Evaluation of Dupilumab in Children With Uncontrolled Asthma

FEV1 was the volume of air (in liters) exhaled from the lungs in the first second of a forced expiration as measured by spirometer. LS means and SE were derived from MMRM model with change from baseline in pre-bronchodilator % predicted FEV1 value up to Week 12 as the response variable, and treatment, baseline weight group, region, ethnicity, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline % predicted FEV1 value and baseline-by-visit interaction as covariates.

FEV1 was the volume of air (in liters) exhaled from the lungs in the first second of a forced expiration as measured by spirometer. Least square (LS) means and standard error (SE) were derived from mixed-effect model with repeated measures (MMRM) model with change from baseline in pre-bronchodilator % predicted FEV1 value up to Week 12 as the response variable, and treatment, baseline weight group, region, ethnicity, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline % predicted FEV1 value and baseline-by-visit interaction as covariates.

ACQ-7-IA had 7 questions, which assessed: frequency of nocturnal awakenings, severity of asthma symptoms in the mornings, limitation of daily activities, shortness of breath due to asthma and wheeze, reliever medication use, and FEV1 (% predicted). Participants recalled their previous week asthma and answered 5 symptom questions on 7-point scale ranging from 0 (no impairment) to 6 (maximum impairment). Total score: mean of scores of all 7 questions; ranging from 0 (totally controlled) to 6 (severely uncontrolled), higher score indicated lower asthma control. LS means and SE were derived from MMRM model with change from baseline in ACQ-7-IA values up to Week 52 as response variable and treatment, age, baseline weight group, region, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline ACQ-7-IA value and baseline-by-visit interaction as covariates.

ACQ-7-IA had 7 questions, which assessed: frequency of nocturnal awakenings, severity of asthma symptoms in the mornings, limitation of daily activities due to asthma, shortness of breath due to asthma and wheeze, reliever medication use, and FEV1 (% predicted). Participants recalled their previous week asthma and answered 5 symptom questions on 7-point scale ranging from 0 (no impairment) to 6 (maximum impairment). Total score: mean of scores of all 7 questions; ranging from 0 (totally controlled) to 6 (severely uncontrolled), higher score indicated lower asthma control. LS means and SE were derived from MMRM model with change from baseline in ACQ-7-IA values up to Week 52 as response variable, and treatment, age, baseline weight group, region, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline ACQ-7-IA value and baseline-by-visit interaction as covariates.

FeNO is a surrogate marker for airway inflammation. FeNO was analyzed using a NIOX instrument or similar analyzer using a flow rate of 50 mL/second, and reported in ppb. LS means and SE were derived from MMRM model with change from baseline in FeNO up to Week 12 as the response variable, and treatment, age, baseline weight group, region, baseline eosinophil level, baseline ICS level, visit, treatment by-visit interaction, baseline FeNO value and baseline-by-visit interaction as covariates.

FeNO is a surrogate marker for airway inflammation. FeNO was analyzed using a NIOX instrument or similar analyzer using a flow rate of 50 mL/second, and reported in ppb. LS means and SE were derived from MMRM model with change from baseline in FeNO up to Week 12 as the response variable, and treatment, age, baseline weight group, region, baseline eosinophil level, baseline ICS level, visit, treatment by-visit interaction, baseline FeNO value and baseline-by-visit interaction as covariates.

FEV1 was the volume of air (in liters) exhaled from the lungs in the first second of a forced expiration as measured by spirometer. LS means and SE were derived from MMRM model with change from baseline in pre-bronchodilator % predicted FEV1 values up to Week 52 as the response variable, and treatment, baseline weight group, region, ethnicity, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline % predicted FEV1 value and baseline-by-visit interaction as covariates.

FEV1 was the volume of air (in liters) exhaled from the lungs in the first second of a forced expiration as measured by spirometer. LS means and SE were derived from MMRM model with change from baseline in pre-bronchodilator % predicted FEV1 values up to Week 52 as the response variable, and treatment, baseline weight group, region, ethnicity, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline % predicted FEV1 value and baseline-by-visit interaction as covariates.

