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Clinical Trial Results:
A 52 Week, Multicentre, Randomized, Double-Blind, Parallel Group, Placebo Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Tralokinumab in Adults and Adolescents with Asthma Inadequately Controlled on Inhaled Corticosteroid Plus Long Acting β2-Agonist (STRATOS 2)

Summary
EudraCT number	2013-005615-27
Trial protocol	GB IT CZ PL
Global end of trial date	21 Sep 2017

Results information
Results version number	v1(current)
This version publication date	07 Apr 2018
First version publication date	07 Apr 2018
Other versions

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

D2210C00008

ISRCTN number

US NCT number

NCT02194699

WHO universal trial number (UTN)

Sponsor organisation name

AstraZeneca

Sponsor organisation address

200 Orchard Ridge Drive, Gaithersburg, United States, MD 20878

Public contact

Global Clinical Lead, AstraZeneca, 1 3013980582, ClinicalTrialTransparency@astrazeneca.com

Scientific contact

Global Clinical Lead, AstraZeneca, 1 3013980582, ClinicalTrialTransparency@astrazeneca.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-000782-PIP01-09

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?

Analysis stage

Final

Date of interim/final analysis

21 Sep 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

21 Sep 2017

Global end of trial reached?

Yes

Global end of trial date

21 Sep 2017

Was the trial ended prematurely?

Main objective of the trial

To evaluate the effect of tralokinumab 300 milligrams (mg) administered every 2 weeks (Q2W) compared with placebo on the annualised asthma exacerbation rate (AAER) in 2 populations. The primary population was the biomarker positive population, defined as all patients with baseline fractional exhaled nitric oxide (FeNO) ≥37 parts per billion (ppb). The secondary population included all adult and adolescent patients with asthma that is inadequately controlled with inhaled corticosteroid (ICS) plus long-acting β2-agonists (LABA).

Protection of trial subjects

This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council for Harmonisation/Good Clinical Practice, applicable regulatory requirements and the AstraZeneca policy on Bioethics.

Background therapy

Patients were maintained on their currently prescribed ICS-LABA therapy and any additional maintenance asthma controller medications throughout the study period.

Evidence for comparator

Actual start date of recruitment

30 Oct 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 179

Country: Number of subjects enrolled

Ukraine: 153

Country: Number of subjects enrolled

Russian Federation: 130

Country: Number of subjects enrolled

Philippines: 123

Country: Number of subjects enrolled

Chile: 81

Country: Number of subjects enrolled

Mexico: 45

Country: Number of subjects enrolled

Czech Republic: 40

Country: Number of subjects enrolled

Japan: 29

Country: Number of subjects enrolled

Canada: 17

Country: Number of subjects enrolled

Italy: 14

Country: Number of subjects enrolled

South Africa: 12

Country: Number of subjects enrolled

United Kingdom: 12

Country: Number of subjects enrolled

Taiwan: 2

Worldwide total number of subjects

837

EEA total number of subjects

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)

Adults (18-64 years)

665

From 65 to 84 years

117

85 years and over

Subject disposition

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Recruitment details

First patient enrolled: 30 Oct 2014; Last Patient Last Visit: 21 Sep 2017. Study performed at 242 sites in 13 countries.

Screening details

1696 patients signed informed consent, 1163 entered screening/run-in period, 856 patients were randomised to receive investigational product (IP) and 847 received treatment (note 847 excludes 2 duplicate patients administered tralokinumab).

Period 1 title

Randomised

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Assessor

Blinding implementation details

Neither the patient nor any of the investigator or sponsor staff who are involved in the treatment or clinical evaluation and monitoring of the patients will be aware of the study treatment received. Since tralokinumab and placebo are visually distinct, IP will be handled by an unblinded IP manager at the site and will be administered by an unblinded investigational site study team member who will not be involved in the management of study patients.

Are arms mutually exclusive

Yes

Tralo 300 mg Q2W

Arm description

Tralokinumab 300 mg administered subcutaneously Q2W over a 52-week treatment period (up to 26 doses).

Arm type

Experimental

Investigational medicinal product name

Tralokinumab

Investigational medicinal product code

CAT-354

Other name

Tralo

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

150 milligrams/millilitre (mg/mL) solution for injection in an accessorised pre-filled syringe, 1.0 mL fill volume. Each patient received 2 injections of 150 mg tralokinumab at each dosing interval to receive a total dose of 300 mg.

