Evaluation of Dupilumab in Patients With Severe Steroid Dependent Asthma

Conditions

Asthma

Brief summary

Primary Objective: To evaluate the efficacy of dupilumab, compared with placebo, for reducing the use of maintenance oral corticosteroids (OCS) in participants with severe steroid-dependent asthma. Secondary Objectives: * To evaluate the safety and tolerability of dupilumab. * To evaluate the effect of dupilumab in improving participants-reported outcomes. * To evaluate dupilumab systemic exposure and the incidence of treatment-emergent antidrug antibodies.

Detailed description

The total study duration per participant was up to 46 weeks, consisting of a screening period of 3 to up to 8 weeks (up to 10 weeks for participants who experienced a clinically significant asthma exacerbation during the screening period), a randomized treatment period of up to 24 weeks, and a post-treatment period of 12 weeks. Participants who completed treatment were considered for eligibility into the long term extension study LTS12551 (NCT02134028).

Rhee CK, Park JW, Park HW, Noh H, Msihid J, Cho YS.

2024-07-012 citations

10.4168/aair.2024.16.4.372

Association Of Baseline Lung Function And Likelihood Of Oral Corticosteroid Reduction In Patients With OCS-Dependent Severe Asthma

Christian Domingo, Marek Lommatzsch, NA Hanania, Giorgio Walter Canonica, David Halpin et al. (14 authors)

Pneumologie2024-03-01

10.1055/s-0044-1781404

Dupilumab Efficacy in Patients With Uncontrolled or Oral Corticosteroid-Dependent Allergic and Nonallergic Asthma.

Brusselle G, Quirce S, Papi A, Kuna P, Chipps BE, Hanania NA, Blaiss M, Msihid J, Jacob-Nara JA, Deniz Y, Rowe PJ, Gall R, Ortiz B, Djandji M, Radwan A.

2022-12-2311 citations

10.1016/j.jaip.2022.11.044

The long-term effect of dupilumab on dyspnea, sleep, and activity in oral corticosteroid-dependent severe asthma

Lawrence Sher, Giovanni Passalacqua, Camille Taillé, Lauren Cohn, Nadia Daizadeh et al. (13 authors)

Annals of Allergy Asthma & Immunology2022-12-095 citations

10.1016/j.anai.2022.12.002

Long-term efficacy of dupilumab in asthma with or without chronic rhinosinusitis and nasal polyps

Patrick Berger, Andrew Menzies‐Gow, Anju T. Peters, Piotr Kuna, Klaus F. Rabe et al. (12 authors)

Annals of Allergy Asthma & Immunology2022-11-0725 citations

10.1016/j.anai.2022.11.006

Effect of dupilumab on improving physical activity in patients with severe asthma

Lawrence D. Sher, G. Passalacqua, L Cohn, N Daizadeh, N Pandit-Abid et al. (10 authors)

Pneumologie2022-05-011 citations

10.1055/s-0042-1747768

Effect of Dupilumab on Lung Function Parameters in Oral Corticosteroid-Dependent Patients With Asthma Enrolled in LIBERTY ASTHMA TRAVERSE

Mario Castro, Alberto Papi, J Corren, I D Pavord, Yuji Tohda et al. (20 authors)

Pneumologie2022-05-01

10.1055/s-0042-1747783

Dupilumab Efficacy in Steroid-Dependent Severe Asthma by Baseline Oral Corticosteroid Dose.

Domingo C, Maspero JF, Castro M, Hanania NA, Ford LB, Halpin DMG, Jackson DJ, Daizadeh N, Djandji M, Mitchell CP, Crikelair N, Jacob-Nara JA, Deniz Y, Rowe PJ, Ortiz B.

2022-04-0810 citations

10.1016/j.jaip.2022.03.020

Dupilumab Reduces Oral Corticosteroid Use in Patients With Corticosteroid-Dependent Severe Asthma: An Analysis of the Phase 3, Open-Label Extension TRAVERSE Trial.

Sher LD, Wechsler ME, Rabe KF, Maspero JF, Daizadeh N, Mao X, Ortiz B, Mannent LP, Laws E, Ruddy M, Pandit-Abid N, Jacob-Nara JA, Gall R, Rowe PJ, Deniz Y, Lederer DJ, Hardin M.

2022-02-2231 citations

10.1016/j.chest.2022.01.071

Preclinical and clinical experience with dupilumab on the correlates of live attenuated vaccines.