The time to first severe exacerbation was defined as date of the first severe exacerbation event - randomization date +1. A severe asthma exacerbation event was defined as a deterioration of asthma during the 52-week treatment period requiring: use of systemic corticosteroids for >=3 days; and/or hospitalization related to asthma symptoms or emergency room visit because of asthma requiring systemic corticosteroid treatment. Kaplan-Meier method was used for analysis.

The time to first severe exacerbation was defined as date of the first severe exacerbation event - randomization date +1. A severe asthma exacerbation event was defined as a deterioration of asthma during the 52-week treatment period requiring: use of systemic corticosteroids for >=3 days; and/or hospitalization related to asthma symptoms or emergency room visit because of asthma requiring systemic corticosteroid treatment. Kaplan-Meier method was used for analysis.

Time to first LOAC event was date of first LOAC event - first dose date +1. A LOAC event was defined as deterioration of asthma during 52-week treatment period that resulted in any of the following: >= 6 additional reliever puffs of salbutamol/albuterol or levosalbutamol/levalbuterol in 24-hour period (compared to baseline) on 2 consecutive days; increase in ICS dose >=4 times than dose at Visit 2 (Week 0); a decrease in ante meridiem (AM)/post meridiem (PM) peak flow of 30% or more on 2 consecutive days of treatment, based on defined stability limit (defined as respective mean AM/PM peak expiratory flow obtained over last 7 days prior to randomization (Day 1); severe exacerbation event. Kaplan-Meier method was used for analysis.

Time to first LOAC event was date of first LOAC event - first dose date +1. A LOAC event was defined as deterioration of asthma during 52-week treatment period that resulted in any of the following: >= 6 additional reliever puffs of salbutamol/albuterol or levosalbutamol/levalbuterol in 24-hour period (compared to baseline) on 2 consecutive days; increase in ICS dose >=4 times than dose at Visit 2 (Week 0); a decrease in AM/PM peak flow of 30% or more on 2 consecutive days of treatment, based on defined stability limit (defined as respective mean AM/PM peak expiratory flow obtained over last 7 days prior to randomization (Day 1); severe exacerbation event. Kaplan-Meier method was used for analysis.

FEV1 was the volume of air (in liters) exhaled from the lungs in the first second of a forced expiration as measured by spirometer. LS means and SE were derived from MMRM model with change from baseline in pre-bronchodilator FEV1 values up to Week 52 as the response variable, and treatment, age, baseline weight group, region, sex, ethnicity, baseline height, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline pre-bronchodilator FEV1 value and baseline-by-visit interaction as covariates.

FEV1 was the volume of air (in liters) exhaled from the lungs in the first second of a forced expiration as measured by spirometer. LS means and SE were derived from MMRM model with change from baseline in pre-bronchodilator FEV1 values up to Week 52 as the response variable, and treatment, age, baseline weight group, region, sex, ethnicity, baseline height, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline pre-bronchodilator FEV1 value and baseline-by-visit interaction as covariates.

FEV1 was the volume of air (in liters) exhaled from the lungs in the first second of a forced expiration as measured by spirometer. LS means and SE were derived from MMRM model with change from baseline in pre-bronchodilator % predicted FEV1 values up to Week 52 as the response variable, and treatment, baseline weight group, region, ethnicity, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline % predicted FEV1 value and baseline-by-visit interaction as covariates.

FEV1 was the volume of air (in liters) exhaled from the lungs in the first second of a forced expiration as measured by spirometer. LS means and SE were derived from MMRM model with change from baseline in pre-bronchodilator % predicted FEV1 values up to Week 52 as the response variable, and treatment, baseline weight group, region, ethnicity, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline % predicted FEV1 value and baseline-by-visit interaction as covariates.

The PEF is a participant's maximum speed of expiration, as measured with a peak flow meter. Peak flow testing for AM PEF was performed in morning prior to taking any salbutamol/albuterol or levosalbutamol/levalbuterol reliever medication. Baseline AM PEF was the mean AM measurement recorded for the 7 days prior to the first dose of investigational product. LS means and SE were derived from MMRM model with change from baseline in AM PEF (liters/minute) values up to Week 52 as the response variable, and treatment, age, baseline weight group, region, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline AM PEF (liters/minute) value and baseline-by-visit interaction as covariates.