Placebo

Arm description

Placebo administered subcutaneously Q2W over a 52-week treatment period (up to 26 doses).

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo solution for injection in an accessorised pre-filled syringe, 1.0 mL fill volume. Each patient received 2 injections of placebo at each dosing interval.

Number of subjects in period 1	Tralo 300 mg Q2W	Placebo
Started	428	428
Completed	420	417
Not completed	8	11
Did not receive treatment	1	5
Without potential for 52 weeks of IP	5	5
Duplicate patient	2	1

Period 2 title

With potential to receive 52 weeks of IP

Is this the baseline period?

Yes ^[1]

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Assessor

Blinding implementation details

Are arms mutually exclusive

Yes

Tralo 300 mg Q2W

Arm description

Tralokinumab 300 mg administered subcutaneously Q2W over a 52-week treatment period (up to 26 doses).

Arm type

Experimental

Investigational medicinal product name

Tralokinumab

Investigational medicinal product code

CAT-354

Other name

Tralo

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

150 mg/mL solution for injection in an accessorised pre-filled syringe, 1.0 mL fill volume. Each patient received 2 injections of 150 mg tralokinumab at each dosing interval to receive a total dose of 300 mg.

Placebo

Arm description

Placebo administered subcutaneously Q2W over a 52-week treatment period (up to 26 doses).

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo solution for injection in an accessorised pre-filled syringe, 1.0 mL fill volume. Each patient received 2 injections of placebo at each dosing interval.

Notes
[1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
Justification: Period 1 presents data for all patients randomised until the start of treatment and Period 2 presents data for all patients with the potential to receive 52 weeks of treatment and who received any study treatment (tralokinumab or placebo). The analysis population for baseline characteristics was the full analysis set, defined as all patients who received at least one dose of study treatment. Period 2 is therefore the baseline period.

Number of subjects in period 2	Tralo 300 mg Q2W	Placebo
Started	420	417
Completed	370	365
Not completed	50	52
Adverse event, serious fatal	1	3
Consent withdrawn by subject	14	20
Adverse event, non-fatal	4	3
Unspecified	24	16
Lost to follow-up	5	8
Protocol deviation	2	2

Baseline characteristics

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Reporting group title

Tralo 300 mg Q2W

Reporting group description

Tralokinumab 300 mg administered subcutaneously Q2W over a 52-week treatment period (up to 26 doses).

Reporting group title

Placebo

Reporting group description

Placebo administered subcutaneously Q2W over a 52-week treatment period (up to 26 doses).

Reporting group values	Tralo 300 mg Q2W	Placebo	Total
Number of subjects	420	417	837
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	29	26	55
Adults (18-64 years)	332	333	665
From 65-84 years	59	58	117
85 years and over	0	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	47.3 ± 15.6	48.0 ± 15.5	-
Sex: Female, Male
Units: Subjects
Female	276	290	566
Male	144	127	271
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	3	3	6
Asian	83	88	171
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	27	24	51
White	283	281	564
More than one race	0	0	0
Unknown or Not Reported	24	21	45

End points

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Reporting group title

Tralo 300 mg Q2W

Reporting group description

Tralokinumab 300 mg administered subcutaneously Q2W over a 52-week treatment period (up to 26 doses).

Reporting group title

Placebo

Reporting group description

Placebo administered subcutaneously Q2W over a 52-week treatment period (up to 26 doses).

Reporting group title

Tralo 300 mg Q2W

Reporting group description

Tralokinumab 300 mg administered subcutaneously Q2W over a 52-week treatment period (up to 26 doses).

Reporting group title

Placebo

Reporting group description

Placebo administered subcutaneously Q2W over a 52-week treatment period (up to 26 doses).

Subject analysis set title

Biomarker positive - Tralo 300 mg Q2W

Subject analysis set type

Sub-group analysis

Subject analysis set description

Tralokinumab 300 mg administered subcutaneously Q2W over a 52-week treatment period (up to 26 doses). Patients in the biomarker positive population (primary population) had baseline FeNO ≥37 ppb.

Subject analysis set title

Biomarker positive - Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Placebo administered subcutaneously Q2W over a 52-week treatment period (up to 26 doses). Patients in the biomarker positive population (primary population) had baseline FeNO ≥37 ppb.