Wechsler ME, Souza-Machado A, Xu C, Mao X, Kapoor U, Khokhar FA, O'Malley JT, Petro CD, Casullo VM, Mannent LP, Rowe PJ, Jacob-Nara JA, Ruddy M, Laws E, Purcell LA, Hardin M.

2021-12-0814 citations

10.1016/j.jacig.2021.12.003

Cost-effectiveness analysis of dupilumab among patients with oral corticosteroid-dependent uncontrolled severe asthma in Japan.

Tohda Y, Matsumoto H, Miyata M, Taguchi Y, Ueyama M, Joulain F, Arakawa I.

2021-12-088 citations

10.1080/02770903.2021.1996596

Effect of dupilumab on patient-reported sleep outcomes in patients with severe asthma

Lawrence Sher, Giovanni Passalacqua, Camille Taillé, Lauren Cohn, Santiago Quirce et al. (10 authors)

2021-09-051 citations

10.1183/13993003.congress-2021.pa3733

Efficacy of dupilumab in patients with oral corticosteroid (OCS)-dependent, severe asthma with and without an allergic phenotype: phase 3 LIBERTY ASTHMA VENTURE

Guy Brusselle, Alberto Papi, Bradley E. Chipps, Jérôme Msihid, Juby A. Jacob‐Nara et al. (11 authors)

2021-09-05

10.1183/13993003.congress-2021.pa2521

Dupilumab sustains long-term OCS reduction in OCS-dependent asthma patients

Lawrence Sher, Michael E. Wechsler, Klaus F. Rabe, Jorge Máspero, Nadia Daizadeh et al. (13 authors)

2021-09-05

10.1183/13993003.congress-2021.pa2519

Effect of dupilumab on improving physical activity in patients with severe asthma

Lawrence Sher, Santiago Quirce, Giovanni Passalacqua, Camille Taillé, Lauren Cohn et al. (10 authors)

2021-09-05

10.1183/13993003.congress-2021.pa880

Effect of dupilumab on oral corticosteroid use in severe asthma patients with improving lung function

Jorge Máspero, David Halpin, David J. Jackson, Nicola A. Hanania, Mario Castro et al. (10 authors)

2020-09-071 citations

10.1183/13993003.congress-2020.5282

Dupilumab shows rapid and sustained suppression of inflammatory biomarkers in corticosteroid (CS)-dependent severe asthma patients in LIBERTY ASTHMA VENTURE

Klaus F. Rabe, Guy Brusselle, Mario Castro, Lawrence Sher, Hongjie Zhu et al. (15 authors)

2018-09-154 citations

10.1183/13993003.congress-2018.pa5003

Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma

Klaus F. Rabe, Parameswaran Nair, Guy Brusselle, Jorge Máspero, Mario Castro et al. (21 authors)

New England Journal of Medicine2018-05-211,110 citations

10.1056/nejmoa1804093

Interventions

DRUGInhaled corticosteroid (ICS) therapy

Oral inhalation, stable dose (high dose) of ICS in combination with up to 2 other controller medicines (second or third controller therapy).

DRUGDupilumab

Solution for injection, Subcutaneous injection in the abdomen, upper thigh or upper arm.

DRUGPlacebo

Solution for injection, Subcutaneous injection in the abdomen, upper thigh or upper arm.

DRUGAlbuterol/Salbutamol

Oral inhalation as needed.

DRUGLevalbuterol/Levosalbutamol

Oral inhalation as needed.

DRUGOral corticosteroid therapy (prednisone/prednisolone)