The PEF is a participant's maximum speed of expiration, as measured with a peak flow meter. Peak flow testing for PM PEF was performed in evening prior to taking any salbutamol/albuterol or levosalbutamol/levalbuterol reliever medication. Baseline PM PEF was the mean PM measurement recorded for the 7 days prior to the first dose of investigational product. LS means and SE were derived from MMRM model with change from baseline in PM PEF (liters/minute) values up to Week 52 as the response variable, and treatment, age, baseline weight group, region, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline PM PEF (liters/minute) value and baseline-by-visit interaction as covariates.

The PEF is a participant's maximum speed of expiration, as measured with a peak flow meter. Peak flow testing for AM PEF was performed in morning prior to taking any salbutamol/albuterol or levosalbutamol/levalbuterol reliever medication. Baseline AM PEF was the mean AM measurement recorded for the 7 days prior to the first dose of investigational product. LS means and SE were derived from MMRM model with change from baseline in AM PEF (liters/minute) values up to Week 52 as the response variable, and treatment, age, baseline weight group, region, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline AM PEF (liters/minute) value and baseline-by-visit interaction as covariates.

The PEF is a participant's maximum speed of expiration, as measured with a peak flow meter. Peak flow testing for PM PEF was performed in evening prior to taking any salbutamol/albuterol or levosalbutamol/levalbuterol reliever medication. Baseline PM PEF was the mean PM measurement recorded for the 7 days prior to the first dose of investigational product. LS means and SE were derived from MMRM model with change from baseline in PM PEF (liters/minute) values up to Week 52 as the response variable, and treatment, age, baseline weight group, region, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline PM PEF (liters/minute) value and baseline-by-visit interaction as covariates.

FVC is a standard pulmonary function test used to quantify respiratory muscle weakness. FVC is the volume of air (in liters) that can be forcibly blown out after full inspiration in the upright position, measured in liters. LS means and SE were derived from MMRM model with change from baseline in FVC values up to Week 52 as the response variable, and treatment, age, baseline weight group, region, sex, ethnicity, baseline height, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline FVC value and baseline-by-visit interaction as covariates.

FVC is a standard pulmonary function test used to quantify respiratory muscle weakness. FVC is the volume of air (in liters) that can be forcibly blown out after full inspiration in the upright position, measured in liters. LS means and SE were derived from MMRM model with change from baseline in FVC values up to Week 52 as the response variable, and treatment, age, baseline weight group, region, sex, ethnicity, baseline height, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline FVC value and baseline-by-visit interaction as covariates.

FEF is the amount of air (in liters) which can be forcibly exhaled from the lungs in the first second of a forced exhalation. FEF 25-75% was defined as the mean FEF between 25% and 75% of the FVC, where FVC was defined as the volume of air (in liters) that can be forcibly blown out after full inspiration in the upright position. LS means and SE were derived from MMRM model with change from baseline in FEF 25-75% values up to Week 52 as the response variable, and treatment, age, baseline weight group, region, sex, ethnicity, baseline height, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline FEF 25-75% value and baseline-by-visit interaction as covariates.

FEF is the amount of air (in liters) which can be forcibly exhaled from the lungs in the first second of a forced exhalation. FEF 25-75% was defined as the mean FEF between 25% and 75% of the FVC, where FVC was defined as the volume of air (in liters) that can be forcibly blown out after full inspiration in the upright position. LS means and SE were derived from MMRM model with change from baseline in FE F25-75% values up to Week 52 as the response variable, and treatment, age, baseline weight group, region, sex, ethnicity, baseline height, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline FEF 25-75% value and baseline-by-visit interaction as covariates.

Participants were assessed for post-bronchodilator FEV1 30 minutes after bronchodilator administration (200 to 400 mg [2 to 4 puffs] of albuterol/salbutamol or 45 to 90 micrograms [2 to 4 puffs] of levalbuterol/levosalbutamol). FEV1 was the volume of air (in liters) exhaled in the first second of a forced expiration as measured by spirometer. LS means and SE were derived from MMRM model with change from baseline in post-bronchodilator FEV1 values up to Week 52 as the response variable, and treatment, baseline weight group, region, ethnicity, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline post-bronchodilator FEV1 value and baseline-by-visit interaction as covariates.