Subject analysis set title

Biomarker negative - Tralo 300 mg Q2W

Subject analysis set type

Sub-group analysis

Subject analysis set description

Tralokinumab 300 mg administered subcutaneously Q2W over a 52-week treatment period (up to 26 doses). Patients in the biomarker negative population (complement population) had baseline FeNO <37 ppb.

Subject analysis set title

Biomarker negative - Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Placebo administered subcutaneously Q2W over a 52-week treatment period (up to 26 doses). Patients in the biomarker negative population (complement population) had baseline FeNO <37 ppb.

Subject analysis set title

Total - Tralo 300 mg Q2W

Subject analysis set type

Sub-group analysis

Subject analysis set description

Tralokinumab 300 mg administered subcutaneously Q2W over a 52-week treatment period (up to 26 doses). 'Total' treatment arm represents all patients receiving tralokinumab and providing pharmacokinetic (PK) blood samples.

Primary: Annualised asthma exacerbation rate (AAER) up to Week 52

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End point title

Annualised asthma exacerbation rate (AAER) up to Week 52

End point description

Asthma exacerbation was defined as a worsening of asthma that led to any of the following: • Use of systemic corticosteroids for at least 3 days; a single depo-injectable dose of corticosteroids was considered equivalent to a 3-day course of systemic corticosteroids. • An emergency room (ER) or urgent care (UC) visit (defined as evaluation and treatment for <24 hours in an ER or UC centre) due to asthma that required systemic corticosteroids (see above). • An inpatient hospitalisation (defined as admission to an inpatient facility and/or evaluation and treatment in a healthcare facility for ≥24 hours) due to asthma. AAER = number of exacerbations*365.25 / (follow-up date – date of randomisation + 1) (where maximum follow-up time for a patient was approximately 52 weeks). AAER in the tralokinumab group was compared to that seen in the placebo group up to Week 52 using a negative binomial model; rate ratios and rate reductions are both presented for comparative statistical analyses.

End point type

Primary

End point timeframe

Baseline (Week 0) up to Week 52

End point values	Tralo 300 mg Q2W	Placebo	Biomarker positive - Tralo 300 mg Q2W	Biomarker positive - Placebo	Biomarker negative - Tralo 300 mg Q2W	Biomarker negative - Placebo
Number of subjects analysed	420	417	108	121	308	290
Units: Events/year
number (confidence interval 95%)	0.84 (0.71 to 1.00)	0.82 (0.69 to 0.97)	0.80 (0.57 to 1.11)	0.95 (0.68 to 1.31)	0.87 (0.71 to 1.06)	0.77 (0.63 to 0.95)

AAER (rate ratio): Biomarker positive

Statistical analysis description

Comparison of AAER (rate ratio): Biomarker positive population; Tralo 300 mg Q2W vs placebo. A variable for the biomarker population (positive, negative) as well as a treatment-by-biomarker population interaction term was included in the analysis model.

Comparison groups

Biomarker positive - Tralo 300 mg Q2W v Biomarker positive - Placebo

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.4656

Method

Negative binomial

Parameter type

Rate ratio

Point estimate

0.84

Confidence interval

level

95%

sides

2-sided

lower limit

0.53

upper limit

1.34

Notes
[1] - The null hypothesis was that the exacerbation rate during the 52-week double-blind treatment period on tralokinumab was equal to the corresponding exacerbation rate on placebo. Covariates in the model included treatment group, geographical region, age group, periostin group at baseline and number of exacerbations in the year before the study.

AAER (rate ratio): Biomarker negative

Statistical analysis description

Comparison of AAER (rate ratio): Biomarker negative population; Tralo 300 mg Q2W vs placebo. A variable for the biomarker population (positive, negative) as well as a treatment-by-biomarker population interaction term was included in the analysis model.

Comparison groups

Biomarker negative - Tralo 300 mg Q2W v Biomarker negative - Placebo

Number of subjects included in analysis

598

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

= 0.4126

Method

Negative binomial

Parameter type

Rate ratio

Point estimate

1.13

Confidence interval

level

95%

sides

2-sided

lower limit

0.85

upper limit

1.5

Notes
[2] - The null hypothesis was that the exacerbation rate during the 52-week double-blind treatment period on tralokinumab was equal to the corresponding exacerbation rate on placebo. Covariates in the model included treatment group, geographical region, age group, periostin group at baseline and number of exacerbations in the year before the study.

