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

Summary
EudraCT number	2014-004940-36
Trial protocol	GB Outside EU/EEA IT DE ES PL HU
Global end of trial date	23 Nov 2017

Results information
Results version number	v2(current)
This version publication date	10 Apr 2019
First version publication date	07 Jun 2018
Other versions	v1
Version creation reason	Correction of full data set Subject Disposition corrected. Baseline Characteristics corrected.

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

EFC13579

ISRCTN number

US NCT number

NCT02414854

WHO universal trial number (UTN)

U1111-1163-1293

Other trial identifiers

Study Name: LIBERTY ASTHMA QUEST

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

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-001501-PIP02-13

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

02 Jan 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

23 Nov 2017

Was the trial ended prematurely?

Main objective of the trial

To evaluate the efficacy of dupilumab (SAR231893 [REGN668]) in subjects with persistent asthma.

Protection of trial subjects

Paediatric Subjects: The study was conducted by investigators experienced in the treatment of paediatric subjects. The parent(s) or guardian(s) as well as the children 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 minimized. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anaesthesia may have been used to minimize distress and discomfort. Adult Subjects: 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. The following applies to both Paediatric and Adult Subjects: 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

Stable dose of medium to high dose inhaled corticosteroid (ICS) in combination with a second controller medication (for example; long-acting beta agonist [LABA], long-acting muscarinic antagonist [LAMA], leukotriene receptor antagonist [LTRA] and methylxanthines) for at least 1 month prior to screening and continued throughout the study. Use of a third controller medication was also allowed. Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication.

Evidence for comparator

Actual start date of recruitment

27 Apr 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 156

Country: Number of subjects enrolled

Australia: 24

Country: Number of subjects enrolled

Brazil: 72

Country: Number of subjects enrolled

Canada: 39

Country: Number of subjects enrolled

Chile: 162

Country: Number of subjects enrolled

Colombia: 25

Country: Number of subjects enrolled

France: 30

Country: Number of subjects enrolled

Germany: 52

Country: Number of subjects enrolled

Hungary: 3

Country: Number of subjects enrolled

Italy: 18

Country: Number of subjects enrolled

Japan: 114

Country: Number of subjects enrolled

Korea, Republic of: 74

Country: Number of subjects enrolled

Mexico: 115

Country: Number of subjects enrolled

Poland: 96

Country: Number of subjects enrolled

Russian Federation: 123

Country: Number of subjects enrolled

South Africa: 61

Country: Number of subjects enrolled

Spain: 39

Country: Number of subjects enrolled

Taiwan: 8

Country: Number of subjects enrolled

Turkey: 74

Country: Number of subjects enrolled

Ukraine: 181

Country: Number of subjects enrolled

United Kingdom: 13

Country: Number of subjects enrolled

United States: 423

Worldwide total number of subjects

1902

EEA total number of subjects

251

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

107

Adults (18-64 years)

1544

From 65 to 84 years

251

85 years and over

Subject disposition

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Recruitment details

4148 subjects were screened from Apr 2015-Sep 2016. 1902 were randomized at 321 centers/22 countries. 2246 were screen failures. 1897 subjects were treated; some received a different treatment than that assigned at randomization and for adverse event (AE) analysis were allocated to treatment actually received.

Screening details

Randomization was stratified by age (<18 years, ≥18 years), blood eosinophil count (<0.3 Giga/L, ≥0.3 Giga/L), ICS dose level (medium, high), and country. Assignment to arms was done centrally using Interactive Voice/Web Response System in 2:2:1:1 ratio to Dupilumab 200 mg q2w, Dupilumab 300 mg q2w, Placebo (for 200 mg)q2w, Placebo (for 300 mg)q2w

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, Carer

Are arms mutually exclusive

Yes

Placebo (for Dupilumab 200 mg) q2w

Arm description

2 subcutaneous injections of matched Placebo (for Dupilumab 200 mg) as a loading dose on Day 1 (Week 0), followed by a single injection every 2 weeks (q2w) from Week 2 to Week 50 in combination with stable ICS and up to 2 other controller medicines (second or third controller therapy). Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication.

Arm type

Placebo

Investigational medicinal product name

Placebo (for Dupilumab 200 mg)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injection (1.14 mL) in the abdomen, upper thigh or upper arm.

Dupilumab 200 mg q2w

Arm description

Arm type

Experimental

Investigational medicinal product name

Dupilumab

Investigational medicinal product code

SAR231893, REGN668

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injection 200 mg (1.14 mL of 175 mg/mL solution) in the abdomen, upper thigh or upper arm.

Placebo (for Dupilumab 300 mg) q2w

Arm description

2 subcutaneous injections of matched Placebo (for Dupilumab 300 mg) as a loading dose on Day 1 (Week 0), followed by a single injection q2w from Week 2 to Week 50 in combination with stable ICS and up to 2 other controller medicines (second or third controller therapy). Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication.

Arm type

Placebo

Investigational medicinal product name

Placebo (for Dupilumab 300 mg)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injection (2.0 mL) in the abdomen, upper thigh or upper arm.

Dupilumab 300 mg q2w

Arm description

Arm type

Experimental

Investigational medicinal product name

Dupilumab

Investigational medicinal product code

SAR231893, REGN668

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injection 300 mg (2.0 mL of 150 mg/mL solution) in the abdomen, upper thigh or upper arm.

Number of subjects in period 1	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Started	317	631	321	633
Treated	315	629	321	632
Completed	295	586	301	582
Not completed	22	45	20	51
Other than specified above	12	37	17	37
Adverse event	9	7	1	12
Poor compliance to protocol	1	1	2	2

Baseline characteristics

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Reporting group title

Placebo (for Dupilumab 200 mg) q2w

Reporting group description

Reporting group title

Dupilumab 200 mg q2w

Reporting group description

Reporting group title

Placebo (for Dupilumab 300 mg) q2w

Reporting group description

Reporting group title

Dupilumab 300 mg q2w

Reporting group description

Reporting group values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w	Total
Number of subjects	317	631	321	633	1902
Age categorical
Units: Subjects
Adolescents (12-17 years)	21	34	18	34	107
Adults (18-64 years)	253	512	263	516	1544
From 65-84 years	43	85	40	83	251
Age continuous
Units: years
arithmetic mean (standard deviation)	48.2 ( 15.6 )	47.9 ( 15.3 )	48.2 ( 14.7 )	47.7 ( 15.6 )	-
Gender categorical
Units: Subjects
Female	198	387	218	394	1197
Male	119	244	103	239	705
Race
Units: Subjects
Caucasian/White	265	510	273	529	1577
Black/of African descent	14	33	12	21	80
Asian/Oriental	33	78	33	79	223
American Indian or Alaska Native	1	0	0	0	1
Native Hawaiian or Other Pacific Islander	0	1	0	0	1
Other	4	9	3	4	20
Ethnicity
Units: Subjects
Hispanic	81	171	79	159	490
Not Hispanic	236	460	242	474	1412
Blood Eosinophil Group
Units: Subjects
<0.15 Giga/L	85	193	83	181	542
≥0.15 - <0.3 Giga/L	84	173	95	175	527
≥0.3 Giga/L	148	264	142	277	831
Missing	0	1	1	0	2
ICS Dose Level
Units: Subjects
High	172	317	167	323	979
Medium	144	310	151	303	908
Low	1	4	3	7	15

End points

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Reporting group title

Placebo (for Dupilumab 200 mg) q2w

Reporting group description

Reporting group title

Dupilumab 200 mg q2w

Reporting group description

Reporting group title

Placebo (for Dupilumab 300 mg) q2w

Reporting group description

Reporting group title

Dupilumab 300 mg q2w

Reporting group description

Primary: Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: Intent-to-Treat (ITT) Population

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End point title

Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: Intent-to-Treat (ITT) Population

End point description

A severe exacerbation was defined as a deterioration of asthma requiring: use of systemic corticosteroids for ≥3 days; or hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids. Annualized event rate was the total number of exacerbations that occurred during the treatment period divided by the total number of subject-years treated. Analysis was performed on ITT population that included all randomized population analyzed according to the treatment group allocated by randomization.

End point type

Primary

End point timeframe

Baseline to Week 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	317	631	321	633
Units: Exacerbation per subject-year
number (confidence interval 95%)	0.871 (0.724 to 1.048)	0.456 (0.389 to 0.534)	0.970 (0.810 to 1.160)	0.524 (0.450 to 0.611)

Dupilumab 300 mg q2w vs Placebo (for 300 mg) q2w

Statistical analysis description

Analysis was performed using negative binomial model with total number of events onset from randomization up to Week 52 or last contact date (whichever comes earlier) as response variable; with 4 treatment groups, age, region, baseline eosinophil strata, baseline ICS dose level, number of severe exacerbation events within 1 year prior to study as covariates; and log transformed standardized observation duration as an offset variable. Here, it is test no. 1 of testing order.

Comparison groups

Dupilumab 300 mg q2w v Placebo (for Dupilumab 300 mg) q2w

Number of subjects included in analysis

954

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

< 0.0001 ^[2]

Method

Negative binomial regression model

Parameter type

Relative risk

Point estimate

0.54

Confidence interval

level

95%

sides

2-sided

lower limit

0.43

upper limit

0.68

Notes
[1] - Hierarchical testing procedure was used to control type I error rate at 0.05 level. The procedure included the 2 primary endpoints and the first 13 secondary endpoints reported and considered 2 pair-wise comparisons: Dupilumab 200 mg q2w vs Placebo (for Dupilumab 200 mg) q2w and Dupilumab 300 mg q2w vs Placebo (for Dupilumab 300 mg) q2w. Testing order is specified in analysis description.
[2] - Hierarchical testing sequence performed continued only when previous endpoint was statistically significant at 0.05. Threshold for significance at 0.05 level.

Dupilumab 200 mg q2w vs Placebo (for 200 mg) q2w

Statistical analysis description

Comparison groups

Dupilumab 200 mg q2w v Placebo (for Dupilumab 200 mg) q2w

Number of subjects included in analysis

948

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

< 0.0001 ^[4]

Method

Negative binomial regression model

Parameter type

Relative risk

Point estimate

0.523

Confidence interval

level

95%

sides

2-sided

lower limit

0.413

upper limit

0.662

Notes
[3] - Testing according to the hierarchical testing procedure (performed only if previous endpoints were statistically significant).
[4] - Threshold for significance at 0.05 level.

Primary: Absolute Change From Baseline in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Week 12: ITT Population

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End point title

Absolute Change From Baseline in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Week 12: ITT Population

End point description

FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.

