamol/levalbuterol (1.25 mg) corresponds to 4 puffs. LS Mean and SE: MMRM model with change from Baseline in numbers of puffs of reliever medication/24 hours values up to Week 24 as the response variable, and intervention, age, region, screening blood eosinophil level, screening FeNO level, visit, intervention by-visit interaction, Baseline number of puffs of reliever medication/24 hours and Baseline value-by-visit interaction as covariates. Analysis was performed on Type 2 non-OCS population. Here, 'number of subjects analysed' = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Dupilumab 200 mg q2w Placebo 1.14 mL q2w
    Number of subjects analysed
    198
    206
    Units: puffs of reliever medication per 24 hour
        least squares mean (standard error)
    -0.64 ± 0.11
    -0.32 ± 0.11
    No statistical analyses for this end point

    Secondary: Change From Baseline in Asthma Quality Of Life Questionnaire With Standardised Activities (>=12 years) (AQLQ) at Week 24

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    End point title
    		 Change From Baseline in Asthma Quality Of Life Questionnaire With Standardised Activities (>=12 years) (AQLQ) at Week 24
    End point description
    AQLQ was designed to measure functional impairments that were most troublesome to subjects as a result of their asthma. The AQLQ comprised of 32 items in 4 domains: symptoms (12 items), activity limitation (11 items), emotional function (5 items), environmental stimuli (4 items). Each item was scored on 7-point likert scale (1=severely impaired to 7=not impaired). 32 items of the questionnaire are averaged to produce one overall quality of life score ranging from 1 (severely impaired) to 7 (not impaired). Higher scores indicated better quality of life. LS Mean SE derived from MMRM model with change from Baseline in AQLQ score values up to Week 24 as the response variable, and intervention, age, region, screening blood eosinophil level, screening FeNO level, visit, intervention by-visit interaction, Baseline AQLQ score value and Baseline value-by-visit interaction as covariates. Type 2 non-OCS population. 'Number of subjects analysed' = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Dupilumab 200 mg q2w Placebo 1.14 mL q2w
    Number of subjects analysed
    197
    203
    Units: score on a scale
        least squares mean (standard error)
    1.09 ± 0.08
    0.76 ± 0.08
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels (EQ-5D-5L) at Week 24

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    End point title
    		 Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels (EQ-5D-5L) at Week 24
    End point description
    EQ-5D-5L: standardised subject-rated questionnaire to assess health related quality of life (HRQOL), included 2 components: EQ-5D descriptive system and EQ Visual Analog Scale (VAS). EQ-5D descriptive system comprised 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/ depression. Each dimension had 5-levels: no problems, slight problems, moderate problems, severe problems and extreme problems. Response options were measured with 5-point Likert scale. The 5D-5L systems were converted into a single index utility score between 0 to 1. Higher score=better health state. EQ-5D-5L VAS rated subject’s current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state). LS Mean SE from MMRM model. Analysis was performed on Type 2 non-OCS population. Here, 'number of subjects analysed' = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Dupilumab 200 mg q2w Placebo 1.14 mL q2w
    Number of subjects analysed
    197
    203
    Units: score on a scale
    least squares mean (standard error)
        Single Index Score
    0.11 ± 0.01
    0.07 ± 0.01
        VAS
    7.47 ± 1.26
    3.88 ± 1.20
    No statistical analyses for this end point

    Secondary: Number of Subjects with Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAE) and Adverse Events of Special Interest (AESI)

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    End point title
    		 Number of Subjects with Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAE) and Adverse Events of Special Interest (AESI)
    End point description
    AE: any untoward medical occurrence in subjects who received investigational medicinal product (IMP) & not necessarily have causal relationship with treatment. TEAEs: AEs developed/worsened in grade/become serious during TEAE period (from 1st IMP dose up to 98 days after last IMP dose).SAE: any untoward medical occurrence at any dose resulted in death, was life-threatening, required inpatient hospitalisation, prolongation of existing hospitalisation, resulted in persistent or significant disability/incapacity, was congenital anomaly/birth defect or was medically important event. AESI:AE(serious/non-serious) of scientific & medical concern specific to Sponsor's product/program, for which ongoing monitoring & immediate notification by Investigator to Sponsor required. Safety population: all randomised subjects who had taken at least 1 dose of IMP, regardless of amount of treatment administered. Safety data collection & analysis: planned separately per doses for dupilumab & placebo.
    End point type
    Secondary
    End point timeframe
    From first dose of IMP administration up to last dose of IMP administration + 98 days (i.e., Up to Week 36)
    End point values
    		 Dupilumab 200 mg q2w Dupilumab 300 mg q2w Placebo 1.14 mL q2w Placebo 2 mL q2w
    Number of subjects analysed
    224
    17
    225
    18
    Units: subjects
    number (not applicable)
        TEAEs
    187
    16
    177
    13
        TESAEs
    21
    0
    21
    2
        AESIs
    9
    1
    8
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of IMP up to 98 days after last dose of IMP (maximum duration: up to Week 36)
    Adverse event reporting additional description
    Reported AEs were TEAEs that developed or worsened or became serious during the TEAE period (defined as the time from the first dose of the IMP up to 98 days after last dose of the IMP). Analysed on safety population. Safety data was planned to be collected and reported separately for each dose of dupilumab and each volume of placebo administered.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Placebo 1.14 mL q2w
    Reporting group description
    		 Subjects without OCS maintenance therapy received placebo 1.14 mL (i.e., matching to dupilumab 200 mg) SC injection q2w for 24 weeks.