AAER (rate reduction): Biomarker positive

Statistical analysis description

Comparison of AAER (rate reduction): Biomarker positive population; Tralo 300 mg Q2W vs placebo. A variable for the biomarker population (positive, negative) as well as a treatment-by-biomarker population interaction term was included in the analysis model.

Comparison groups

Biomarker positive - Tralo 300 mg Q2W v Biomarker positive - Placebo

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.4656

Method

Negative binominal

Parameter type

Rate reduction

Point estimate

15.83

Confidence interval

level

95%

sides

2-sided

lower limit

-33.71

upper limit

47.01

Notes
[3] - The null hypothesis was that the exacerbation rate during the 52-week double-blind treatment period on tralokinumab was equal to the corresponding exacerbation rate on placebo. Covariates in the model included treatment group, geographical region, age group, periostin group at baseline and number of exacerbations in the year before the study.

AAER (rate ratio): FAS

Statistical analysis description

Comparison of AAER (rate ratio): FAS population; Tralo 300 mg Q2W vs placebo.

Comparison groups

Tralo 300 mg Q2W v Placebo

Number of subjects included in analysis

837

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

P-value

= 0.8027

Method

Negative binomial

Parameter type

Rate ratio

Point estimate

1.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.81

upper limit

1.31

Notes
[4] - The null hypothesis was that the exacerbation rate during the 52-week double-blind treatment period on tralokinumab was equal to the corresponding exacerbation rate on placebo. Covariates in the model included treatment group, geographical region, age group, periostin group at baseline and number of exacerbations in the year before the study.

AAER (rate reduction): FAS

Statistical analysis description

Comparison of AAER (rate reduction): FAS population; Tralo 300 mg Q2W vs placebo.

Comparison groups

Tralo 300 mg Q2W v Placebo

Number of subjects included in analysis

837

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

= 0.8027

Method

Negative binominal

Parameter type

Rate reduction

Point estimate

-3.14

Confidence interval

level

95%

sides

2-sided

lower limit

-31.46

upper limit

19.08

Notes
[5] - The null hypothesis was that the exacerbation rate during the 52-week double-blind treatment period on tralokinumab was equal to the corresponding exacerbation rate on placebo. Covariates in the model included treatment group, geographical region, age group, periostin group at baseline and number of exacerbations in the year before the study.

Secondary: Percent change from baseline to Week 52 in pre-dose/pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV1)

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End point title

Percent change from baseline to Week 52 in pre-dose/pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV1)

End point description

Lung function was assessed by FEV1 which was measured by spirometry. Spirometry was performed by the Investigator or authorised delegate according to American Thoracic Society/European Respiratory Society guidelines. The mean percent change from baseline in pre-BD FEV1 at Week 52 is presented. Only patients with data available at the timepoints of testing were included in the analysis.

End point type

Secondary

End point timeframe

Baseline (Week 0) and Week 52

End point values	Tralo 300 mg Q2W	Placebo	Biomarker positive - Tralo 300 mg Q2W	Biomarker positive - Placebo	Biomarker negative - Tralo 300 mg Q2W	Biomarker negative - Placebo
Number of subjects analysed	384	358	99	103	282	250
Units: Percent change from baseline
arithmetic mean (standard deviation)	14.546 ± 26.065	10.528 ± 25.475	18.769 ± 29.628	16.632 ± 31.906	13.103 ± 24.641	8.395 ± 21.962

Pre-BD FEV1: Biomarker positive

Statistical analysis description

Comparison of % change from baseline in pre-dose/pre-BD FEV1 at Week 52: Biomarker positive population; Tralo 300 mg Q2W vs placebo. Restricted maximum likelihood (REML) based repeated measures analysis on patients with a baseline pre-dose/pre-BD FEV1 assessment. A variable for the biomarker population (positive, negative) as well as a treatment-by-biomarker population interaction term and a 3-way biomarker population-by-treatment-by-visit interaction term was included in the analysis model.

Comparison groups

Biomarker positive - Tralo 300 mg Q2W v Biomarker positive - Placebo

Number of subjects included in analysis

202

Analysis specification

Pre-specified

Analysis type

superiority ^[6]

P-value

= 0.6033

Method

Repeated measures analysis

Parameter type

Least square (LS) Mean difference

Point estimate

1.86

Confidence interval

level

95%

sides

2-sided

lower limit

-5.16

upper limit

8.88

Notes
[6] - Fixed categorical effects of treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

Pre-BD FEV1: Biomarker negative

Statistical analysis description

Comparison of % change from baseline in pre-dose/pre-BD FEV1 at Week 52: Biomarker negative population; Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis on patients with a baseline pre-dose/pre-BD FEV1 assessment. A variable for the biomarker population (positive, negative) as well as a treatment-by-biomarker population interaction term and a 3-way biomarker population-by-treatment-by-visit interaction term was included in the analysis model.