End point type

Primary

End point timeframe

Baseline, Week 12

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	317	631	321	633
Units: liter
arithmetic mean (standard deviation)
Baseline (n=317,631,321,633)	1.76 ( 0.61 )	1.78 ( 0.62 )	1.75 ( 0.57 )	1.78 ( 0.60 )
Week 12 (n=307,611,313,610)	1.92 ( 0.70 )	2.07 ( 0.76 )	1.93 ( 0.68 )	2.09 ( 0.70 )
Change at Week 12 (n=307,611,313,610)	0.15 ( 0.36 )	0.28 ( 0.45 )	0.18 ( 0.39 )	0.31 ( 0.43 )

Dupilumab 300 mg q2w vs Placebo (for 300 mg) q2w

Statistical analysis description

Analysis was performed using mixed-effect model with repeated measures (MMRM) model with change from baseline in FEV1 values up to Week 12 as response variable; and treatment, age, sex, baseline height, region, baseline eosinophil strata, baseline ICS dose level, visit, treatment by-visit interaction, baseline FEV1 value and baseline-by-visit interaction as covariates. Here, it is test no. 2 of testing order.

Comparison groups

Dupilumab 300 mg q2w v Placebo (for Dupilumab 300 mg) q2w

Number of subjects included in analysis

954

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

< 0.0001 ^[6]

Method

Mixed models analysis

Parameter type

Least Square (LS) Mean Difference

Point estimate

0.13

Confidence interval

level

95%

sides

2-sided

lower limit

0.08

upper limit

0.18

Notes
[5] - Testing according to the hierarchical testing procedure (performed only if previous endpoints were statistically significant).
[6] - Threshold for significance at 0.05 level.

Dupilumab 200 mg q2w vs Placebo (for 200 mg) q2w

Statistical analysis description

Analysis was performed using MMRM model with change from baseline in FEV1 values up to Week 12 as response variable; and treatment, age, sex, baseline height, region, baseline eosinophil strata, baseline ICS dose level, visit, treatment by-visit interaction, baseline FEV1 value and baseline-by-visit interaction as covariates. Here, it is test no. 4 of testing order.

Comparison groups

Dupilumab 200 mg q2w v Placebo (for Dupilumab 200 mg) q2w

Number of subjects included in analysis

948

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

< 0.0001 ^[8]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

0.14

Confidence interval

level

95%

sides

2-sided

lower limit

0.08

upper limit

0.19

Notes
[7] - Testing according to the hierarchical testing procedure (performed only if previous endpoints were statistically significant).
[8] - Threshold for significance at 0.05 level.

Secondary: Percent Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population

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End point title

Percent Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population

End point description

FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. Analysis was performed on ITT population. Number of subjects analyzed=subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	307	611	313	610
Units: percent change
arithmetic mean (standard deviation)	10.16 ( 23.88 )	18.74 ( 30.86 )	11.87 ( 26.40 )	20.89 ( 34.14 )

Dupilumab 300 mg q2w vs Placebo (for 300 mg) q2w

Statistical analysis description

Analysis performed using MMRM model(n=954 for 300 vs placebo)with percent change from baseline in FEV1 values up to Week 12 as response variable; & treatment, age, sex, baseline height, region, baseline eosinophil strata, baseline ICS dose level, visit, treatment by-visit interaction, baseline FEV1 value & baseline-by-visit interaction as covariates. Hierarchical testing procedure used to control type I error & handle multiple secondary endpoint analyses. Here, it is test no. 5 of testing order.

Comparison groups

Dupilumab 300 mg q2w v Placebo (for Dupilumab 300 mg) q2w

Number of subjects included in analysis

923

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

< 0.0001 ^[10]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

9.41

Confidence interval

level

95%

sides

2-sided

lower limit

5.74

upper limit

13.07

Notes
[9] - Testing according to the hierarchical testing procedure (performed only if previous endpoints were statistically significant).
[10] - Threshold for significance at 0.05 level.

Secondary: Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: ITT Population With Baseline Eosinophil ≥0.15 Giga/L

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End point title

Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: ITT Population With Baseline Eosinophil ≥0.15 Giga/L

End point description

A severe exacerbation was defined as a deterioration of asthma requiring: use of systemic corticosteroids for ≥3 days; or hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids. Annualized event rate was the total number of exacerbations that occurred during the treatment period divided by the total number of subject-years treated. Analysis was performed ITT population with baseline eosinophil ≥0.15 Giga/L.

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	232	437	237	452
Units: Exacerbation per subject-year
number (confidence interval 95%)	1.007 (0.814 to 1.245)	0.445 (0.368 to 0.538)	1.081 (0.879 to 1.329)	0.434 (0.359 to 0.525)

Dupilumab 300 mg q2w vs Placebo (for 300 mg) q2w

Statistical analysis description

Comparison groups

Dupilumab 300 mg q2w v Placebo (for Dupilumab 300 mg) q2w

Number of subjects included in analysis

689

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

P-value

< 0.0001 ^[12]

Method

Negative binomial regression model

Parameter type

Relative risk

Point estimate

0.402

Confidence interval

level

95%

sides

2-sided

lower limit

0.307

upper limit

0.526

Notes
[11] - Testing according to the hierarchical testing procedure (performed only if previous endpoints were statistically significant).
[12] - Threshold for significance at 0.05 level.

Secondary: Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil ≥0.15 Giga/L

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End point title

Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil ≥0.15 Giga/L

End point description

FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. Analysis was performed ITT population with baseline eosinophil ≥0.15 Giga/L. Here 'n' signifies number of subjects with available data for specified category.

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	232	437	237	452
Units: liter
arithmetic mean (standard deviation)
Baseline (n=232,437,237,452)	1.77 ( 0.63 )	1.81 ( 0.63 )	1.75 ( 0.55 )	1.79 ( 0.59 )
Change at Week 12 (n=224,425,229,434)	0.17 ( 0.36 )	0.34 ( 0.46 )	0.21 ( 0.38 )	0.35 ( 0.45 )

Dupilumab 300 mg q2w vs Placebo (for 300 mg) q2w

Statistical analysis description

Comparison groups

Dupilumab 300 mg q2w v Placebo (for Dupilumab 300 mg) q2w

Number of subjects included in analysis

689

Analysis specification

Pre-specified

Analysis type

superiority ^[13]

P-value

< 0.0001 ^[14]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

0.15

Confidence interval

level

95%

sides

2-sided

lower limit

0.09

upper limit

0.21

Notes
[13] - Testing according to the hierarchical testing procedure (performed only if previous endpoints were statistically significant).
[14] - Threshold for significance at 0.05 level.

Secondary: Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: ITT Population With Baseline Eosinophil ≥0.3 Giga/L

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End point title

Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: ITT Population With Baseline Eosinophil ≥0.3 Giga/L

End point description

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	148	264	142	277
Units: Exacerbation per subject-year
number (confidence interval 95%)	1.081 (0.846 to 1.382)	0.370 (0.289 to 0.475)	1.236 (0.972 to 1.571)	0.403 (0.317 to 0.512)

Dupilumab 300 mg q2w vs Placebo (for 300 mg) q2w

Statistical analysis description

Comparison groups

Dupilumab 300 mg q2w v Placebo (for Dupilumab 300 mg) q2w

Number of subjects included in analysis

419

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

P-value

< 0.0001 ^[16]

Method

Negative binomial regression model

Parameter type

Relative risk

Point estimate

0.326

Confidence interval

level

95%

sides

2-sided

lower limit

0.234

upper limit

0.454

Notes
[15] - Testing according to the hierarchical testing procedure (performed only if previous endpoints were statistically significant).
[16] - Threshold for significance at 0.05 level.

Secondary: Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil ≥0.3 Giga/L

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End point title

Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil ≥0.3 Giga/L

End point description

FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. Analysis was performed ITT population with baseline eosinophil ≥0.3 Giga/L. Here 'n' signifies number of subjects with available data for specified category.

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	148	264	142	277
Units: liter
arithmetic mean (standard deviation)
Baseline (n=148,264,142,277)	1.78 ( 0.66 )	1.81 ( 0.64 )	1.73 ( 0.54 )	1.75 ( 0.59 )
Change at Week 12 (n=144,256,139,266)	0.19 ( 0.39 )	0.39 ( 0.45 )	0.20 ( 0.40 )	0.43 ( 0.43 )

Dupilumab 300 mg q2w vs Placebo (for 300 mg) q2w

Statistical analysis description

Comparison groups

Dupilumab 300 mg q2w v Placebo (for Dupilumab 300 mg) q2w

Number of subjects included in analysis

419

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

P-value

< 0.0001 ^[18]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

0.24

Confidence interval

level

95%

sides

2-sided

lower limit

0.16

upper limit

0.32

Notes
[17] - Testing according to the hierarchical testing procedure (performed only if previous endpoints were statistically significant).
[18] - Threshold for significance at 0.05 level.

Secondary: Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: ITT Population With Baseline Eosinophil <0.3 Giga/L

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End point title

Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: ITT Population With Baseline Eosinophil <0.3 Giga/L

End point description

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	169	366	178	356
Units: Exacerbation per subject-year
number (confidence interval 95%)	0.675 (0.515 to 0.884)	0.512 (0.418 to 0.628)	0.732 (0.562 to 0.954)	0.610 (0.502 to 0.742)

Dupilumab 300 mg q2w vs Placebo (for 300 mg) q2w

Statistical analysis description

Comparison groups

Placebo (for Dupilumab 300 mg) q2w v Dupilumab 300 mg q2w

Number of subjects included in analysis

534

Analysis specification

Pre-specified

Analysis type

superiority ^[19]

P-value

= 0.2599 ^[20]

Method

Negative binomial regression model

Parameter type

Relative risk

Point estimate

0.834

Confidence interval

level

95%

sides

2-sided

lower limit

0.608

upper limit

1.144

Notes
[19] - Testing according to the hierarchical testing procedure (performed only if previous endpoints were statistically significant).
[20] - Threshold for significance at 0.05 level.

Secondary: Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: ITT Population With High Dose ICS at Baseline

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End point title

Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: ITT Population With High Dose ICS at Baseline

End point description

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	172	317	167	323
Units: Exacerbation per subject-year
number (confidence interval 95%)	1.040 (0.824 to 1.314)	0.560 (0.455 to 0.690)	1.038 (0.818 to 1.317)	0.639 (0.523 to 0.780)

No statistical analyses for this end point

Secondary: Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With High Dose ICS at Baseline

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End point title

Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With High Dose ICS at Baseline

End point description

FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. Analysis was performed on ITT population with high dose ICS at baseline. Number of subjects analysed=subjects evaluable for this endpoint at specified timepoint.