Participants were assessed for post-bronchodilator FEV1 30 minutes after bronchodilator administration (200 to 400 mg [2 to 4 puffs] of albuterol/salbutamol or 45 to 90 micrograms [2 to 4 puffs] of levalbuterol/levosalbutamol). FEV1 was the volume of air (in liters) exhaled in the first second of a forced expiration as measured by spirometer. LS means and SE were derived from MMRM model with change from baseline in post-bronchodilator FEV1 values up to Week 52 as the response variable, and treatment, baseline weight group, region, ethnicity, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline post-bronchodilator FEV1 value and baseline-by-visit interaction as covariates.

The morning asthma symptom score evaluated participant's overall asthma symptoms experienced during the previous night. It ranged from 0 (no asthma symptoms, slept through the night) to 4 (bad night, awake most of the night because of asthma), where lower scores indicate more mild symptoms and higher scores indicate more severe symptoms. LS means and SE were derived from MMRM model with change from baseline in AM asthma symptom score values up to Week 52 as the response variable, and treatment, age, baseline weight group, region, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline AM asthma symptom score value and baseline-by-visit interaction as covariates.

The evening asthma symptom score evaluated participant's overall asthma symptoms experienced during the day. It ranged from 0 (very well, no asthma symptoms) to 4 (asthma very bad, unable to carry out daily activities as usual), where lower scores indicate more mild symptoms and higher scores indicate more severe symptoms. LS means and SE were derived from MMRM model with change from baseline in PM asthma symptom score values up to Week 52 as response variable, and treatment, age, baseline weight group, region, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline PM asthma symptom score value and baseline-by-visit interaction as covariates.

The morning asthma symptom score evaluated participant's overall asthma symptoms experienced during the previous night. It ranged from 0 (no asthma symptoms, slept through the night) to 4 (bad night, awake most of the night because of asthma), where lower scores indicate more mild symptoms and higher scores indicate more severe symptoms. LS means and SE were derived from MMRM model with change from baseline in AM asthma symptom score values up to Week 52 as the response variable, and treatment, age, baseline weight group, region, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline AM asthma symptom score value and baseline-by-visit interaction as covariates.

The evening asthma symptom score evaluated participant's overall asthma symptoms experienced during the day. It ranged from 0 (very well, no asthma symptoms) to 4 (asthma very bad, unable to carry out daily activities as usual), where lower scores indicate more mild symptoms and higher scores indicate more severe symptoms. LS means and SE were derived from MMRM model with change from baseline in PM asthma symptom score values up to Week 52 as response variable, and treatment, age, baseline weight group, region, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline PM asthma symptom score value and baseline-by-visit interaction as covariates.

ACQ-5-IA has 5 questions, reflecting top-scoring 5 asthma symptoms: frequency of nocturnal awakenings, severity of asthma symptoms in the mornings, limitation of daily activities, shortness of breath due to asthma 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 ranging from 0 (no impairment) to 6 (maximum impairment). ACQ-5-IA total score was mean of the scores of all 5 questions and, therefore, ranged from 0 (totally controlled) to 6 (severely uncontrolled), higher scores indicated lower asthma control. LS means and SE were derived from MMRM model with change from baseline in ACQ-5-IA values up to Week 52 as the response variable, and treatment, age, baseline weight group, region, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline ACQ-5-IA value and baseline-by-visit interaction as covariates.

ACQ-5-IA has 5 questions, reflecting top-scoring 5 asthma symptoms: frequency of nocturnal awakenings, severity of asthma symptoms in the mornings, limitation of daily activities, shortness of breath due to asthma 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 ranging from 0 (no impairment) to 6 (maximum impairment). ACQ-5-IA total score was mean of the scores of all 5 questions and, therefore, ranged from 0 (totally controlled) to 6 (severely uncontrolled), higher scores indicated lower asthma control. LS means and SE were derived from MMRM model with change from baseline in ACQ-5-IA values up to Week 52 as the response variable, and treatment, age, baseline weight group, region, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline ACQ-5-IA value and baseline-by-visit interaction as covariates.