Oral administration.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

12 Years to No maximum

Healthy volunteers

No

Inclusion criteria

: Adult and adolescent (12 years of age or older) participants with a physician diagnosis of asthma for \>=12 months, based on the Global Initiative for Asthma (GINA) 2014 guidelines and the following criteria: * Participants with severe asthma and a well-documented, regular prescribed treatment of maintenance corticosteroids in the 6 months prior to Visit 1 and using a stable OCS dose (ie, no change of OCS dose) for 4 weeks prior to Visit 1. Participants must be taking 5 to 35 mg/day of prednisone/prednisolone, or the equivalent, at Visit 1 and at the randomization visit. In addition, the participants must agree to switch to study-required prednisone/prednisolone as their OCS and use it per protocol for the duration of the study. * Existing treatment with high-dose inhaled corticosteroid (ICS; \>500 mcg total daily dose of fluticasone propionate or equivalent) in combination with a second controller (ie, long-acting beta agonist \[LABA\], leukotriene receptor antagonist \[LTRA\]) for at least 3 months with a stable dose of ICS for \>=1 month prior to Visit 1. In addition, participants requiring a third controller for their asthma are considered eligible for this study, and it should also be used for at least 3 months with a stable dose \>= 1 month prior to Visit 1. * A forced expiratory volume in 1 second (FEV1) \<80% of predicted normal for adults and \<=90% of predicted normal for adolescents at Visit 1. * Evidence of asthma as documented by either: reversibility of at least 12% and 200 mL in FEV1 after the administration of 200 to 400 mcg (2 to 4 inhalations of albuterol/salbutamol or levalbuterol/levosalbutamol, or of a nebulized solution of albuterol/salbutamol or levalbuterol/levosalbutamol, if considered as a standard office practice) before randomization or documented in the 12 months prior to Visit 1 OR airway hyperresponsiveness (methacholine: provocative concentration that causes a positive reaction \[PC20\] of \<8 mg/mL) documented in the 12 months prior to Visit 1.

Exclusion criteria

* Participants \<12 years of age or the minimum legal age for adolescents in the country of the investigative site, whichever is higher (for those countries where local regulations permit enrollment of adults only, participant recruitment will be restricted to those who were \>=18 years of age). * Participants who weighed \<30.0 kg. * Chronic obstructive pulmonary disease (COPD) or other lung diseases (eg, idiopathic pulmonary fibrosis, Churg-Strauss Syndrome, allergic bronchopulmonary aspergillosis, cystic fibrosis) which may impair lung function. * Clinical evidence or imaging (eg, chest X-ray, computed tomography, magnetic resonance imaging) within 12 months of Visit 1 with clinically significant findings of lung disease(s) other than asthma, as per local standard of care. * A participant who experiences a deterioration of asthma that results in emergency treatment or hospitalization within 4 weeks of Screening Visit 1. * A participant who requires 12 puffs or more of rescue medication on any 1 day in the week prior to Visit 1. * A participant who has experienced an upper or lower respiratory tract infection within the 4 weeks prior to screening. * Current smoker or cessation of smoking within 6 months prior to Visit 1. * Previous smoker with a smoking history \>10 pack-years. * Comorbid disease that might interfere with the evaluation of the investigational medicinal product. The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Design outcomes

Primary

Measure	Time frame	Description
Percentage Reduction From Baseline in Oral Corticosteroids (OCS) Dose at Week 24 While Maintaining Asthma Control	Baseline, Week 24	Percentage reduction of OCS dose was calculated as (optimized OCS dose \[mg/day\] at baseline - final OCS dose at Week 24)/optimized OCS dose at baseline x 100. Result is presented as Least Squares Mean (Standard Error) percentage reduction from baseline derived from ANCOVA model with missing data multiply imputed.
Supplementary Presentation of Primary Outcome Measure Data: Median Percentage Reduction From Baseline in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control	Baseline, Week 24	The Primary Outcome Measure (Percentage Reduction From Baseline in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control) is summarized above, as LS Mean (SE). Table below provides a supplementary presentation of the Primary Outcome Measure data; result is presented as median (inter-quartile range). Percentage reduction of OCS dose was calculated as (optimized OCS dose \[mg/day\] at baseline - final OCS dose at Week 24)/optimized OCS dose at baseline x 100.

Secondary

Measure	Time frame	Description
Percentage of Participants Achieving >= 50% Reduction in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control	Week 24	Participants were classified according to the binary status of whether or not the 50% OCS dose reduction criterion was achieved at week 24.
Percentage of Participants Achieving a Reduction in Oral Corticosteroids Dose to <5 mg/Day at Week 24 While Maintaining Asthma Control	Week 24	Participants were classified according to the binary status of whether or not the reduction of OCS dose to \<5 mg/day was achieved at Week 24.
Percentage of Participants Achieving Maximum Possible Reduction in Oral Corticosteroids Dose Per Protocol at Week 24 While Maintaining Asthma Control	Week 24	For all participants except those with baseline OCS dose at 35 mg/day, the maximum possible reduction corresponds to reduction to 0 mg/day (no longer requiring OCS). For participants starting with 35 mg/day at baseline, the maximum possible reduction is 32.5 mg/day (i.e. minimum dose per protocol is 2.5 mg).
Percentage of Participants Who No Longer Required Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control	Week 24	Participants were classified according to the binary status of whether or not the participant still required OCS at Week 24 while maintaining asthma control.
Absolute Reduction From Baseline in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control	Baseline and Week 24	Absolute reduction was calculated by subtracting Week 24 value from baseline value.