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	167	310	162	309
Units: liter
arithmetic mean (standard deviation)	0.14 ( 0.34 )	0.27 ( 0.42 )	0.20 ( 0.40 )	0.32 ( 0.43 )

No statistical analyses for this end point

Secondary: Change From Baseline in Asthma Quality of Life Questionnaire With Standardized Activities (AQLQ [S]) Self- Administered Global Score at Week 24: ITT Population

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End point title

Change From Baseline in Asthma Quality of Life Questionnaire With Standardized Activities (AQLQ [S]) Self- Administered Global Score at Week 24: ITT Population

End point description

The AQLQ is a disease-specific, self-administered quality of life questionnaire designed to measure functional impairments that are most important to subjects with asthma. The AQLQ comprises of 32 items in 4 domains: symptoms (12 items), activity limitation (11 items), emotional function (5 items), environmental stimuli (4 items). Each item is scored on a 7-point likert scale (1=maximal impairment, 7=no impairment). The 32 items of the questionnaire are averaged to produce one overall quality of life score ranging from 1 (severely impaired) to 7 (not impaired at all). Higher scores indicate better quality of life. Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	317	631	321	633
Units: scores on a scale
arithmetic mean (standard deviation)
Baseline (n=299,591,314,603)	4.26 ( 1.02 )	4.31 ( 1.08 )	4.30 ( 1.03 )	4.28 ( 1.05 )
Week 24 (n=298,592,302,596)	5.23 ( 1.07 )	5.46 ( 1.12 )	5.30 ( 1.15 )	5.47 ( 1.09 )
Change at Week 24 (n=281,560,295,569)	0.95 ( 1.03 )	1.13 ( 1.14 )	1.02 ( 1.10 )	1.17 ( 1.11 )

No statistical analyses for this end point

Secondary: Change From Baseline in AQLQ (S) Self- Administered Global Score at Week 24: ITT Population With Baseline Eosinophil ≥0.3 Giga/L

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End point title

Change From Baseline in AQLQ (S) Self- Administered Global Score at Week 24: ITT Population With Baseline Eosinophil ≥0.3 Giga/L

End point description

The AQLQ is a disease-specific, self-administered quality of life questionnaire designed to measure functional impairments that are most important to subjects with asthma. The AQLQ comprises of 32 items in 4 domains: symptoms (12 items), activity limitation (11 items), emotional function (5 items), environmental stimuli (4 items). Each item is scored on a 7-point likert scale (1=maximal impairment, 7=no impairment). The 32 items of the questionnaire are averaged to produce one overall quality of life score ranging from 1 (severely impaired) to 7 (not impaired at all). Higher scores indicate better quality of life. Analysis was performed on ITT population with baseline eosinophil ≥0.3 Giga/L. Here 'n' signifies number of subjects with available data for specified category.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	148	264	142	277
Units: scores on a scale
arithmetic mean (standard deviation)
Baseline (n=136,254,138,263)	4.24 ( 0.98 )	4.24 ( 1.11 )	4.21 ( 0.97 )	4.36 ( 1.05 )
Change at Week 24 (n=129,241,130,244)	0.97 ( 1.01 )	1.39 ( 1.15 )	1.02 ( 1.25 )	1.30 ( 1.15 )

No statistical analyses for this end point

Secondary: Change From Baseline in Asthma Control Questionnaire 5-item Version (ACQ-5) Score at Week 24: ITT Population

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End point title

Change From Baseline in Asthma Control Questionnaire 5-item Version (ACQ-5) Score at Week 24: ITT Population

End point description

The ACQ-5 has 5 questions, reflecting the top-scoring five asthma symptoms: woken at night by symptoms, wake in the mornings with symptoms, limitation of daily activities, shortness of breath and wheeze. Subjects were asked to recall how their asthma had been during the previous week and to respond to each of the five symptom questions on a 7-point scale ranged from 0 (no impairment) to 6 (maximum impairment). ACQ-5 total score was mean of the scores of all 5 questions and, therefore, ranged from 0 (totally controlled) to 6 (severely uncontrolled). Higher score indicated lower asthma control. Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	317	631	321	633
Units: scores on a scale
arithmetic mean (standard deviation)
Baseline (n=317,631,321,633)	2.71 ( 0.73 )	2.76 ( 0.80 )	2.77 ( 0.77 )	2.77 ( 0.76 )
Week 24 (n=296,590,297,585)	1.67 ( 1.06 )	1.33 ( 1.05 )	1.58 ( 1.08 )	1.37 ( 1.10 )
Change at Week 24 (n=296,590,297,585)	-1.06 ( 1.01 )	-1.43 ( 1.05 )	-1.19 ( 1.10 )	-1.38 ( 1.10 )

No statistical analyses for this end point

Secondary: Annualized Rate of Severe Exacerbation Events Resulting in Hospitalization or Emergency Room Visit During The 52-Week Treatment Period: ITT Population

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End point title

Annualized Rate of Severe Exacerbation Events Resulting in Hospitalization or Emergency Room Visit During The 52-Week Treatment Period: ITT Population

End point description

A severe exacerbation was defined as a deterioration of asthma requiring: use of systemic corticosteroids for ≥3 days; or hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids. Annualized event rate was the total number of exacerbations (resulted hospitalization or emergency room visit) that occurred during the treatment period divided by the total number of subject-years treated. Analysis was performed on ITT population.

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	317	631	321	633
Units: Exacerbation per subject-year
number (confidence interval 95%)	0.081 (0.049 to 0.135)	0.043 (0.027 to 0.068)	0.034 (0.017 to 0.066)	0.025 (0.014 to 0.043)

No statistical analyses for this end point

Secondary: Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil <0.3 Giga/L

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End point title

Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil <0.3 Giga/L

End point description

FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. Analysis was performed ITT population with baseline eosinophil <0.3 Giga/L. Number of subjects analysed=subjects evaluable for this endpoint at specified timepoint.

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	163	354	173	344
Units: liter
arithmetic mean (standard deviation)	0.12 ( 0.32 )	0.21 ( 0.43 )	0.17 ( 0.39 )	0.21 ( 0.41 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil ≥0.3 Giga/L

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End point title

Percent Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil ≥0.3 Giga/L

End point description

FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. Analysis was performed on ITT population with baseline eosinophil ≥0.3 Giga/L. Number of subjects analyzed=subjects evaluable for this endpoint at specified timepoint.

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	144	256	139	266
Units: percent change
arithmetic mean (standard deviation)	13.40 ( 27.01 )	26.41 ( 33.69 )	13.05 ( 25.27 )	30.58 ( 38.22 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With High Dose ICS at Baseline

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End point title

Percent Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With High Dose ICS at Baseline

End point description

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	167	310	162	309
Units: percent change
arithmetic mean (standard deviation)	8.47 ( 20.94 )	17.99 ( 28.43 )	13.22 ( 26.52 )	23.41 ( 37.26 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil ≥0.15 Giga/L

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End point title

Percent Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil ≥0.15 Giga/L

End point description

FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. Analysis was performed on ITT population with baseline eosinophil ≥0.15 Giga/L. Number of subjects analyzed=subjects evaluable for this endpoint at specified timepoint.

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	224	425	229	434
Units: percent change
arithmetic mean (standard deviation)	11.43 ( 24.71 )	22.04 ( 31.96 )	13.49 ( 25.18 )	24.04 ( 35.71 )

No statistical analyses for this end point

Secondary: Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Weeks 2, 4, 8, 24, 36, and 52: ITT Population

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End point title

Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Weeks 2, 4, 8, 24, 36, and 52: ITT Population

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 24, 36, and 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	317	631	321	633
Units: liter
arithmetic mean (standard deviation)
Change at Week 2 (n=315,610,313,625)	0.08 ( 0.35 )	0.22 ( 0.38 )	0.10 ( 0.34 )	0.25 ( 0.40 )
Change at Week 4 (n=307,613,311,614)	0.13 ( 0.35 )	0.24 ( 0.40 )	0.13 ( 0.34 )	0.27 ( 0.41 )
Change at Week 8 (n=305,604,311,609)	0.15 ( 0.38 )	0.28 ( 0.42 )	0.19 ( 0.40 )	0.29 ( 0.43 )
Change at Week 24 (n=300,599,296,596)	0.13 ( 0.40 )	0.31 ( 0.45 )	0.19 ( 0.44 )	0.30 ( 0.44 )
Change at Week 36 (n=289,590,301,584)	0.14 ( 0.41 )	0.31 ( 0.48 )	0.21 ( 0.42 )	0.32 ( 0.45 )
Change at Week 52 (n=240,477,250,488)	0.12 ( 0.38 )	0.31 ( 0.50 )	0.20 ( 0.42 )	0.32 ( 0.44 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Pre-Bronchodilator FEV1 at Weeks 2, 4, 8, 24, 36, and 52: ITT Population

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End point title

Percent Change From Baseline in Pre-Bronchodilator FEV1 at Weeks 2, 4, 8, 24, 36, and 52: ITT Population

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 24, 36, and 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	317	631	321	633
Units: percent change
arithmetic mean (standard deviation)
Change at Week 2 (n=315,610,313,625)	5.78 ( 23.36 )	14.32 ( 26.55 )	6.60 ( 21.84 )	17.38 ( 30.82 )
Change at Week 4 (n=307,613,311,614)	9.61 ( 25.54 )	16.11 ( 28.12 )	8.67 ( 23.55 )	18.77 ( 32.73 )
Change at Week 8 (n=305,604,311,609)	10.27 ( 25.60 )	18.81 ( 29.80 )	12.24 ( 25.78 )	19.85 ( 33.63 )
Change at Week 24 (n=300,599,296,596)	9.42 ( 26.76 )	19.76 ( 30.64 )	12.86 ( 28.14 )	20.75 ( 35.35 )
Change at Week 36 (n=289,590,301,584)	10.57 ( 26.41 )	19.92 ( 32.26 )	13.45 ( 27.69 )	22.08 ( 35.93 )
Change at Week 52 (n=240,477,250,488)	8.37 ( 23.59 )	19.96 ( 33.35 )	12.89 ( 27.70 )	21.57 ( 34.08 )

No statistical analyses for this end point

Secondary: Change From Baseline in Percent Predicted FEV1 at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

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End point title

Change From Baseline in Percent Predicted FEV1 at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 24, 36, and 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	317	631	321	633
Units: percent predicted of FEV1
arithmetic mean (standard deviation)
Change at Week 2 (n=315,610,313,625)	2.58 ( 11.36 )	7.10 ( 12.28 )	3.32 ( 10.98 )	8.44 ( 13.20 )
Change at Week 4 (n=307,613,311,614)	4.55 ( 11.69 )	7.92 ( 12.81 )	4.13 ( 11.41 )	9.20 ( 14.10 )
Change at Week 8 (n=305,604,311,609)	4.93 ( 12.30 )	9.27 ( 13.13 )	6.08 ( 12.55 )	9.70 ( 14.15 )
Change at Week 12 (n=307,611,313,610)	5.02 ( 12.10 )	9.22 ( 13.87 )	5.90 ( 13.02 )	10.28 ( 14.44 )
Change at Week 24 (n=300,599,296,596)	4.38 ( 12.85 )	9.98 ( 13.94 )	6.41 ( 14.02 )	10.14 ( 14.75 )
Change at Week 36 (n=289,590,301,584)	5.09 ( 12.99 )	10.12 ( 14.61 )	6.82 ( 13.54 )	10.94 ( 15.06 )
Change at Week 52 (n=240,477,250,488)	4.25 ( 12.06 )	10.08 ( 14.79 )	6.68 ( 13.56 )	11.02 ( 14.59 )

No statistical analyses for this end point

Secondary: Change From Baseline in Morning (AM)/Evening (PM) Peak Expiratory Flow (PEF) at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