Comparison groups

Biomarker negative - Tralo 300 mg Q2W v Biomarker negative - Placebo

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

= 0.1276

Method

Repeated measures analysis

Parameter type

LS Mean difference

Point estimate

3.37

Confidence interval

level

95%

sides

2-sided

lower limit

-0.97

upper limit

7.7

Notes
[7] - Fixed categorical effects of treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

Pre-BD FEV1: FAS

Statistical analysis description

Comparison of % change from baseline in pre-dose/pre-BD FEV1 at Week 52: FAS population; Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis on patients with a baseline pre-dose/pre-BD FEV1 assessment

Comparison groups

Tralo 300 mg Q2W v Placebo

Number of subjects included in analysis

742

Analysis specification

Pre-specified

Analysis type

superiority ^[8]

P-value

= 0.1164

Method

Repeated measures analysis

Parameter type

LS Mean difference

Point estimate

2.95

Confidence interval

level

95%

sides

2-sided

lower limit

-0.73

upper limit

6.62

Notes
[8] - Fixed categorical effects of treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

Secondary: Change from baseline to Week 52 in total asthma symptom score (bi-weekly means)

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End point title

Change from baseline to Week 52 in total asthma symptom score (bi-weekly means)

End point description

Asthma symptoms during night-time and daytime were recorded by the patient each morning and evening in the Asthma Daily Diary. Symptoms were recorded using a 4-point response scale, which ranged from 0 to 3, where 0 indicated no asthma symptoms. Asthma symptom daytime score (recorded in the evening), night-time score (recorded in the morning), and total score were calculated separately. The daily asthma symptom total score was calculated by taking the sum of the night-time and daytime asthma symptom scores recorded each day, ranging from 0 to 6. A lower symptom score indicated a better outcome. The change from baseline in bi-weekly mean daily asthma symptom total score is presented. Only patients with data available at the timepoints of testing were included in the analysis.

End point type

Secondary

End point timeframe

Baseline (Week 0) and Week 52

End point values	Tralo 300 mg Q2W	Placebo	Biomarker positive - Tralo 300 mg Q2W	Biomarker positive - Placebo	Biomarker negative - Tralo 300 mg Q2W	Biomarker negative - Placebo
Number of subjects analysed	297	309	79	81	215	223
Units: Scores on a scale
arithmetic mean (standard deviation)	-1.04 ± 1.04	-1.02 ± 1.24	-1.18 ± 0.98	-1.06 ± 1.25	-0.98 ± 1.04	-1.02 ± 1.24

Total asthma symptom score: Biomarker positive

Statistical analysis description

Comparison of mean change from baseline in total asthma symptom score at Week 52: Biomarker positive population; Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis. A variable for the biomarker population (positive, negative) as well as a treatment-by-biomarker population interaction term and a 3-way biomarker population-by-treatment-by-visit interaction term was included in the analysis model.

Comparison groups

Biomarker positive - Tralo 300 mg Q2W v Biomarker positive - Placebo

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

= 0.1456

Method

Repeated measures analysis

Parameter type

LS Mean difference

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.47

upper limit

0.07

Notes
[9] - Fixed categorical effects of baseline asthma symptom score, treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

Total asthma symptom score: Biomarker negative

Statistical analysis description

Comparison of mean change from baseline in total asthma symptom score at Week 52: Biomarker negative population; Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis. A variable for the biomarker population (positive, negative) as well as a treatment-by-biomarker population interaction term and a 3-way biomarker population-by-treatment-by-visit interaction term was included in the analysis model.

Comparison groups

Biomarker negative - Tralo 300 mg Q2W v Biomarker negative - Placebo

Number of subjects included in analysis

438

Analysis specification

Pre-specified

Analysis type

superiority ^[10]

P-value

= 0.6548

Method

Repeated measures analysis

Parameter type

LS Mean difference

Point estimate

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.13

upper limit

0.2

Notes
[10] - Fixed categorical effects of baseline asthma symptom score, treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

Total asthma symptom score: FAS

Statistical analysis description

Comparison of mean change from baseline in total asthma symptom score at Week 52: FAS population; Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis.