    Reporting group title
    Dupilumab 200 mg q2w
    Reporting group description
    		 Subjects without OCS maintenance therapy received dupilumab 400 mg loading dose (2 doses of 200 mg) SC injection on Day 1 (Week 0) followed by dupilumab 200 mg SC injection q2w for 24 weeks.

    Reporting group title
    Placebo 2 mL q2w
    Reporting group description
    		 Subjects without OCS maintenance therapy received placebo 2 mL (i.e., matching to dupilumab 300 mg) SC injection q2w for 24 weeks.

    Reporting group title
    Dupilumab 300 mg q2w
    Reporting group description
    		 Subjects on OCS maintenance therapy received dupilumab 600 mg loading dose (2 doses of 300 mg) SC injection on Day 1 (Week 0) followed by dupilumab 300 mg SC injection q2w for 24 weeks.

    Serious adverse events
    		 Placebo 1.14 mL q2w Dupilumab 200 mg q2w Placebo 2 mL q2w Dupilumab 300 mg q2w
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 225 (9.33%)
    21 / 224 (9.38%)
    2 / 18 (11.11%)
    0 / 17 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 224 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    9 / 225 (4.00%)
    7 / 224 (3.13%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 7
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Cavitation
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 224 (0.45%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vocal Cord Polyp
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 224 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Panic Attack
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 224 (0.45%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle Fracture
         subjects affected / exposed
    2 / 225 (0.89%)
    0 / 224 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius Fracture
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 224 (0.45%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 224 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular Block Second Degree
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 224 (0.45%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cor Pulmonale Chronic
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 224 (0.45%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 224 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain Stem Infarction
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 224 (0.45%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Chalazion
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 224 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Functional Gastrointestinal Disorder
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 224 (0.45%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric Polyps
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 224 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large Intestine Polyp
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 224 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 224 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 224 (0.45%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 224 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 225 (0.44%)
    1 / 224 (0.45%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral Disc Protrusion
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 224 (0.45%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 224 (0.45%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoporosis
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 224 (0.45%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal Osteoarthritis
         subjects affected / exposed
    0 / 225 (0.00%)
    2 / 224 (0.89%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bartholin's Abscess
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 224 (0.45%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Covid-19 Pneumonia
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 224 (0.45%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 224 (0.45%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 224 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 224 (0.00%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 225 (0.89%)
    1 / 224 (0.45%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes Mellitus Inadequate Control
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 224 (0.45%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo 1.14 mL q2w Dupilumab 200 mg q2w Placebo 2 mL q2w Dupilumab 300 mg q2w
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    128 / 225 (56.89%)
    146 / 224 (65.18%)
    13 / 18 (72.22%)
    16 / 17 (94.12%)
    General disorders and administration site conditions
    Face Oedema
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 224 (0.45%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    1
    Injection Site Erythema
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 224 (0.45%)
    0 / 18 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    1
    0
    2
    Injection Site Pain
         subjects affected / exposed
    0 / 225 (0.00%)
    3 / 224 (1.34%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    3
    0
    1
    Injection Site Reaction
         subjects affected / exposed
    3 / 225 (1.33%)
    10 / 224 (4.46%)
    0 / 18 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    4
    27
    0
    3
    Injection Site Swelling
         subjects affected / exposed
    1 / 225 (0.44%)
    1 / 224 (0.45%)
    0 / 18 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    1
    1
    0
    8