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End point title

Change From Baseline in Morning (AM)/Evening (PM) Peak Expiratory Flow (PEF) at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

End point description

The PEF is a subject’s maximum speed of expiration, as measured with a peak flow meter. Peak flow testing for PEF was performed at home (morning and evening) while sitting or standing prior to using any medication (if needed) for asthma. Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 24, 36, and 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	317	631	321	633
Units: liters/min
arithmetic mean (standard deviation)
AM: Change at Week 2 (n=314,620,320,630)	4.19 ( 31.30 )	15.21 ( 39.45 )	3.45 ( 28.95 )	14.46 ( 36.29 )
AM: Change at Week 4 (n=313,619,319,625)	6.23 ( 42.42 )	21.81 ( 53.85 )	5.55 ( 43.69 )	19.67 ( 46.47 )
AM: Change at Week 8 (n=308,614,318,613)	7.42 ( 49.30 )	25.70 ( 58.52 )	12.22 ( 50.50 )	23.18 ( 52.65 )
AM: Change at Week 12 (n=305,608,314,608)	9.85 ( 50.40 )	27.81 ( 65.30 )	14.23 ( 56.18 )	25.88 ( 57.09 )
AM: Change at Week 24 (n=299,590,305,588)	5.55 ( 53.27 )	28.71 ( 69.64 )	15.43 ( 60.83 )	23.74 ( 63.71 )
AM: Change at Week 36 (n=289,576,297,564)	3.24 ( 61.68 )	31.19 ( 71.59 )	12.57 ( 61.88 )	23.93 ( 65.04 )
AM: Change at Week 52 (n=270,544,282,529)	2.85 ( 64.60 )	29.86 ( 75.44 )	10.99 ( 64.68 )	26.67 ( 71.63 )
PM: Change at Week 2 (n=313,617,319,629)	3.33 ( 36.81 )	13.80 ( 40.59 )	3.87 ( 33.98 )	11.35 ( 36.10 )
PM: Change at Week 4 (n=312,617,319,623)	5.01 ( 45.09 )	17.94 ( 55.30 )	2.73 ( 46.83 )	14.90 ( 47.42 )
PM: Change at Week 8 (n=308,613,315,610)	2.82 ( 50.10 )	21.06 ( 61.80 )	7.68 ( 56.73 )	17.26 ( 53.37 )
PM: Change at Week 12 (n=306,606,311,605)	3.24 ( 53.42 )	19.75 ( 68.14 )	8.52 ( 56.74 )	18.70 ( 55.60 )
PM: Change at Week 24 (n=299,583,300,585)	-4.89 ( 55.07 )	19.95 ( 71.50 )	7.56 ( 63.25 )	15.82 ( 61.91 )
PM: Change at Week 36 (n=286,570,291,557)	-6.75 ( 62.44 )	21.79 ( 75.00 )	2.64 ( 65.21 )	14.35 ( 64.66 )
PM: Change at Week 52 (n=269,526,268,523)	-6.43 ( 62.82 )	18.77 ( 77.37 )	2.83 ( 67.01 )	15.58 ( 72.51 )

No statistical analyses for this end point

Secondary: Change From Baseline in Forced Vital Capacity (FVC) at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

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End point title

Change From Baseline in Forced Vital Capacity (FVC) at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

End point description

FVC is a standard pulmonary function test used to quantify respiratory muscle weakness. FVC is the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters. Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 24, 36, and 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	317	631	321	633
Units: liter
arithmetic mean (standard deviation)
Change at Week 2 (n=315,610,313,625)	0.08 ( 0.42 )	0.23 ( 0.44 )	0.10 ( 0.37 )	0.25 ( 0.46 )
Change at Week 4 (n=307,613,311,614)	0.12 ( 0.39 )	0.26 ( 0.45 )	0.12 ( 0.38 )	0.27 ( 0.47 )
Change at Week 8 (n=305,604,311,609)	0.13 ( 0.41 )	0.28 ( 0.45 )	0.18 ( 0.42 )	0.29 ( 0.50 )
Change at Week 12 (n=307,611,313,610)	0.13 ( 0.41 )	0.29 ( 0.49 )	0.18 ( 0.44 )	0.29 ( 0.51 )
Change at Week 24 (n=300,599,296,596)	0.11 ( 0.45 )	0.29 ( 0.48 )	0.18 ( 0.46 )	0.29 ( 0.51 )
Change at Week 36 (n=289,590,301,584)	0.11 ( 0.45 )	0.30 ( 0.52 )	0.19 ( 0.47 )	0.31 ( 0.52 )
Change at Week 52 (n=240,477,250,488)	0.08 ( 0.45 )	0.29 ( 0.53 )	0.18 ( 0.45 )	0.31 ( 0.50 )

No statistical analyses for this end point

Secondary: Change From Baseline in Forced Expiratory Flow (FEF) 25-75% at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

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End point title

Change From Baseline in Forced Expiratory Flow (FEF) 25-75% at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

End point description

FEF is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. FEF25-75% is defined as the mean forced expiratory flow between the 25% and 75% of the FVC. Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 24, 36, and 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	317	631	321	633
Units: liters/sec
arithmetic mean (standard deviation)
Change at Week 2 (n=315,610,313,625)	0.09 ( 0.40 )	0.22 ( 0.47 )	0.11 ( 0.44 )	0.27 ( 0.48 )
Change at Week 4 (n=307,613,311,614)	0.16 ( 0.45 )	0.24 ( 0.48 )	0.15 ( 0.44 )	0.29 ( 0.48 )
Change at Week 8 (n=305,604,311,609)	0.18 ( 0.45 )	0.29 ( 0.52 )	0.20 ( 0.49 )	0.32 ( 0.51 )
Change at Week 12 (n=307,611,313,610)	0.18 ( 0.46 )	0.30 ( 0.53 )	0.19 ( 0.50 )	0.35 ( 0.53 )
Change at Week 24 (n=300,599,296,596)	0.17 ( 0.47 )	0.34 ( 0.57 )	0.22 ( 0.56 )	0.35 ( 0.54 )
Change at Week 36 (n=289,590,301,584)	0.18 ( 0.49 )	0.35 ( 0.59 )	0.22 ( 0.49 )	0.36 ( 0.56 )
Change at Week 52 (n=240,477,250,488)	0.16 ( 0.50 )	0.36 ( 0.63 )	0.24 ( 0.55 )	0.36 ( 0.55 )

No statistical analyses for this end point

Secondary: Change From Baseline in Post-Bronchodilator FEV1 at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

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End point title

Change From Baseline in Post-Bronchodilator FEV1 at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

End point description

FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. Analysis was performed ITT population. Here 'n' signifies number of subjects with available data for specified category.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 24, 36, and 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	317	631	321	633
Units: liter
arithmetic mean (standard deviation)
Change at Week 2 (n=310,609,311,617)	-0.07 ( 0.31 )	0.10 ( 0.37 )	-0.04 ( 0.33 )	0.09 ( 0.34 )
Change at Week 4 (n=308,614,311,615)	-0.02 ( 0.31 )	0.10 ( 0.39 )	-0.04 ( 0.36 )	0.10 ( 0.36 )
Change at Week 8 (n=305,607,305,604)	-0.02 ( 0.31 )	0.12 ( 0.40 )	0.03 ( 0.35 )	0.11 ( 0.37 )
Change at Week 12 (n=305,610,313,612)	-0.02 ( 0.33 )	0.12 ( 0.40 )	0.01 ( 0.35 )	0.11 ( 0.38 )
Change at Week 24 (n=302,599,302,601)	-0.05 ( 0.36 )	0.13 ( 0.43 )	-0.01 ( 0.40 )	0.10 ( 0.39 )
Change at Week 36 (n=290,586,302,589)	-0.03 ( 0.34 )	0.12 ( 0.44 )	0.01 ( 0.38 )	0.11 ( 0.39 )
Change at Week 52 (n=239,499,255,494)	-0.08 ( 0.38 )	0.12 ( 0.44 )	-0.02 ( 0.39 )	0.11 ( 0.40 )

No statistical analyses for this end point

Secondary: Annualized Rate of Loss of Asthma Control (LOAC) Event During The 52-Week Treatment Period: ITT Population

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End point title

Annualized Rate of Loss of Asthma Control (LOAC) Event During The 52-Week Treatment Period: ITT Population

End point description

LOAC was defined as any of the following: >=6 additional reliever puffs of salbutamol/albuterol or levosalbutamol/levalbuterol in a 24-hour period (compared to baseline) on 2 consecutive days; increase in ICS >=4 times the dose at randomization; use of systemic corticosteroids for >=3 days; hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids. Annualized event rate was the total number of LOAC that occurred during the treatment period divided by the total number of subject-years treated. Analysis was performed on ITT population.

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	317	631	321	633
Units: LOAC per subject-year
number (confidence interval 95%)	2.972 (2.573 to 3.432)	1.853 (1.654 to 2.076)	2.965 (2.572 to 3.420)	1.740 (1.554 to 1.947)

No statistical analyses for this end point

Secondary: Time to First Severe Exacerbation Event: Kaplan-Meier Estimates During The 52-Week Treatment Period: ITT Population

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End point title

Time to First Severe Exacerbation Event: Kaplan-Meier Estimates During The 52-Week Treatment Period: ITT Population

End point description

The time to first severe exacerbation was defined as follows: date of the first event - randomization date +1. For subjects who had no event on or before Visit 18 (Week 52) or last contact date, the time was censored at the date of Visit 18 or the last contact date, whichever was earlier. The median time to first severe exacerbation was not estimated; therefore, the probability of severe exacerbation at Weeks 12, 24, 36, and 52, are presented as the descriptive statistics. Analysis was performed on ITT population.

End point type

Secondary

End point timeframe

Baseline up to Week 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	317	631	321	633
Units: probability of severe exacerbation
number (confidence interval 95%)
Probability at Week 12	0.165 (0.127 to 0.209)	0.094 (0.073 to 0.119)	0.193 (0.152 to 0.238)	0.137 (0.112 to 0.166)
Probability at Week 24	0.275 (0.227 to 0.326)	0.177 (0.148 to 0.208)	0.297 (0.247 to 0.347)	0.211 (0.180 to 0.243)
Probability at Week 36	0.364 (0.311 to 0.418)	0.235 (0.203 to 0.270)	0.376 (0.322 to 0.428)	0.268 (0.234 to 0.303)
Probability at Week 52	0.434 (0.378 to 0.489)	0.295 (0.259 to 0.331)	0.437 (0.382 to 0.491)	0.325 (0.288 to 0.362)

No statistical analyses for this end point

Secondary: Time to First LOAC Event: Kaplan-Meier Estimates During The 52-Week Treatment Period: ITT Population

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End point title

Time to First LOAC Event: Kaplan-Meier Estimates During The 52-Week Treatment Period: ITT Population

End point description

The time to first LOAC event was defined as follows: date of the first event - first dose date +1. For subjects who had no event on or before last dose date + 14 days or last contact date, the time was censored at the last dose date + 14 days or the last contact date, whichever was earlier. Analysis was performed on ITT population.