Other

Measure	Time frame	Description
Annualized Rate of Severe Exacerbation Events During The 24-Week Treatment Period	Baseline to Week 24	A severe asthma exacerbation event was defined as a deterioration of asthma during the 24-week treatment period requiring: use of systemic corticosteroids for \>=3 days (at least double the dose currently used); and/or hospitalization related to asthma symptoms or emergency room visit because of asthma requiring intervention with a systemic corticosteroid treatment. Annualized event rate was the total number of exacerbations that occurred during the treatment period divided by the total number of participant-years treated.
Change From Baseline in Asthma Control Questionnaire 5-Question Version (ACQ-5) Score at Weeks 2, 4, 8, 12, 16, 20, and 24	Baseline and at Weeks 2, 4, 8, 12, 16, 20, and 24	The ACQ-5 has 5 questions, reflecting top-scoring 5 asthma symptoms: woken at night by symptoms, wake in mornings with symptoms, limitation of daily activities, shortness of breath and wheeze. Participants were asked to recall how their asthma had been during previous week and to respond to each of 5 symptom questions on a 7-point scale ranged from 0 (no impairment) to 6 (maximum impairment). ACQ-5 total score was mean of scores of all 5 questions and, therefore, ranged from 0 (totally controlled) to 6 (severely uncontrolled). Higher score indicated lower asthma control.
Change From Baseline in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Weeks 12 and 24	Baseline, Week 12 and Week 24	FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer.
Change From Baseline in Asthma Quality of Life Questionnaire (AQLQ) Global Score at Week 12 and Week 24	Baseline, Week 12 and Week 24	AQLQ is a disease-specific, self-administered quality of life questionnaire designed to measure functional impairments that were most important to participants with asthma. 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 a 7-point likert scale (1=maximal impairment, 7=no impairment). The 32 items of the questionnaire were averaged to produce one overall quality of life score ranging from 1 (severely impaired) to 7 (not impaired at all). Higher scores indicate better quality of life.
Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels (EQ-5D-5L) Scores at Week 12 and Week 24	Baseline, Week 12 and Week 24	EQ-5D-5L is a standardized health-related quality of life questionnaire developed by EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal. EQ-5D consists of EQ-5D descriptive system and EQ visual analogue scale (VAS). EQ-5D descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The 5D-5L systems are converted into a single index utility score between 0 to 1, where higher score indicates a better health state. EQ-5D-5L-VAS records participant's self-rated health on a vertical VAS that allows them to indicate their health state that can range from 0 (worst imaginable) to 100 (best imaginable).
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Total Score at Week 12 and Week 24	Baseline, Week 12 and Week 24	The HADS is a general scale to detect states of anxiety and depression already used and validated in asthma, which includes HADS-A and HADS-D subscales. The instrument is comprised of 14 items: 7 related to anxiety (HADS-A) and 7 to depression (HADS-D). Each item on the questionnaire is scored from 0-3. And, the total score is the sum of the scores of the 14 items ranging from 0 (no symptoms) to 42 (severe symptoms), with higher scores indicating higher anxiety/depression complains.
Change From Baseline in Sino Nasal Outcome Test-22 (SNOT-22) Global Score at Week 12 and Week 24	Baseline, Week 12 and Week 24	The SNOT-22 is a validated measure of health related quality of life in sino nasal disease. It is a 22 item questionnaire with each item assigned a score ranging from 0-5. The total score may range from 0 (no disease) -110 (worst disease), lower scores represent better health related quality of life.

Countries

Argentina, Belgium, Brazil, Canada, Chile, Colombia, Hungary, Israel, Italy, Mexico, Netherlands, Poland, Romania, Russia, Spain, Ukraine, United States

Participant flow

Recruitment details

The study was conducted at 68 centers in 17 countries. A total of 390 participants were screened between October 2015 & April 2017, of which,210 were randomized & treated. 180 participants were screen failures mainly due to exclusion criteria met & inclusion criteria not met. Assignment was done by Interactive Voice/Web Response System(IVRS/IWRS).