Comparison groups

Tralo 300 mg Q2W v Placebo

Number of subjects included in analysis

606

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

P-value

= 0.5763

Method

Repeated measures analysis

Parameter type

LS Mean difference

Point estimate

-0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.18

upper limit

0.1

Notes
[11] - Fixed categorical effects of baseline asthma symptom score, treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

Secondary: Change from baseline to Week 52 in Asthma Quality of Life Questionnaire for 12 Years and Older (AQLQ(S)+12) total score

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End point title

Change from baseline to Week 52 in Asthma Quality of Life Questionnaire for 12 Years and Older (AQLQ(S)+12) total score

End point description

The AQLQ(S)+12 is a questionnaire that measures health-related quality of life for patients with asthma aged 12 and older. The questionnaire comprises 32 questions and has 4 separate domains (asthma symptoms, activity limitations, emotional function and environmental stimuli). Patients were asked to recall their experiences during the previous 2 weeks and to score each of the questions on a 7-point scale ranging from 7 (no impairment) to 1 (severe impairment). The total score was calculated as the mean response to all questions, ranging from 1 (severe impairment) to 7 (no impairment). Individual AQLQ(S)+12 total score changes of ≥0.5 were considered to be clinically meaningful. The mean change from baseline in AQLQ(S)+12 score at Week 52 is presented. Only patients with data available at the timepoints of testing were included in the analysis.

End point type

Secondary

End point timeframe

Baseline (Week 0) and Week 52

End point values	Tralo 300 mg Q2W	Placebo	Biomarker positive - Tralo 300 mg Q2W	Biomarker positive - Placebo	Biomarker negative - Tralo 300 mg Q2W	Biomarker negative - Placebo
Number of subjects analysed	321	318	77	84	242	230
Units: Scores on a scale
arithmetic mean (standard deviation)	1.18 ± 1.07	1.21 ± 1.24	1.35 ± 1.06	1.20 ± 1.22	1.13 ± 1.07	1.23 ± 1.25

AQLQ(S)+12 total score: Biomarker positive

Statistical analysis description

Comparison of change in mean score from baseline for AQLQ(S)+12 at Week 52: Biomarker positive population; Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis. A variable for the biomarker population (positive, negative) as well as a treatment-by-biomarker population interaction term and a 3-way biomarker population-by-treatment-by-visit interaction term was included in the analysis model.

Comparison groups

Biomarker positive - Tralo 300 mg Q2W v Biomarker positive - Placebo

Number of subjects included in analysis

161

Analysis specification

Pre-specified

Analysis type

superiority ^[12]

P-value

= 0.0874

Method

Repeated measures analysis

Parameter type

LS Mean difference

Point estimate

0.27

Confidence interval

level

95%

sides

2-sided

lower limit

-0.04

upper limit

0.57

Notes
[12] - Fixed categorical effects of baseline AQLQ (S)+12 score, treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

AQLQ(S)+12 total score: Biomarker negative

Statistical analysis description

Comparison of change in mean score from baseline for AQLQ(S)+12 at Week 52: Biomarker negative population; Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis. A variable for the biomarker population (positive, negative) as well as a treatment-by-biomarker population interaction term and a 3-way biomarker population-by-treatment-by-visit interaction term was included in the analysis model.

Comparison groups

Biomarker negative - Tralo 300 mg Q2W v Biomarker negative - Placebo

Number of subjects included in analysis

472

Analysis specification

Pre-specified

Analysis type

superiority ^[13]

P-value

= 0.9083

Method

Repeated measures analysis

Parameter type

LS Mean difference

Point estimate

-0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2

upper limit

0.17

Notes
[13] - Fixed categorical effects of baseline AQLQ (S)+12 score, treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

AQLQ(S)+12 total score: FAS

Statistical analysis description

Comparison of change in mean score from baseline for AQLQ(S)+12 at Week 52: FAS population; Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis.