ACQ-7-IA had 7 questions, assessed: frequency of nocturnal awakenings, severity of asthma symptoms in the mornings, limitation of daily activities, shortness of breath due to asthma and wheeze, reliever medication use, and FEV1 (% predicted). Participants recalled their previous week asthma and answered 5 symptom questions on 7-point scale ranging from 0 (no impairment) to 6 (maximum impairment). Total score:mean of scores of all 7 questions; ranging from 0 (totally controlled) to 6 (severely uncontrolled), higher score indicated lower asthma control. LS means and SE were derived from MMRM model with change from baseline in ACQ-7-IA values up to Week 52 as response variable and treatment, age, baseline weight group, region, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline ACQ-7-IA value and baseline-by-visit interaction as covariates.

ACQ-7-IA had 7 questions, assessed: frequency of nocturnal awakenings, severity of asthma symptoms in the mornings, limitation of daily activities due to asthma, shortness of breath due to asthma and wheeze, reliever medication use, and FEV1 (% predicted). Participants recalled their previous week asthma and answered 5 symptom questions on 7-point scale ranging from 0 (no impairment) to 6 (maximum impairment). Total score: mean of scores of all 7 questions; ranging from 0 (totally controlled) to 6 (severely uncontrolled), higher score indicated lower asthma control. LS means and SE were derived from MMRM model with change from baseline in ACQ-7-IA values up to Week 52 as response variable, and treatment, age, baseline weight group, region, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline ACQ-7-IA value and baseline-by-visit interaction as covariates.

Participants might be administered salbutamol/albuterol or levosalbutamol/levalbuterol as reliever medication as needed. Number of reliever medication inhalations were recorded daily in electronic diary/PEF meter. When Nebulizer solutions were used as alternative delivery method, nebulizer dose was converted to number of puffs as per conversion factor: salbutamol/albuterol nebulizer solution (2.5 mg) and levosalbutamol/levalbuterol (1.25 mg) corresponds to 4 puffs. Change From Baseline in number of puffs of reliever medication used per 24 hours at specified weeks was reported. LS means and SE were derived from MMRM model with change from baseline in number of puffs of reliever medication/24 hours values up to Week 52 as response variable and treatment, age, baseline: weight group, region, eosinophil level, FeNO level, ICS dose level, visit, treatment by-visit interaction, baseline number of puffs of reliever medication/24 hours value and baseline-by-visit interaction as covariates.

Participants might be administered salbutamol/albuterol or levosalbutamol/levalbuterol as reliever medication as needed. Number of reliever medication inhalations were recorded daily in electronic diary/PEF meter. When Nebulizer solutions were used as alternative delivery method, nebulizer dose was converted to number of puffs as per conversion factor: salbutamol/albuterol nebulizer solution (2.5 mg) and levosalbutamol/levalbuterol (1.25 mg) corresponds to 4 puffs. Change From Baseline in number of puffs of reliever medication used per 24 hours at specified weeks was reported. LS means and SE were derived from MMRM model with change from baseline in number of puffs of reliever medication/24 hours values up to Week 52 as response variable and treatment, age, baseline: weight group, region, eosinophil level, FeNO level, ICS dose level, visit, treatment by-visit interaction, baseline number of puffs of reliever medication/24 hours value and baseline-by-visit interaction as covariates.

Participants recorded every morning the number of asthma-related nocturnal awakenings requiring use of rescue medication that occurred during the previous night. Change from baseline in number of nocturnal awakenings per night at specified weeks was reported. LS means and SE were derived from MMRM model with change from baseline in number of nocturnal awakenings values up to Week 52 as the response variable, and treatment, age, baseline weight group, region, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline number of nocturnal awakenings value and baseline-by-visit interaction as covariates.

Participants recorded every morning the number of asthma-related nocturnal awakenings requiring use of rescue medication that occurred during the previous night. Change from baseline in number of nocturnal awakenings per night at specified weeks was reported. LS means and SE were derived from MMRM model with change from baseline in number of nocturnal awakenings values up to Week 52 as the response variable, and treatment, age, baseline weight group, region, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline number of nocturnal awakenings value and baseline-by-visit interaction as covariates.