Pre-assignment details

Screening period included an OCS optimization phase (up to 10 weeks) where participants using OCS other than prednisone/prednisolone switched to these OCS. At the end of period, participants were randomized in 1:1 ratio (dupilumab:placebo).Randomization was stratified by optimized OCS dose (=\<10 & \>10 mg/day) at randomization visit & by country.

Participants by arm

Arm	Count
Placebo q2w 2 subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1, followed by a single injection q2w for 24 weeks in combination with OCS - (prednisone or prednisolone) and stable ICS. OCS dose was reduced according to a predetermined titration schedule every 4 weeks until Week 20.	107
Dupilumab 300 mg q2w 2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection q2w for 24 weeks in combination with OCS - (prednisone or prednisolone) and stable ICS. OCS dose was reduced according to a predetermined titration schedule every 4 weeks until Week 20.	103
Total	210

Withdrawals & dropouts

Period	Reason	FG001
Overall Study	Adverse Event	1
Overall Study	Other than specified above	1
Overall Study	Protocol Violation	1

Baseline characteristics

Characteristic	Placebo q2w	Dupilumab 300 mg q2w	Total
Age, Continuous	50.7 years STANDARD_DEVIATION 12.8	51.9 years STANDARD_DEVIATION 12.5	51.3 years STANDARD_DEVIATION 12.6
Age, Customized <18 years	2 Participants	1 Participants	3 Participants
Age, Customized >=65 years	17 Participants	11 Participants	28 Participants
Age, Customized Between 18 and 64 years	88 Participants	91 Participants	179 Participants
Baseline Blood Eosinophil Count >=0.15 - <0.3 Giga/L	28 Participants	33 Participants	61 Participants
Baseline Blood Eosinophil Count <0.15 Giga/L	38 Participants	22 Participants	60 Participants
Baseline Blood Eosinophil Count >=0.3 Giga/L	41 Participants	48 Participants	89 Participants
Baseline Optimized Daily OCS Dose	11.75 mg/day STANDARD_DEVIATION 6.31	10.75 mg/day STANDARD_DEVIATION 5.9	11.26 mg/day STANDARD_DEVIATION 6.12
Daily OCS Dose at Visit 1 (i.e. preoptimization)	11.83 mg/day STANDARD_DEVIATION 6.02	11.79 mg/day STANDARD_DEVIATION 6.4	11.81 mg/day STANDARD_DEVIATION 6.2
Ethnicity (NIH/OMB) Hispanic or Latino	22 Participants	23 Participants	45 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	85 Participants	80 Participants	165 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	2 Participants	0 Participants	2 Participants
Race/Ethnicity, Customized Asian/Oriental	2 Participants	0 Participants	2 Participants
Race/Ethnicity, Customized Black/of African descent	1 Participants	4 Participants	5 Participants
Race/Ethnicity, Customized Caucasian/White	100 Participants	97 Participants	197 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized Other	2 Participants	1 Participants	3 Participants
Sex: Female, Male Female	65 Participants	62 Participants	127 Participants
Sex: Female, Male Male	42 Participants	41 Participants	83 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 107	0 / 103
other Total, other adverse events	30 / 107	29 / 103
serious Total, serious adverse events	6 / 107	9 / 103

Outcome results

Primary

Percentage Reduction From Baseline in Oral Corticosteroids (OCS) Dose at Week 24 While Maintaining Asthma Control

Percentage reduction of OCS dose was calculated as (optimized OCS dose \[mg/day\] at baseline - final OCS dose at Week 24)/optimized OCS dose at baseline x 100. Result is presented as Least Squares Mean (Standard Error) percentage reduction from baseline derived from ANCOVA model with missing data multiply imputed.

Time frame: Baseline, Week 24

Population: Analysis was performed on intent-to-treat (ITT) population which included randomized population analysed according to the treatment group allocated by randomization regardless of whether the treatment kit was used or not.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo q2w	Percentage Reduction From Baseline in Oral Corticosteroids (OCS) Dose at Week 24 While Maintaining Asthma Control	41.85 Percentage reduction from baseline	Standard Error 4.57
Dupilumab 300 mg q2w	Percentage Reduction From Baseline in Oral Corticosteroids (OCS) Dose at Week 24 While Maintaining Asthma Control	70.09 Percentage reduction from baseline	Standard Error 4.9