End point type

Secondary

End point timeframe

Baseline up to Week 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	317	631	321	633
Units: days
median (confidence interval 95%)	110.0 (84.00 to 144.00)	230.0 (187.00 to 276.00)	102.0 (74.00 to 130.00)	264.0 (207.00 to 319.00)

No statistical analyses for this end point

Secondary: Change From Baseline in ACQ-5 Score at Weeks 2, 4, 8, 12, 36, and 52: ITT Population

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End point title

Change From Baseline in ACQ-5 Score at Weeks 2, 4, 8, 12, 36, and 52: ITT Population

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 36, and 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	317	631	321	633
Units: scores on a scale
arithmetic mean (standard deviation)
Change at Week 2 (n=304,599,305,615)	-0.52 ( 0.85 )	-0.88 ( 0.91 )	-0.58 ( 0.97 )	-0.89 ( 0.94 )
Change at Week 4 (n=297,599,305,605)	-0.76 ( 0.90 )	-1.07 ( 0.98 )	-0.77 ( 1.01 )	-1.06 ( 1.01 )
Change at Week 8 (n=301,595,310,593)	-0.94 ( 0.96 )	-1.26 ( 1.03 )	-1.05 ( 1.04 )	-1.24 ( 1.06 )
Change at Week 12 (n=303,605,312,603)	-0.98 ( 1.00 )	-1.33 ( 1.03 )	-1.09 ( 1.09 )	-1.35 ( 1.06 )
Change at Week 36 (n=285,583,299,572)	-1.21 ( 1.01 )	-1.50 ( 1.14 )	-1.22 ( 1.09 )	-1.52 ( 1.09 )
Change at Week 52 (n=236,470,245,477)	-1.07 ( 1.08 )	-1.50 ( 1.05 )	-1.25 ( 1.05 )	-1.50 ( 1.08 )

No statistical analyses for this end point

Secondary: Change From Baseline in Asthma Control Questionnaire 7-item Version (ACQ-7) Score at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

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End point title

Change From Baseline in Asthma Control Questionnaire 7-item Version (ACQ-7) Score at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

End point description

The ACQ-7 has 7 questions, the first 5 questions assess the most common asthma symptoms: woken at night by symptoms, wake in the mornings with symptoms, limitation of daily activities, shortness of breath and wheeze plus short-acting bronchodilator use, and FEV1 (pre-bronchodilator % predicted). Subjects were asked to recall how their asthma had been during the previous week and to respond to each of the five symptom questions on a 7-point scale ranged from 0 (no impairment) to 6 (maximum impairment). Clinic staff scored the FEV1% predicted on a 7-point scale. The questions were equally weighted and the ACQ-7 total score was mean of the scores of all 7 questions and, therefore, ranged from 0 (totally controlled) to 6 (severely uncontrolled). Higher score indicated lower asthma control. Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 24, 36, and 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	317	631	321	633
Units: scores on a scale
arithmetic mean (standard deviation)
Change at Week 2 (n=304,599,305,615)	-0.46 ( 0.70 )	-0.79 ( 0.77 )	-0.50 ( 0.80 )	-0.82 ( 0.81 )
Change at Week 4 (n=297,599,305,605)	-0.65 ( 0.76 )	-0.94 ( 0.85 )	-0.65 ( 0.85 )	-0.97 ( 0.87 )
Change at Week 8 (n=301,595,310,593)	-0.81 ( 0.80 )	-1.11 ( 0.90 )	-0.90 ( 0.89 )	-1.12 ( 0.92 )
Change at Week 12 (n=303,605,312,603)	-0.85 ( 0.83 )	-1.17 ( 0.90 )	-0.92 ( 0.93 )	-1.20 ( 0.92 )
Change at Week 24 (n=296,590,297,585)	-0.89 ( 0.91 )	-1.25 ( 0.92 )	-1.01 ( 0.96 )	-1.22 ( 0.96 )
Change at Week 36 (n=285,583,299,572)	-1.04 ( 0.84 )	-1.32 ( 1.01 )	-1.05 ( 0.94 )	-1.35 ( 0.95 )
Change at Week 52 (n=236,470,245,477)	-0.91 ( 0.92 )	-1.32 ( 0.91 )	-1.07 ( 0.91 )	-1.34 ( 0.93 )

No statistical analyses for this end point

Secondary: Change From Baseline in Morning Asthma Symptom Score at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

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End point title

Change From Baseline in Morning Asthma Symptom Score at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

End point description

Morning asthma symptom score was determined using AM (ante meridiem) symptom scoring system which evaluated subject’s overall asthma symptoms experienced during the night. It ranged from 0 to 4 as: 0 = No asthma symptoms, slept through the night, 1= Slept well, but some complaints in the morning, no night-time awakenings, 2= Woke up once because of asthma (including early awakening), 3= Woke up several times because of asthma (including early awakening), 4= Bad night, awake most of the night because of asthma. Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 24, 36, and 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	317	631	321	633
Units: scores on a scale
arithmetic mean (standard deviation)
Change at Week 2 (n=314,624,321,631)	-0.07 ( 0.43 )	-0.18 ( 0.49 )	-0.09 ( 0.49 )	-0.15 ( 0.50 )
Change at Week 4 (n=313,623,319,627)	-0.16 ( 0.59 )	-0.26 ( 0.59 )	-0.16 ( 0.61 )	-0.27 ( 0.64 )
Change at Week 8 (n=308,620,318,615)	-0.26 ( 0.64 )	-0.40 ( 0.68 )	-0.25 ( 0.62 )	-0.37 ( 0.70 )
Change at Week 12 (n=306,614,315,609)	-0.30 ( 0.64 )	-0.45 ( 0.71 )	-0.30 ( 0.69 )	-0.44 ( 0.72 )
Change at Week 24 (n=302,602,306,592)	-0.35 ( 0.69 )	-0.52 ( 0.76 )	-0.36 ( 0.73 )	-0.50 ( 0.73 )
Change at Week 36 (n=292,583,299,572)	-0.38 ( 0.69 )	-0.54 ( 0.81 )	-0.38 ( 0.76 )	-0.56 ( 0.77 )
Change at Week 52 (n=275,553,286,540)	-0.41 ( 0.71 )	-0.55 ( 0.84 )	-0.41 ( 0.78 )	-0.60 ( 0.79 )

No statistical analyses for this end point

Secondary: Change From Baseline in Evening Asthma Symptom Score at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

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End point title

Change From Baseline in Evening Asthma Symptom Score at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

End point description

Evening asthma symptom score was determined using PM (post meridiem) symptom scoring system which evaluated subject’s overall asthma symptoms experienced during the day. It ranged from 0 to 4 as: 0=very well, no asthma symptoms, 1=one episode of wheezing, cough, or breathlessness, 2=more than one episode of wheezing, cough, or breathlessness without interference of normal activities, 3=wheezing, cough, or breathlessness most of the day, which interfered to some extent with normal activities, 4=asthma very bad, unable to carry out daily activities as usual. Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 24, 36, and 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	317	631	321	633
Units: scores on a scale
arithmetic mean (standard deviation)
Change at Week 2 (n=313,624,320,631)	-0.05 ( 0.45 )	-0.17 ( 0.48 )	-0.06 ( 0.45 )	-0.16 ( 0.52 )
Change at Week 4 (n=313,623,319,628)	-0.11 ( 0.59 )	-0.27 ( 0.61 )	-0.14 ( 0.58 )	-0.29 ( 0.64 )
Change at Week 8 (n=308,619,318,612)	-0.24 ( 0.64 )	-0.41 ( 0.70 )	-0.22 ( 0.63 )	-0.40 ( 0.70 )
Change at Week 12 (n=307,612,314,606)	-0.26 ( 0.66 )	-0.45 ( 0.72 )	-0.30 ( 0.68 )	-0.46 ( 0.73 )
Change at Week 24 (n=301,596,301,590)	-0.33 ( 0.72 )	-0.52 ( 0.78 )	-0.36 ( 0.72 )	-0.52 ( 0.73 )
Change at Week 36 (n=289,576,292,566)	-0.39 ( 0.73 )	-0.56 ( 0.81 )	-0.39 ( 0.75 )	-0.56 ( 0.80 )
Change at Week 52 (n=274,536,270,535)	-0.41 ( 0.74 )	-0.57 ( 0.84 )	-0.42 ( 0.75 )	-0.61 ( 0.78 )

No statistical analyses for this end point

Secondary: Change From Baseline in Number of Nocturnal Awakenings Per Night at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

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End point title

Change From Baseline in Number of Nocturnal Awakenings Per Night at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

End point description

Subjects recorded every morning on awakening the number of asthma-related nocturnal awakenings requiring use of rescue medication that occurred during the previous night. Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 24, 36, and 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	317	631	321	633
Units: number of nocturnal awakenings/night
arithmetic mean (standard deviation)
Change at Week 2 (n=314,624,321,631)	-0.06 ( 0.49 )	-0.15 ( 0.55 )	-0.04 ( 0.62 )	-0.11 ( 0.67 )
Change at Week 4 (n=313,623,319,627)	-0.10 ( 0.61 )	-0.19 ( 0.66 )	-0.11 ( 0.70 )	-0.20 ( 0.67 )
Change at Week 8 (n=308,620,318,615)	-0.18 ( 0.65 )	-0.29 ( 0.72 )	-0.17 ( 0.62 )	-0.24 ( 0.72 )
Change at Week 12 (n=306,614,315,609)	-0.21 ( 0.66 )	-0.33 ( 0.75 )	-0.18 ( 0.67 )	-0.28 ( 0.73 )
Change at Week 24 (n=302,602,306,592)	-0.23 ( 0.78 )	-0.36 ( 0.81 )	-0.26 ( 0.65 )	-0.30 ( 0.73 )
Change at Week 36 (n=292,583,299,572)	-0.25 ( 0.74 )	-0.34 ( 0.81 )	-0.26 ( 0.71 )	-0.36 ( 0.74 )
Change at Week 52 (n=275,553,286,540)	-0.24 ( 0.69 )	-0.35 ( 0.88 )	-0.26 ( 0.74 )	-0.41 ( 0.78 )

No statistical analyses for this end point

Secondary: Change From Baseline in Number of Puffs of Daily Reliever Medication Used Per 24 Hours at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

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End point title

Change From Baseline in Number of Puffs of Daily Reliever Medication Used Per 24 Hours at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