    Pyrexia
         subjects affected / exposed
    10 / 225 (4.44%)
    7 / 224 (3.13%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    11
    8
    0
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 224 (0.00%)
    0 / 18 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    1
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Bronchiectasis
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 224 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cough
         subjects affected / exposed
    14 / 225 (6.22%)
    13 / 224 (5.80%)
    3 / 18 (16.67%)
    2 / 17 (11.76%)
         occurrences all number
    17
    17
    3
    5
    Haemoptysis
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 224 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oropharyngeal Pain
         subjects affected / exposed
    5 / 225 (2.22%)
    4 / 224 (1.79%)
    1 / 18 (5.56%)
    2 / 17 (11.76%)
         occurrences all number
    5
    4
    2
    3
    Productive Cough
         subjects affected / exposed
    2 / 225 (0.89%)
    4 / 224 (1.79%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    2
    4
    1
    0
    Rhinitis Allergic
         subjects affected / exposed
    8 / 225 (3.56%)
    7 / 224 (3.13%)
    1 / 18 (5.56%)
    1 / 17 (5.88%)
         occurrences all number
    13
    7
    1
    1
    Investigations
    Blood Creatine Phosphokinase Increased
         subjects affected / exposed
    8 / 225 (3.56%)
    18 / 224 (8.04%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    9
    22
    0
    0
    Blood Glucose Increased
         subjects affected / exposed
    3 / 225 (1.33%)
    9 / 224 (4.02%)
    2 / 18 (11.11%)
    0 / 17 (0.00%)
         occurrences all number
    3
    11
    2
    0
    Eosinophil Count Increased
         subjects affected / exposed
    3 / 225 (1.33%)
    0 / 224 (0.00%)
    1 / 18 (5.56%)
    1 / 17 (5.88%)
         occurrences all number
    3
    0
    1
    1
    Protein Urine Present
         subjects affected / exposed
    4 / 225 (1.78%)
    5 / 224 (2.23%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    4
    5
    1
    0
    Qrs Axis Abnormal
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 224 (0.45%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    1
    Injury, poisoning and procedural complications
    Skin Laceration
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 224 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 225 (1.78%)
    5 / 224 (2.23%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    4
    5
    0
    1
    Blood and lymphatic system disorders
    Eosinophilia
         subjects affected / exposed
    0 / 225 (0.00%)
    5 / 224 (2.23%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    5
    0
    2
    Leukocytosis
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 224 (0.00%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Neutropenia
         subjects affected / exposed
    0 / 225 (0.00%)
    1 / 224 (0.45%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 224 (0.00%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal Discomfort
         subjects affected / exposed
    1 / 225 (0.44%)
    2 / 224 (0.89%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    2
    0
    1
    Abdominal Pain
         subjects affected / exposed
    2 / 225 (0.89%)
    1 / 224 (0.45%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    2
    1
    0
    1
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 225 (0.44%)
    0 / 224 (0.00%)
    1 / 18 (5.56%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    1
    2
    Chronic Gastritis
         subjects affected / exposed
    2 / 225 (0.89%)
    1 / 224 (0.45%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    2
    1
    1
    0
    Gingival Pain
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 224 (0.00%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 225 (0.44%)
    1 / 224 (0.45%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    0
    1
    Hepatobiliary disorders
    Hepatic Function Abnormal
         subjects affected / exposed
    4 / 225 (1.78%)
    5 / 224 (2.23%)
    1 / 18 (5.56%)
    1 / 17 (5.88%)
         occurrences all number
    4
    5
    2
    3
    Skin and subcutaneous tissue disorders
    Dermatitis Allergic
         subjects affected / exposed
    2 / 225 (0.89%)
    7 / 224 (3.13%)
    1 / 18 (5.56%)
    2 / 17 (11.76%)
         occurrences all number
    4
    7
    1
    2
    Dermatitis Atopic
         subjects affected / exposed
    2 / 225 (0.89%)
    2 / 224 (0.89%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    2
    2
    1
    0
    Skin Irritation
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 224 (0.00%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Renal and urinary disorders
    Renal Cyst
         subjects affected / exposed
    1 / 225 (0.44%)
    1 / 224 (0.45%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 225 (1.78%)
    11 / 224 (4.91%)
    0 / 18 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    5
    11
    0
    2
    Musculoskeletal Chest Pain
         subjects affected / exposed
    2 / 225 (0.89%)
    1 / 224 (0.45%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    2
    1
    0
    1
    Osteoarthritis
         subjects affected / exposed
    1 / 225 (0.44%)
    3 / 224 (1.34%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    1
    3
    1
    0
    Pain In Extremity
         subjects affected / exposed
    2 / 225 (0.89%)