Comparison: The outcome measure was analyzed using analysis of covariance (ANCOVA) model which included percentage reduction of OCS dose at Week 24 as the response variable, and treatment group, baseline eosinophil level, optimized OCS dose at baseline, region as covariates. Missing data was imputed using a pattern mixture model by multiple imputation approach.p-value: <0.000195% CI: [15.81, 40.67]ANCOVA

Primary

Supplementary Presentation of Primary Outcome Measure Data: Median Percentage Reduction From Baseline in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control

The Primary Outcome Measure (Percentage Reduction From Baseline in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control) is summarized above, as LS Mean (SE). Table below provides a supplementary presentation of the Primary Outcome Measure data; result is presented as median (inter-quartile range). Percentage reduction of OCS dose was calculated as (optimized OCS dose \[mg/day\] at baseline - final OCS dose at Week 24)/optimized OCS dose at baseline x 100.

Time frame: Baseline, Week 24

Population: Analysis population included ITT patients with available data.

Arm	Measure	Value (MEDIAN)
Placebo q2w	Supplementary Presentation of Primary Outcome Measure Data: Median Percentage Reduction From Baseline in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control	50.0 percentage reduction from baseline
Dupilumab 300 mg q2w	Supplementary Presentation of Primary Outcome Measure Data: Median Percentage Reduction From Baseline in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control	100.0 percentage reduction from baseline

Secondary

Absolute Reduction From Baseline in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control

Absolute reduction was calculated by subtracting Week 24 value from baseline value.

Time frame: Baseline and Week 24

Population: Analysis was performed on ITT population but not included in the hierarchical testing procedure. Here, number analyzed= participants with available data for specified categories.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo q2w	Absolute Reduction From Baseline in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control	Baseline	11.75 mg/day	Standard Deviation 6.31
Placebo q2w	Absolute Reduction From Baseline in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control	Week 24	6.32 mg/day	Standard Deviation 6.75
Placebo q2w	Absolute Reduction From Baseline in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control	Absolute reduction at Week 24	5.45 mg/day	Standard Deviation 6.8
Dupilumab 300 mg q2w	Absolute Reduction From Baseline in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control	Baseline	10.75 mg/day	Standard Deviation 5.9
Dupilumab 300 mg q2w	Absolute Reduction From Baseline in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control	Week 24	3.13 mg/day	Standard Deviation 5.44
Dupilumab 300 mg q2w	Absolute Reduction From Baseline in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control	Absolute reduction at Week 24	7.66 mg/day	Standard Deviation 6.1

Secondary

Percentage of Participants Achieving >= 50% Reduction in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control

Participants were classified according to the binary status of whether or not the 50% OCS dose reduction criterion was achieved at week 24.

Time frame: Week 24

Population: Analysis was performed on ITT population.

Arm	Measure	Value (NUMBER)
Placebo q2w	Percentage of Participants Achieving >= 50% Reduction in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control	53.3 percentage of participants
Dupilumab 300 mg q2w	Percentage of Participants Achieving >= 50% Reduction in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control	79.6 percentage of participants

Comparison: The outcome measure was analyzed using a logistic regression model. The model included the binary status of whether or not a participant achieved the 50% OCS dose reduction criterion as the response variable, and treatment groups, optimized OCS dose at baseline, regions, and baseline eosinophil level subgroups as covariates. Missing data was imputed by using a pattern mixture model by multiple imputation approach.p-value: <0.000195% CI: [2.06, 7.67]Regression, Logistic

Secondary

Percentage of Participants Achieving a Reduction in Oral Corticosteroids Dose to <5 mg/Day at Week 24 While Maintaining Asthma Control

Participants were classified according to the binary status of whether or not the reduction of OCS dose to \<5 mg/day was achieved at Week 24.

Time frame: Week 24

Population: Analysis was performed on ITT population.