PAQLQ(S)-IA, a disease-specific, interviewer-administered QoL questionnaire designed to measure functional impairments that are most important to children >=7 years with asthma. The PAQLQ(S)-IA comprises of 23 items in 3 domains: symptoms (10 items), activity limitation (5 items) and emotional function (8 items). Each item was scored on a 7-point likert scale (1=maximal impairment to 7=no impairment). 23 items of questionnaire were averaged to produce 1 overall quality of life score ranging from 1 (severely impaired) to 7 (not impaired at all), higher scores indicated better quality of life. LS means and SE were derived from MMRM model with change from baseline in PAQLQ(S)-IA global score values up to Week 52 as the response variable, and treatment, age, baseline weight group, region, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline PAQLQ(S)-IA global score value and baseline-by-visit interaction as covariates.

PAQLQ(S)-IA, a disease-specific, interviewer-administered QoL questionnaire designed to measure functional impairments that are most important to children >=7 years with asthma. The PAQLQ(S)-IA comprises of 23 items in 3 domains: symptoms (10 items), activity limitation (5 items) and emotional function (8 items). Each item was scored on a 7-point likert scale (1=maximal impairment to 7=no impairment). 23 items of questionnaire were averaged to produce 1 overall quality of life score ranging from 1 (severely impaired) to 7 (not impaired at all), higher scores indicated better quality of life. LS means and SE were derived from MMRM model with change from baseline in PAQLQ(S)-IA global score values up to Week 52 as the response variable, and treatment, age, baseline weight group, region, baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, baseline PAQLQ(S)-IA global score value and baseline-by-visit interaction as covariates.

The number of days missed from school by the participant and the number of days missed from work by the caregiver of participant due to a LOAC were collected in the electronic-case report form (eCRF). Cumulative number of missed days (school days and work days) up to week 52 were computed and summarized using mean and standard deviation (SD).

The number of days missed from school by the participant and the number of days missed from work by the caregiver of participant due to a LOAC were collected in the eCRF. Cumulative number of missed days (school days and work days) up to week 52 were computed and summarized using mean and SD.

The number of days missed from school for the participant and the missed number of days from work for the caregiver due to a LOAC were collected in the eCRF. The percentage of participants who had at least 5 days (school days and work days) missed due to LOAC over the study period was reported.

The number of days missed from school for the participant and the missed number of days from work for the caregiver due to a LOAC were collected in the eCRF. The percentage of participants who had at least 5 days (school days and work days) missed due to LOAC over the study period was reported.

Adverse event (AE) was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and did not necessary have to had a causal relationship with treatment.TEAEs were defined as AEs that developed or worsened in grade or became serious during TEAE period which was defined as the period from the time of first dose of study drug to the end of post-treatment period. A serious adverse events (SAE) was any untoward medical occurrence that at any dose resulted in: death; or life-threatening experience; or required inpatient hospitalization or prolongation of existing hospitalization; or resulted in persistent or significant disability/incapacity; or was a congenital anomaly/birth defect or a medically important event. TEAEs included both SAEs and non-SAEs.

Data for this outcome measure was planned to be collected and analyzed separately for dupilumab 100 mg and 200 mg dose and not planned to be collected and analyzed for placebo arm.

ADA response was categorized as: treatment emergent and treatment boosted response. 1) Treatment emergent was defined as an ADA positive response in the assay post first dose, when baseline results were negative or missing. 2) Treatment boosted was defined as: an ADA positive response in the assay post first dose that was greater-than or equal to 4-fold over baseline titer levels, when baseline results were positive. The criteria for positive was defined as "30 to > 10,000", where low titer (< 1,000); moderate (1,000 <= titer <= 10,000) and high titer (> 10,000).

Seroconversion was defined as a post-vaccination titer >=40 (1/dilution) for those with a pre-vaccination titer <10 (1/dilution), or a >= 4-fold increase in post-vaccination titer for those with a pre-vaccination titer >=10 (1/dilution).