End point description

Subjects might administered salbutamol/albuterol or levosalbutamol/levalbuterol as reliever medication as needed during the study. The number of salbutamol/albuterol or levosalbutamol/levalbuterol inhalations were recorded daily by the subjects in an electronic diary/peak expiratory flow (PEF) meter. In the case that Nebulizer solutions were used as an alternative delivery method, the nebulizer dose was converted to number of puffs as per following conversion factor: salbutamol/albuterol nebulizer solution (2.5 mg) corresponds to 4 puffs. Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 24, 36, and 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	317	631	321	633
Units: Number of puffs of reliever medication
arithmetic mean (standard deviation)
Change at Week 2 (n=313,623,318,630)	-0.21 ( 1.55 )	-0.56 ( 1.96 )	-0.10 ( 1.71 )	-0.47 ( 1.91 )
Change at Week 4 (n=312,622,319,626)	-0.26 ( 2.19 )	-0.68 ( 2.61 )	-0.34 ( 3.42 )	-0.73 ( 2.42 )
Change at Week 8 (n=308,617,314,607)	-0.50 ( 2.23 )	-1.02 ( 2.86 )	-0.65 ( 2.96 )	-0.94 ( 2.86 )
Change at Week 12 (n=306,610,310,603)	-0.52 ( 2.28 )	-1.23 ( 3.03 )	-0.89 ( 3.06 )	-1.08 ( 2.72 )
Change at Week 24 (n=294,588,300,582)	-0.77 ( 2.60 )	-1.27 ( 3.05 )	-0.99 ( 3.21 )	-1.15 ( 2.83 )
Change at Week 36 (n=285,564,287,558)	-0.99 ( 2.49 )	-1.30 ( 2.99 )	-1.06 ( 3.57 )	-1.23 ( 3.01 )
Change at Week 52 (n=270,522,265,521)	-0.90 ( 2.58 )	-1.45 ( 3.33 )	-1.12 ( 3.64 )	-1.39 ( 2.97 )

No statistical analyses for this end point

Secondary: Change From Baseline in AQLQ (S) Self-Administered Global Score at Weeks 12, 36, and 52: ITT Population

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End point title

Change From Baseline in AQLQ (S) Self-Administered Global Score at Weeks 12, 36, and 52: ITT Population

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 12, 36, and 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	317	631	321	633
Units: scores on a scale
arithmetic mean (standard deviation)
Change at Week 12 (n=286,573,308,586)	0.90 ( 0.97 )	1.09 ( 1.03 )	0.94 ( 1.01 )	1.09 ( 1.09 )
Change at Week 36 (n=271,554,295, 548)	1.05 ( 1.08 )	1.26 ( 1.17 )	1.08 ( 1.16 )	1.33 ( 1.15 )
Change at Week 52 (n=224,465,243,459)	1.00 ( 1.12 )	1.28 ( 1.16 )	1.02 ( 1.10 )	1.34 ( 1.16 )

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) Scores at Weeks 12, 24, 36, and 52: ITT Population

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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) Scores at Weeks 12, 24, 36, and 52: ITT Population

End point description

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. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. 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 subject’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). Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.

End point type

Secondary

End point timeframe

Baseline, Weeks 12, 24, 36, and 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	317	631	321	633
Units: scores on a scale
arithmetic mean (standard deviation)
Single Index: Change at Week 12(n=280,567,301,576)	0.07 ( 0.17 )	0.09 ( 0.18 )	0.08 ( 0.18 )	0.09 ( 0.18 )
Single Index: Change at Week 24(n=275,552,292,559)	0.07 ( 0.17 )	0.09 ( 0.17 )	0.08 ( 0.18 )	0.08 ( 0.20 )
Single Index: Change at Week 36(n=264,548,290,537)	0.08 ( 0.19 )	0.09 ( 0.20 )	0.10 ( 0.18 )	0.09 ( 0.20 )
Single Index: Change at Week 52(n=220,457,238,448)	0.07 ( 0.20 )	0.10 ( 0.19 )	0.08 ( 0.19 )	0.10 ( 0.20 )
VAS Score: Change at Week 12 (n=280,567,301,576)	7.69 ( 17.43 )	11.10 ( 18.90 )	6.39 ( 20.42 )	9.80 ( 19.56 )
VAS Score: Change at Week 24 (n=275,552,292,559)	8.33 ( 17.58 )	11.44 ( 18.48 )	8.59 ( 20.37 )	9.21 ( 19.61 )
VAS Score: Change at Week 36 (n=264,548,290,537)	9.70 ( 18.24 )	11.61 ( 19.09 )	9.31 ( 20.09 )	11.41 ( 19.40 )
VAS Score: Change at Week 52 (n=220,457,238,448)	8.35 ( 18.51 )	12.98 ( 18.71 )	9.52 ( 20.81 )	11.90 ( 19.60 )

No statistical analyses for this end point

Secondary: Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Total Score at Weeks 12, 24, 36, and 52: ITT Population

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End point title

Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Total Score at Weeks 12, 24, 36, and 52: ITT Population

End point description

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. The anxiety/depression score is the sum of the scores of the 7 related items; one can score between 0 and 21 for either anxiety or depression. 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. Analysis was performed on ITT population; 29 participants in Japan who received an incorrectly translated HADS questionnaire were excluded. Here 'n' signifies number of subjects with available data for specified category.

End point type

Secondary

End point timeframe

Baseline, Weeks 12, 24, 36, and 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	311	621	317	624
Units: scores on a scale
arithmetic mean (standard deviation)
Change at Week 12 (n=274,551,297,569)	-2.11 ( 5.29 )	-1.91 ( 5.65 )	-1.55 ( 6.11 )	-1.98 ( 5.89 )
Change at Week 24 (n=270,537,286,552)	-2.17 ( 5.71 )	-1.93 ( 5.97 )	-1.73 ( 6.36 )	-1.88 ( 6.39 )
Change at Week 36 (n=260,535,286,532)	-2.52 ( 5.89 )	-2.02 ( 6.34 )	-2.67 ( 6.80 )	-2.13 ( 6.67 )
Change at Week 52 (n=213,443,234,438)	-2.00 ( 6.29 )	-2.36 ( 6.28 )	-1.86 ( 6.79 )	-2.17 ( 7.04 )

No statistical analyses for this end point

Secondary: Change From Baseline in 22-Item Sino Nasal Outcome Test (SNOT-22) Score at Weeks 12, 24, 36, and 52: ITT Population With Bilateral Nasal Polyposis/Chronic Rhinosinusitis

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End point title

Change From Baseline in 22-Item Sino Nasal Outcome Test (SNOT-22) Score at Weeks 12, 24, 36, and 52: ITT Population With Bilateral Nasal Polyposis/Chronic Rhinosinusitis

End point description

The SNOT-22 is a validated measure of health related quality of life in sinonasal 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. Analysis was performed on ITT population with bilateral nasal polyposis/chronic rhinosinusitis. Here 'n' signifies number of subjects with available data for specified category.

End point type

Secondary

End point timeframe

Baseline, Weeks 12, 24, 36, and 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	63	126	70	123
Units: scores on a scale
arithmetic mean (standard deviation)
Change at Week 12 (n=51,113,61,102)	-6.82 ( 17.19 )	-13.55 ( 16.85 )	-11.30 ( 16.11 )	-16.07 ( 20.54 )
Change at Week 24 (n=52,111,58,102)	-7.21 ( 17.10 )	-14.68 ( 18.77 )	-9.55 ( 16.04 )	-17.41 ( 20.81 )
Change at Week 36 (n=49,111,57,100)	-6.10 ( 19.03 )	-15.23 ( 18.20 )	-8.51 ( 20.36 )	-18.86 ( 21.34 )
Change at Week 52 (n=42,89,49,85)	-6.95 ( 17.10 )	-15.78 ( 17.72 )	-9.98 ( 18.01 )	-19.81 ( 22.39 )

No statistical analyses for this end point

Secondary: Change From Baseline in Standardized Rhinoconjunctivitis Quality Of Life Questionnaire, Ages 12+ (RQLQ[S]+12) Score at Weeks 12, 24, 36, and 52: ITT Population With Comorbid Allergic Rhinitis

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End point title

Change From Baseline in Standardized Rhinoconjunctivitis Quality Of Life Questionnaire, Ages 12+ (RQLQ[S]+12) Score at Weeks 12, 24, 36, and 52: ITT Population With Comorbid Allergic Rhinitis

End point description

RQLQ(S)+12 is a self-administered questionnaire with standardized activities developed to measure health-related quality of life signs and symptoms that are most problematic in those 12 to 75 years of age, as a result of perennial or seasonal allergic rhinitis. There are 28 items on RQLQ(S) in 7 domains: activities (3 items), sleep (3 items), non-nose/eye symptoms (7 items), practical problems (3 items), nasal symptoms (4 items), eye symptoms (4 items) and emotional (4 items). RQLQ(S)+12 responses are based on 7-point likert scale with responses ranging from 0 (not troubled) to 6 (extremely troubled). Individual items within RQLQ(S)+12 are equally weighted. The overall score is calculated as the mean score of all items. Higher scores indicated more health-related quality of life impairment (lower scores better). Analysis was performed on ITT population with comorbid allergic rhinitis. Here 'n' signifies number of subjects with available data for specified category.

End point type

Secondary

End point timeframe

Baseline, Weeks 12, 24, 36, and 52

End point values	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Number of subjects analysed	194	390	214	409
Units: scores on a scale
arithmetic mean (standard deviation)
Change at Week 12 (n=167,332,192,348)	-0.50 ( 0.98 )	-0.70 ( 0.99 )	-0.44 ( 1.05 )	-0.64 ( 1.06 )
Change at Week 24 (n=164,322,182,342)	-0.50 ( 0.92 )	-0.73 ( 1.09 )	-0.54 ( 1.10 )	-0.60 ( 1.10 )
Change at Week 36 (n=158,323,184,332)	-0.56 ( 0.96 )	-0.78 ( 1.15 )	-0.58 ( 1.20 )	-0.75 ( 1.12 )
Change at Week 52 (n=129,263,149,274)	-0.41 ( 0.97 )	-0.90 ( 1.17 )	-0.47 ( 1.33 )	-0.76 ( 1.13 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Week 64) or entry in the LTS12551 open-label extension study regardless of seriousness or relationship to investigational product.

Adverse event reporting additional description

Reported AEs are treatment emergent AEs that developed/worsened during ‘treatment-emergent period’ (from first dose of IMP until 98 days after last dose of IMP or entry in the LTS12551 study). Safety population: all subjects who received at least 1 dose or part of a dose of IMP, analyzed according to treatment that subjects actually received.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Placebo (for Dupilumab 200 mg) q2w

Reporting group description

2 subcutaneous injections of matched Placebo (for Dupilumab 200 mg) as a loading dose on Day 1 (Week 0), followed by a single injection q2w from Week 2 to Week 50 in combination with stable ICS and up to 2 other controller medicines (second or third controller therapy). Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication. 2 subjects were excluded, who were randomized to this arm but received single injection of Dupilumab 200 mg q2w and 300 mg q2w, respectively.

Reporting group title

Dupilumab 200 mg q2w

Reporting group description

2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1 (Week 0), followed by a single 200 mg injection q2w from Week 2 to Week 50 in combination with stable ICS and up to 2 other controller medicines (second or third controller therapy). Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication. 2 subject were included, who were randomized to Placebo (for Dupilumab 200 mg) arm and Dupilumab 300 mg arm, respectively but both received Dupilumab 200 mg.