Arm	Measure	Value (NUMBER)
Placebo q2w	Percentage of Participants Achieving a Reduction in Oral Corticosteroids Dose to <5 mg/Day at Week 24 While Maintaining Asthma Control	37.4 percentage of participants
Dupilumab 300 mg q2w	Percentage of Participants Achieving a Reduction in Oral Corticosteroids Dose to <5 mg/Day at Week 24 While Maintaining Asthma Control	71.8 percentage of participants

Comparison: The outcome measure was analyzed using a logistic regression model. The model included the binary status of whether or not a participant achieved a reduction of OCS dose to \<5 mg/day at Week 24 as the response variable, treatment groups, optimized OCS dose at baseline, regions, and baseline eosinophil level subgroups as covariates. Missing data was imputed by using a pattern mixture model by multiple imputation approach.p-value: <0.000195% CI: [2.39, 8.39]Regression, Logistic

Secondary

Percentage of Participants Achieving Maximum Possible Reduction in Oral Corticosteroids Dose Per Protocol at Week 24 While Maintaining Asthma Control

For all participants except those with baseline OCS dose at 35 mg/day, the maximum possible reduction corresponds to reduction to 0 mg/day (no longer requiring OCS). For participants starting with 35 mg/day at baseline, the maximum possible reduction is 32.5 mg/day (i.e. minimum dose per protocol is 2.5 mg).

Time frame: Week 24

Population: Analysis was performed on ITT population.

Arm	Measure	Value (NUMBER)
Placebo q2w	Percentage of Participants Achieving Maximum Possible Reduction in Oral Corticosteroids Dose Per Protocol at Week 24 While Maintaining Asthma Control	29.9 percentage of participants
Dupilumab 300 mg q2w	Percentage of Participants Achieving Maximum Possible Reduction in Oral Corticosteroids Dose Per Protocol at Week 24 While Maintaining Asthma Control	52.4 percentage of participants

Comparison: The outcome was analyzed using a logistic regression model. The model included binary status of whether or not a participant achieved their maximum possible reduction of OCS dose per protocol at Week 24 as the response variable, treatment groups, optimized OCS dose at baseline, regions, and baseline eosinophil level subgroups as covariates. Missing data was imputed by using a pattern mixture model by multiple imputation approach.p-value: 0.002495% CI: [1.4, 4.73]Regression, Logistic

Secondary

Percentage of Participants Who No Longer Required Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control

Participants were classified according to the binary status of whether or not the participant still required OCS at Week 24 while maintaining asthma control.

Time frame: Week 24

Population: Analysis was performed on ITT population with baseline OCS dose less than or equal to 30 mg/day.

Arm	Measure	Value (NUMBER)
Placebo q2w	Percentage of Participants Who No Longer Required Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control	29.2 percentage of participants
Dupilumab 300 mg q2w	Percentage of Participants Who No Longer Required Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control	52.4 percentage of participants

Comparison: The outcome measure was analyzed using a logistic regression model. The model included the binary status of whether or not a participant no longer required OCS at Week 24 as the response variable, and treatment groups, optimized OCS dose at baseline, regions, and baseline eosinophil level subgroups as covariates. Missing data was imputed using a pattern mixture model by multiple imputation approach.p-value: 0.001595% CI: [1.47, 5.1]Regression, Logistic

Other Pre-specified

Annualized Rate of Severe Exacerbation Events During The 24-Week Treatment Period

A severe asthma exacerbation event was defined as a deterioration of asthma during the 24-week treatment period requiring: use of systemic corticosteroids for \>=3 days (at least double the dose currently used); and/or hospitalization related to asthma symptoms or emergency room visit because of asthma requiring intervention with a systemic corticosteroid treatment. Annualized event rate was the total number of exacerbations that occurred during the treatment period divided by the total number of participant-years treated.

Time frame: Baseline to Week 24

Population: Analysis was performed ITT population.

Arm	Measure	Value (NUMBER)
Placebo q2w	Annualized Rate of Severe Exacerbation Events During The 24-Week Treatment Period	1.597 Exacerbation per participant-year
Dupilumab 300 mg q2w	Annualized Rate of Severe Exacerbation Events During The 24-Week Treatment Period	0.649 Exacerbation per participant-year

Other Pre-specified

Change From Baseline in Asthma Control Questionnaire 5-Question Version (ACQ-5) Score at Weeks 2, 4, 8, 12, 16, 20, and 24

The ACQ-5 has 5 questions, reflecting top-scoring 5 asthma symptoms: woken at night by symptoms, wake in mornings with symptoms, limitation of daily activities, shortness of breath and wheeze. Participants were asked to recall how their asthma had been during previous week and to respond to each of 5 symptom questions on a 7-point scale ranged from 0 (no impairment) to 6 (maximum impairment). ACQ-5 total score was mean of scores of all 5 questions and, therefore, ranged from 0 (totally controlled) to 6 (severely uncontrolled). Higher score indicated lower asthma control.