    4 / 224 (1.79%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    2
    4
    0
    2
    Tenosynovitis
         subjects affected / exposed
    0 / 225 (0.00%)
    2 / 224 (0.89%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Infections and infestations
    Bacterial Infection
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 224 (0.00%)
    2 / 18 (11.11%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Bronchitis
         subjects affected / exposed
    10 / 225 (4.44%)
    10 / 224 (4.46%)
    1 / 18 (5.56%)
    1 / 17 (5.88%)
         occurrences all number
    14
    15
    1
    1
    Conjunctivitis
         subjects affected / exposed
    4 / 225 (1.78%)
    6 / 224 (2.68%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    4
    6
    0
    1
    Gastroenteritis
         subjects affected / exposed
    7 / 225 (3.11%)
    9 / 224 (4.02%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    7
    10
    0
    1
    Influenza
         subjects affected / exposed
    0 / 225 (0.00%)
    3 / 224 (1.34%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    0
    3
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    13 / 225 (5.78%)
    14 / 224 (6.25%)
    0 / 18 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    17
    22
    0
    0
    Respiratory Tract Infection
         subjects affected / exposed
    7 / 225 (3.11%)
    6 / 224 (2.68%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    9
    9
    0
    1
    Tonsillitis
         subjects affected / exposed
    2 / 225 (0.89%)
    1 / 224 (0.45%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    2
    1
    0
    1
    Upper Respiratory Tract Infection
         subjects affected / exposed
    58 / 225 (25.78%)
    54 / 224 (24.11%)
    4 / 18 (22.22%)
    8 / 17 (47.06%)
         occurrences all number
    85
    87
    4
    11
    Urinary Tract Infection
         subjects affected / exposed
    7 / 225 (3.11%)
    6 / 224 (2.68%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    7
    6
    0
    1
    Metabolism and nutrition disorders
    Hyperphosphataemia
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 224 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hyperuricaemia
         subjects affected / exposed
    5 / 225 (2.22%)
    7 / 224 (3.13%)
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    8
    8
    0
    1
    Hypokalaemia
         subjects affected / exposed
    5 / 225 (2.22%)
    4 / 224 (1.79%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    8
    4
    1
    0
    Metabolic Disorder
         subjects affected / exposed
    0 / 225 (0.00%)
    0 / 224 (0.00%)
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 May 2018
    Following changes were done: Changed the dose regimen from 4 arms to 2 arms, specified the dose regimens and added the rationale for dose selection. Optimised study procedures. Removed data monitoring committee. Optimised inclusion and exclusion criteria. Allowed OCS dependent subjects to be enrolled in the study. Optimised IMP and non-investigational medicinal product (NIMP) management. Prohibited traditional Chinese medicine or other herbal medications during study. Updated information related to cytochrome P450 substrates. Re-organised endpoints based on new product data and selected doses. Updated AESI list and safety instruction. Changed statistical considerations based on new product data and the changes on the study design.
    25 Nov 2019
    Following changes were done: Modified primary population to ‘persistent asthma subjects with type 2 inflammation’. Rationale and definition were added to reflect revised primary population (persistent asthma subjects with type 2 inflammation). Added inclusion criteria "For subjects not requiring maintenance OCS, screening blood eosinophil count >=150 cells/mcL or FENO >=25 ppb; for subjects requiring maintenance OCS, there was no minimum requirement for blood eosinophil count and FENO level". Updated exclusion criteria to make it more precise. Subjects with history of systemic hypersensitivity or anaphylaxis to any biologic therapy, including any excipients, should be excluded from study. When failure of a subject to meet inclusion criteria was caused by incidental transitory conditions (e.g. subjects did not fill in ACQ correctly), subject was be allowed to be re-screened. Removed description of population ‘subjects with 200 mg q2w regimen’ in primary, secondary and other endpoints. Removed key secondary endpoint ‘absolute change from baseline in pre-bronchodilator FEV1 at Week 12 in overall population’. Added ‘spirometry would be performed centrally, and all recordings would be centrally read by independent experts’. Modified ACQ-7 as ‘Subject should complete first 6 items of ACQ-7 before spirometry test’. Changed ‘Nitrate’ to ‘Nitrite’. Removed example for method of test and name of company. Added measurement for blood eosinophil count and FENO as ‘Entry criteria at Visit 1 include blood eosinophil count >=150 cells/mcL or FENO >=25ppb for non-OCS maintenance subjects’. Modified as ‘anaphylactic reactions or systemic allergic reactions that were related to IMP and required treatment’. Sample size was recalculated based on observed effect size from QUEST study in revised primary analysis population of subjects with type 2 inflammation. Analysis and definition of ADA modified. Updated general guidance for follow up laboratory abnormalities. Added two appendices.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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