Reporting group title

Placebo (for Dupilumab 300 mg) q2w

Reporting group description

Reporting group title

Dupilumab 300 mg q2w

Reporting group description

2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1 (Week 0), followed by a single 300 mg injection q2w from Week 2 to Week 50 in combination with stable ICS and up to 2 other controller medicines (second or third controller therapy). Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication. 1 subject was excluded, who was randomized to this arm but received single injection of Dupilumab 200 mg q2w. 1 subject was included, who was randomized to Placebo (for Dupilumab 200 mg) arm but received Dupilumab 300 mg.

Serious adverse events	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Total subjects affected by serious adverse events
subjects affected / exposed	26 / 313 (8.31%)	51 / 631 (8.08%)	28 / 321 (8.72%)	56 / 632 (8.86%)
number of deaths (all causes)	3	1	0	5
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma Of Colon
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anaplastic Thyroid Cancer
subjects affected / exposed	1 / 313 (0.32%)	0 / 631 (0.00%)	0 / 321 (0.00%)	0 / 632 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Basal Cell Carcinoma
subjects affected / exposed	0 / 313 (0.00%)	2 / 631 (0.32%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast Cancer
subjects affected / exposed	1 / 313 (0.32%)	0 / 631 (0.00%)	1 / 321 (0.31%)	0 / 632 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clear Cell Renal Cell Carcinoma
subjects affected / exposed	1 / 313 (0.32%)	0 / 631 (0.00%)	0 / 321 (0.00%)	0 / 632 (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
Dysplastic Naevus
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Haemangioblastoma
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Malignant Melanoma
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	2 / 632 (0.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Papillary Thyroid Cancer
subjects affected / exposed	1 / 313 (0.32%)	0 / 631 (0.00%)	0 / 321 (0.00%)	0 / 632 (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
Rectal Adenocarcinoma
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Small Intestine Carcinoma
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Uterine Leiomyoma
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	1 / 321 (0.31%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Hypotension
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	1 / 321 (0.31%)	0 / 632 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombophlebitis Superficial
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	1 / 313 (0.32%)	0 / 631 (0.00%)	0 / 321 (0.00%)	0 / 632 (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
Pregnancy, puerperium and perinatal conditions
Abortion Threatened
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	1 / 321 (0.31%)	0 / 632 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ectopic Pregnancy
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	1 / 321 (0.31%)	0 / 632 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest Pain
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Impaired Healing
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injection Site Erythema
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injection Site Inflammation
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injection Site Oedema
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Non-Cardiac Chest Pain
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	1 / 321 (0.31%)	0 / 632 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic Reaction
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anaphylactic Shock
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Social circumstances
Pregnancy Of Partner
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Victim Of Sexual Abuse
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Reproductive system and breast disorders
Cervical Cyst
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian Cyst
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	10 / 313 (3.19%)	11 / 631 (1.74%)	5 / 321 (1.56%)	7 / 632 (1.11%)
occurrences causally related to treatment / all	0 / 12	0 / 14	0 / 5	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Eosinophilic Pneumonia Chronic
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	1 / 321 (0.31%)	0 / 632 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Interstitial Lung Disease
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Laryngeal Oedema
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Nasal Polyps
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Noninfective Bronchitis
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Pleurisy
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax Spontaneous
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary Embolism
subjects affected / exposed	1 / 313 (0.32%)	1 / 631 (0.16%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Respiratory Depression
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Psychiatric disorders
Adjustment Disorder With Depressed Mood
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Anxiety
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	1 / 321 (0.31%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Completed Suicide
subjects affected / exposed	1 / 313 (0.32%)	0 / 631 (0.00%)	0 / 321 (0.00%)	0 / 632 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Depression
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Major Depression
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Investigations
Alanine Aminotransferase Increased
subjects affected / exposed	0 / 313 (0.00%)	2 / 631 (0.32%)	0 / 321 (0.00%)	0 / 632 (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
Injury, poisoning and procedural complications
Concussion
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	1 / 321 (0.31%)	0 / 632 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Contusion
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Facial Bones Fracture
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	2 / 632 (0.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Femur Fracture
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fibula Fracture
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	1 / 321 (0.31%)	0 / 632 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Foot Fracture
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Ligament Rupture
subjects affected / exposed	1 / 313 (0.32%)	0 / 631 (0.00%)	0 / 321 (0.00%)	0 / 632 (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 Limb Fracture
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Multiple Injuries
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Pneumothorax Traumatic
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	1 / 321 (0.31%)	0 / 632 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post-Traumatic Pain
subjects affected / exposed	1 / 313 (0.32%)	0 / 631 (0.00%)	0 / 321 (0.00%)	0 / 632 (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
Postoperative Thoracic Procedure Complication
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	1 / 321 (0.31%)	0 / 632 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Procedural Pneumothorax
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	1 / 321 (0.31%)	0 / 632 (0.00%)
occurrences causally related to treatment / all	0 / 0	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 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Rib Fracture
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	1 / 321 (0.31%)	0 / 632 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Road Traffic Accident
subjects affected / exposed	1 / 313 (0.32%)	0 / 631 (0.00%)	2 / 321 (0.62%)	0 / 632 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal Compression Fracture
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal Cord Injury
subjects affected / exposed	1 / 313 (0.32%)	0 / 631 (0.00%)	0 / 321 (0.00%)	0 / 632 (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
Ulna Fracture
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper Limb Fracture
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wrist Fracture
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Sickle Cell Anaemia
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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 Coronary Syndrome
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Acute Myocardial Infarction
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	2 / 632 (0.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Angina Pectoris
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial Fibrillation
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrioventricular Block Second Degree
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac Failure Congestive
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Cardio-Respiratory Arrest
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	2 / 632 (0.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
Coronary Artery Disease
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Ischaemic Cardiomyopathy
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial Ischaemia
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tachyarrhythmia
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Nervous system disorders
Headache
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Ischaemic Stroke
subjects affected / exposed	1 / 313 (0.32%)	0 / 631 (0.00%)	0 / 321 (0.00%)	0 / 632 (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
Loss Of Consciousness
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Migraine
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	1 / 321 (0.31%)	0 / 632 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sciatica
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Seizure
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Syncope
subjects affected / exposed	1 / 313 (0.32%)	0 / 631 (0.00%)	1 / 321 (0.31%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Eosinophilia
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	1 / 321 (0.31%)	0 / 632 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Retinal Detachment
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Retinal Tear
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal Hernia
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal Pain
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Diverticular Perforation
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Diverticulum
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	1 / 321 (0.31%)	0 / 632 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulum Intestinal
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Enteritis
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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 Volvulus
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Haemorrhoids
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	1 / 321 (0.31%)	0 / 632 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hiatus Hernia
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Impaired Gastric Emptying
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Inguinal Hernia
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	1 / 321 (0.31%)	0 / 632 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Large Intestine Polyp
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	1 / 321 (0.31%)	0 / 632 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal Motility Disorder
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal Ulcer
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis Acute
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Strangulated Umbilical Hernia
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Umbilical Hernia
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis Acute
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	2 / 632 (0.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis Chronic
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Portal Vein Thrombosis
subjects affected / exposed	1 / 313 (0.32%)	0 / 631 (0.00%)	0 / 321 (0.00%)	0 / 632 (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
Renal Infarct
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Urinary Incontinence
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Primary Hyperaldosteronism
subjects affected / exposed	1 / 313 (0.32%)	0 / 631 (0.00%)	0 / 321 (0.00%)	0 / 632 (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
Musculoskeletal and connective tissue disorders
Costochondritis
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Intervertebral Disc Protrusion
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	1 / 321 (0.31%)	0 / 632 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal Chest Pain
subjects affected / exposed	1 / 313 (0.32%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myalgia
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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	1 / 313 (0.32%)	0 / 631 (0.00%)	2 / 321 (0.62%)	2 / 632 (0.32%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pathological Fracture
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Polychondritis
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Infections and infestations
Abscess
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Atypical Pneumonia
subjects affected / exposed	1 / 313 (0.32%)	0 / 631 (0.00%)	0 / 321 (0.00%)	0 / 632 (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
Bronchitis
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	2 / 632 (0.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Capnocytophaga Infection
subjects affected / exposed	1 / 313 (0.32%)	0 / 631 (0.00%)	0 / 321 (0.00%)	0 / 632 (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
Chronic Sinusitis
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium Difficile Colitis
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	1 / 321 (0.31%)	0 / 632 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	1 / 321 (0.31%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis A
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis C
subjects affected / exposed	1 / 313 (0.32%)	0 / 631 (0.00%)	0 / 321 (0.00%)	0 / 632 (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
Mastoiditis
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Medical Device Site Infection
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Otitis Media
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Pneumonia
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	2 / 321 (0.62%)	4 / 632 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post Procedural Cellulitis
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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
Pyelonephritis
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis Chronic
subjects affected / exposed	1 / 313 (0.32%)	0 / 631 (0.00%)	0 / 321 (0.00%)	0 / 632 (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
Tick-Borne Viral Encephalitis
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	0 / 321 (0.00%)	1 / 632 (0.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper Respiratory Tract Infection
subjects affected / exposed	0 / 313 (0.00%)	0 / 631 (0.00%)	1 / 321 (0.31%)	0 / 632 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary Tract Infection
subjects affected / exposed	0 / 313 (0.00%)	1 / 631 (0.16%)	0 / 321 (0.00%)	0 / 632 (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