Time frame: Baseline and at Weeks 2, 4, 8, 12, 16, 20, and 24

Population: Analysis was performed on ITT population. Here, number analyzed = participants with available data for specified categories.

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo q2w	Change From Baseline in Asthma Control Questionnaire 5-Question Version (ACQ-5) Score at Weeks 2, 4, 8, 12, 16, 20, and 24	Change at Week 8	-0.39 score on a scale	Standard Deviation 1.13
Placebo q2w	Change From Baseline in Asthma Control Questionnaire 5-Question Version (ACQ-5) Score at Weeks 2, 4, 8, 12, 16, 20, and 24	Change at Week 16	-0.57 score on a scale	Standard Deviation 1.05
Placebo q2w	Change From Baseline in Asthma Control Questionnaire 5-Question Version (ACQ-5) Score at Weeks 2, 4, 8, 12, 16, 20, and 24	Change at Week 4	-0.36 score on a scale	Standard Deviation 0.81
Placebo q2w	Change From Baseline in Asthma Control Questionnaire 5-Question Version (ACQ-5) Score at Weeks 2, 4, 8, 12, 16, 20, and 24	Change at Week 20	-0.53 score on a scale	Standard Deviation 1.09
Placebo q2w	Change From Baseline in Asthma Control Questionnaire 5-Question Version (ACQ-5) Score at Weeks 2, 4, 8, 12, 16, 20, and 24	Change at Week 12	-0.54 score on a scale	Standard Deviation 1.17
Placebo q2w	Change From Baseline in Asthma Control Questionnaire 5-Question Version (ACQ-5) Score at Weeks 2, 4, 8, 12, 16, 20, and 24	Change at Week 24	-0.57 score on a scale	Standard Deviation 1.19
Placebo q2w	Change From Baseline in Asthma Control Questionnaire 5-Question Version (ACQ-5) Score at Weeks 2, 4, 8, 12, 16, 20, and 24	Change at Week 2	-0.18 score on a scale	Standard Deviation 0.67
Dupilumab 300 mg q2w	Change From Baseline in Asthma Control Questionnaire 5-Question Version (ACQ-5) Score at Weeks 2, 4, 8, 12, 16, 20, and 24	Change at Week 24	-0.94 score on a scale	Standard Deviation 1.22
Dupilumab 300 mg q2w	Change From Baseline in Asthma Control Questionnaire 5-Question Version (ACQ-5) Score at Weeks 2, 4, 8, 12, 16, 20, and 24	Change at Week 2	-0.49 score on a scale	Standard Deviation 0.86
Dupilumab 300 mg q2w	Change From Baseline in Asthma Control Questionnaire 5-Question Version (ACQ-5) Score at Weeks 2, 4, 8, 12, 16, 20, and 24	Change at Week 4	-0.61 score on a scale	Standard Deviation 1.01
Dupilumab 300 mg q2w	Change From Baseline in Asthma Control Questionnaire 5-Question Version (ACQ-5) Score at Weeks 2, 4, 8, 12, 16, 20, and 24	Change at Week 8	-0.68 score on a scale	Standard Deviation 1.06
Dupilumab 300 mg q2w	Change From Baseline in Asthma Control Questionnaire 5-Question Version (ACQ-5) Score at Weeks 2, 4, 8, 12, 16, 20, and 24	Change at Week 12	-0.92 score on a scale	Standard Deviation 1.09
Dupilumab 300 mg q2w	Change From Baseline in Asthma Control Questionnaire 5-Question Version (ACQ-5) Score at Weeks 2, 4, 8, 12, 16, 20, and 24	Change at Week 16	-0.87 score on a scale	Standard Deviation 1.18
Dupilumab 300 mg q2w	Change From Baseline in Asthma Control Questionnaire 5-Question Version (ACQ-5) Score at Weeks 2, 4, 8, 12, 16, 20, and 24	Change at Week 20	-0.83 score on a scale	Standard Deviation 1.19

Other Pre-specified

Change From Baseline in Asthma Quality of Life Questionnaire (AQLQ) Global Score at Week 12 and Week 24

AQLQ is a disease-specific, self-administered quality of life questionnaire designed to measure functional impairments that were most important to participants with asthma. 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 a 7-point likert scale (1=maximal impairment, 7=no impairment). The 32 items of the questionnaire were averaged to produce one overall quality of life score ranging from 1 (severely impaired) to 7 (not impaired at all). Higher scores indicate better quality of life.