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Placebo (for Dupilumab 200 mg) q2w	Dupilumab 200 mg q2w	Placebo (for Dupilumab 300 mg) q2w	Dupilumab 300 mg q2w
Total subjects affected by non serious adverse events
subjects affected / exposed	185 / 313 (59.11%)	363 / 631 (57.53%)	197 / 321 (61.37%)	378 / 632 (59.81%)
Injury, poisoning and procedural complications
Accidental Overdose
subjects affected / exposed	16 / 313 (5.11%)	31 / 631 (4.91%)	16 / 321 (4.98%)	34 / 632 (5.38%)
occurrences all number	17	34	16	42
Nervous system disorders
Headache
subjects affected / exposed	26 / 313 (8.31%)	47 / 631 (7.45%)	25 / 321 (7.79%)	40 / 632 (6.33%)
occurrences all number	34	71	37	83
General disorders and administration site conditions
Injection Site Erythema
subjects affected / exposed	13 / 313 (4.15%)	76 / 631 (12.04%)	22 / 321 (6.85%)	98 / 632 (15.51%)
occurrences all number	30	329	96	353
Injection Site Oedema
subjects affected / exposed	2 / 313 (0.64%)	23 / 631 (3.65%)	5 / 321 (1.56%)	40 / 632 (6.33%)
occurrences all number	3	65	9	119
Respiratory, thoracic and mediastinal disorders
Rhinitis Allergic
subjects affected / exposed	16 / 313 (5.11%)	21 / 631 (3.33%)	15 / 321 (4.67%)	18 / 632 (2.85%)
occurrences all number	22	22	16	18
Musculoskeletal and connective tissue disorders
Back Pain
subjects affected / exposed	16 / 313 (5.11%)	30 / 631 (4.75%)	7 / 321 (2.18%)	25 / 632 (3.96%)
occurrences all number	16	35	8	28
Infections and infestations
Bronchitis
subjects affected / exposed	47 / 313 (15.02%)	73 / 631 (11.57%)	43 / 321 (13.40%)	70 / 632 (11.08%)
occurrences all number	72	98	70	104
Influenza
subjects affected / exposed	29 / 313 (9.27%)	36 / 631 (5.71%)	22 / 321 (6.85%)	38 / 632 (6.01%)
occurrences all number	35	41	28	44
Sinusitis
subjects affected / exposed	27 / 313 (8.63%)	36 / 631 (5.71%)	29 / 321 (9.03%)	26 / 632 (4.11%)
occurrences all number	40	43	35	34
Upper Respiratory Tract Infection
subjects affected / exposed	37 / 313 (11.82%)	70 / 631 (11.09%)	48 / 321 (14.95%)	77 / 632 (12.18%)
occurrences all number	57	111	77	110
Urinary Tract Infection
subjects affected / exposed	17 / 313 (5.43%)	17 / 631 (2.69%)	12 / 321 (3.74%)	20 / 632 (3.16%)
occurrences all number	25	20	12	22
Viral Upper Respiratory Tract Infection
subjects affected / exposed	60 / 313 (19.17%)	121 / 631 (19.18%)	64 / 321 (19.94%)	112 / 632 (17.72%)
occurrences all number	76	166	104	154

More information

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Were there any global substantial amendments to the protocol? Yes

21 May 2015

It included following changes: - Stratification on ICS dose (medium/high) was added; - Number of randomization strata for age, eosinophil count was reduced.

21 Sep 2015

It included following changes: - The biomarkers were splitted into 3 subgroups; - The vaccine category considered for evaluation were limited; - Clinical handling of subjects with missed dose(s) of investigational medicinal product (IMP) was clarified; - Hepatitis/human immunodeficiency virus (HIV)/anti-nuclear antibody (ANA) test at Visit 17 was added for subjects who plan to participate in the open label extension (OLE) study; - hepatitis B virus (HBV) deoxyribonucleic acid (DNA) test was added for subjects believed to be false positive for (hepatitis C virus) HBc antibody (Ab) or if the HBV serological status was unclear and HCV ribonucleic acid (RNA) was added for subjects believed to be false positive for HCV Ab at Visits 1 & 17; - The eligibility criteria regarding IMP compliance was deleted for OLE study; - Exclusion criteria regarding hepatitis and tuberculosis was modified; - Exclusion criteria regarding washout period of live attenuated vaccinations was modified; - Exclusion criteria on birth control for male subjects with a female partner of childbearing potential was modified; - Lactate dehydrogenase & differentiation in conjugated and non-conjugated bilirubin was added in case of total bilirubin above normal into serum chemistry panel; - Post-bronchodilator FEV1 at Visit 2 was added; - Spirometry operation requirement was clarified; - Table of handling procedures for dupilumab and anti-drug antibody (ADA) was removed; - Difference between withdrawal from IMP and withdrawal from the study and how this should be documented was clarified; - Local amendments 1 and 3 were incorporated into global protocol; - Lower limit of pre-bronchodilator FEV1 was removed in inclusion criteria for all subjects and the upper limit of pre-bronchodilator FEV1 was revised in inclusion criteria for adolescents to decrease screening failure rate and to adapt the criterion to adolescent values of pre-bronchodilator FEV1.

09 Aug 2016

It included following changes: Criteria for adverse event of special interest (AESI) was changed; - Study procedures were simplified for subjects who permanently discontinued the study; - Sampling times of ADA was changed, ADA response definitions were added; - Sample size and planned database lock date was modified; - Loading dose analysis was added; - The recognized controller classes were clarified; - Temporary and permanent treatment discontinuation criteria were clarified; - Hepatitis serology testing and interpretation of the results in context of eligibility criteria were clarified - Chest X-Ray or MRI (MRI for Germany only) at Visit 17 was introduced for subjects who plan to participate in the OLE study and if available chest imaging was over 12 months from entry into the open label extension study; - Height measurement was added for adolescents at each site visit for accurate calculation of spirometry parameters when doing spirometry; - Local amendments 5 and 6 were incorporated into global protocol.

26 May 2017

It included following changes: - Wording referring to the sample size was modified.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: Intent-to-Treat (ITT) Population

Primary: Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: Intent-to-Treat (ITT) Population

Primary: Absolute Change From Baseline in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Week 12: ITT Population

Primary: Absolute Change From Baseline in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Week 12: ITT Population

Secondary: Percent Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population

Secondary: Percent Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population

Secondary: Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: ITT Population With Baseline Eosinophil ≥0.15 Giga/L

Secondary: Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: ITT Population With Baseline Eosinophil ≥0.15 Giga/L

Secondary: Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil ≥0.15 Giga/L

Secondary: Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil ≥0.15 Giga/L

Secondary: Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: ITT Population With Baseline Eosinophil ≥0.3 Giga/L

Secondary: Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: ITT Population With Baseline Eosinophil ≥0.3 Giga/L

Secondary: Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil ≥0.3 Giga/L

Secondary: Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil ≥0.3 Giga/L

Secondary: Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: ITT Population With Baseline Eosinophil <0.3 Giga/L

Secondary: Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: ITT Population With Baseline Eosinophil <0.3 Giga/L

Secondary: Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: ITT Population With High Dose ICS at Baseline

Secondary: Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: ITT Population With High Dose ICS at Baseline

Secondary: Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With High Dose ICS at Baseline

Secondary: Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With High Dose ICS at Baseline

Secondary: Change From Baseline in Asthma Quality of Life Questionnaire With Standardized Activities (AQLQ [S]) Self- Administered Global Score at Week 24: ITT Population

Secondary: Change From Baseline in Asthma Quality of Life Questionnaire With Standardized Activities (AQLQ [S]) Self- Administered Global Score at Week 24: ITT Population

Secondary: Change From Baseline in AQLQ (S) Self- Administered Global Score at Week 24: ITT Population With Baseline Eosinophil ≥0.3 Giga/L

Secondary: Change From Baseline in AQLQ (S) Self- Administered Global Score at Week 24: ITT Population With Baseline Eosinophil ≥0.3 Giga/L

Secondary: Change From Baseline in Asthma Control Questionnaire 5-item Version (ACQ-5) Score at Week 24: ITT Population

Secondary: Change From Baseline in Asthma Control Questionnaire 5-item Version (ACQ-5) Score at Week 24: ITT Population

Secondary: Annualized Rate of Severe Exacerbation Events Resulting in Hospitalization or Emergency Room Visit During The 52-Week Treatment Period: ITT Population

Secondary: Annualized Rate of Severe Exacerbation Events Resulting in Hospitalization or Emergency Room Visit During The 52-Week Treatment Period: ITT Population

Secondary: Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil <0.3 Giga/L

Secondary: Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil <0.3 Giga/L

Secondary: Percent Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil ≥0.3 Giga/L

Secondary: Percent Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil ≥0.3 Giga/L

Secondary: Percent Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With High Dose ICS at Baseline

Secondary: Percent Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With High Dose ICS at Baseline

Secondary: Percent Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil ≥0.15 Giga/L

Secondary: Percent Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil ≥0.15 Giga/L

Secondary: Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Weeks 2, 4, 8, 24, 36, and 52: ITT Population

Secondary: Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Weeks 2, 4, 8, 24, 36, and 52: ITT Population

Secondary: Percent Change From Baseline in Pre-Bronchodilator FEV1 at Weeks 2, 4, 8, 24, 36, and 52: ITT Population

Secondary: Percent Change From Baseline in Pre-Bronchodilator FEV1 at Weeks 2, 4, 8, 24, 36, and 52: ITT Population

Secondary: Change From Baseline in Percent Predicted FEV1 at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

Secondary: Change From Baseline in Percent Predicted FEV1 at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

Secondary: Change From Baseline in Morning (AM)/Evening (PM) Peak Expiratory Flow (PEF) at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

Secondary: Change From Baseline in Morning (AM)/Evening (PM) Peak Expiratory Flow (PEF) at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

Secondary: Change From Baseline in Forced Vital Capacity (FVC) at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

Secondary: Change From Baseline in Forced Vital Capacity (FVC) at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

Secondary: Change From Baseline in Forced Expiratory Flow (FEF) 25-75% at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

Secondary: Change From Baseline in Forced Expiratory Flow (FEF) 25-75% at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

Secondary: Change From Baseline in Post-Bronchodilator FEV1 at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

Secondary: Change From Baseline in Post-Bronchodilator FEV1 at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

Secondary: Annualized Rate of Loss of Asthma Control (LOAC) Event During The 52-Week Treatment Period: ITT Population

Secondary: Annualized Rate of Loss of Asthma Control (LOAC) Event During The 52-Week Treatment Period: ITT Population

Secondary: Time to First Severe Exacerbation Event: Kaplan-Meier Estimates During The 52-Week Treatment Period: ITT Population

Secondary: Time to First Severe Exacerbation Event: Kaplan-Meier Estimates During The 52-Week Treatment Period: ITT Population

Secondary: Time to First LOAC Event: Kaplan-Meier Estimates During The 52-Week Treatment Period: ITT Population

Secondary: Time to First LOAC Event: Kaplan-Meier Estimates During The 52-Week Treatment Period: ITT Population

Secondary: Change From Baseline in ACQ-5 Score at Weeks 2, 4, 8, 12, 36, and 52: ITT Population

Secondary: Change From Baseline in ACQ-5 Score at Weeks 2, 4, 8, 12, 36, and 52: ITT Population

Secondary: Change From Baseline in Asthma Control Questionnaire 7-item Version (ACQ-7) Score at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

Secondary: Change From Baseline in Asthma Control Questionnaire 7-item Version (ACQ-7) Score at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

Secondary: Change From Baseline in Morning Asthma Symptom Score at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

Secondary: Change From Baseline in Morning Asthma Symptom Score at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

Secondary: Change From Baseline in Evening Asthma Symptom Score at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

Secondary: Change From Baseline in Evening Asthma Symptom Score at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

Secondary: Change From Baseline in Number of Nocturnal Awakenings Per Night at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

Secondary: Change From Baseline in Number of Nocturnal Awakenings Per Night at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

Secondary: Change From Baseline in Number of Puffs of Daily Reliever Medication Used Per 24 Hours at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

Secondary: Change From Baseline in Number of Puffs of Daily Reliever Medication Used Per 24 Hours at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

Secondary: Change From Baseline in AQLQ (S) Self-Administered Global Score at Weeks 12, 36, and 52: ITT Population

Secondary: Change From Baseline in AQLQ (S) Self-Administered Global Score at Weeks 12, 36, and 52: ITT Population

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