Comparison groups

Tralo 300 mg Q2W v Placebo

Number of subjects included in analysis

639

Analysis specification

Pre-specified

Analysis type

superiority ^[14]

P-value

= 0.4506

Method

Repeated measures analysis

Parameter type

LS Mean difference

Point estimate

0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

0.22

Notes
[14] - Fixed categorical effects of baseline AQLQ (S)+12 score, treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

Secondary: Change from baseline to Week 52 in Asthma Control Questionnaire-6 (ACQ-6) score

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End point title

Change from baseline to Week 52 in Asthma Control Questionnaire-6 (ACQ-6) score

End point description

The ACQ-6 questionnaire is a shortened version of the ACQ (omitting FEV1 measurement) that assesses asthma symptoms (night-time awakenings, symptoms on waking, activity limitation, dyspnoea, wheezing) and rescue short-acting β2-agonists medication use during the past week. Questions were weighted equally and scored on a 7-point scale from 0 (totally controlled) to 6 (severely uncontrolled). The mean ACQ-6 score was the mean of the responses, ranging from 0 (totally controlled) to 6 (severely uncontrolled). Mean scores of ≤0.75 indicate well-controlled asthma, scores between 0.75 and ≤1.5 indicate partly controlled asthma and a score >1.5 indicates not well-controlled asthma. Individual changes of at least 0.5 were considered to be clinically meaningful. The mean change from baseline in ACQ-6 score at Week 52 is presented. Only patients with data available at the timepoints of testing were included in the analysis.

End point type

Secondary

End point timeframe

Baseline (Week 0) and Week 52

End point values	Tralo 300 mg Q2W	Placebo	Biomarker positive - Tralo 300 mg Q2W	Biomarker positive - Placebo	Biomarker negative - Tralo 300 mg Q2W	Biomarker negative - Placebo
Number of subjects analysed	341	334	85	86	254	243
Units: Scores on a scale
arithmetic mean (standard deviation)	-1.12 ± 1.02	-1.11 ± 1.13	-1.26 ± 1.01	-1.14 ± 1.12	-1.07 ± 1.02	-1.11 ± 1.13

ACQ-6 score: Biomarker positive

Statistical analysis description

Comparison of change in mean score from baseline for ACQ-6 at Week 52: Biomarker positive population; Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis. A variable for the biomarker population (positive, negative) as well as a treatment-by-biomarker population interaction term and a 3-way biomarker population-by-treatment-by-visit interaction term was included in the analysis model.

Comparison groups

Biomarker positive - Tralo 300 mg Q2W v Biomarker positive - Placebo

Number of subjects included in analysis

171

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

P-value

= 0.04

Method

Repeated measures analysis

Parameter type

LS Mean difference

Point estimate

-0.27

Confidence interval

level

95%

sides

2-sided

lower limit

-0.53

upper limit

-0.01

Notes
[15] - Fixed categorical effects of baseline ACQ-6 score, treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

ACQ-6 score: Biomarker negative

Statistical analysis description

Comparison of change in mean score from baseline for ACQ-6 at Week 52: Biomarker negative population; Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis. A variable for the biomarker population (positive, negative) as well as a treatment-by-biomarker population interaction term and a 3-way biomarker population-by-treatment-by-visit interaction term was included in the analysis model.

Comparison groups

Biomarker negative - Tralo 300 mg Q2W v Biomarker negative - Placebo

Number of subjects included in analysis

497

Analysis specification

Pre-specified

Analysis type

superiority ^[16]

P-value

= 0.9735

Method

Repeated measures analysis

Parameter type

LS Mean difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.16

upper limit

0.16

Notes
[16] - Fixed categorical effects of baseline ACQ-6 score, treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

ACQ-6 score: FAS

Statistical analysis description

Comparison of change in mean score from baseline for ACQ-6 at Week 52: FAS population; Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis.

Comparison groups

Tralo 300 mg Q2W v Placebo

Number of subjects included in analysis

675

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

P-value

= 0.2432

Method

Repeated measures analysis

Parameter type

LS Mean difference

Point estimate

-0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-0.21

upper limit

0.05

Notes
[17] - Fixed categorical effects of baseline ACQ-6 score, treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

Secondary: AAER associated with an ER/UC visit, or a hospitalisation up to Week 52

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End point title

AAER associated with an ER/UC visit, or a hospitalisation up to Week 52

End point description

The annual rate of exacerbations associated with an ER/UC visit or hospitalisation up to Week 52 are presented for non-adjudicated data (i.e. events assessed by the Investigator and recorded in the electronic case report form). AAER = number of exacerbations*365.25 / (follow-up date – date of randomisation + 1) (where maximum follow-up time for a patient was approximately 52 weeks).

End point type

Secondary

End point timeframe

Baseline (Week 0) up to Week 52

End point values	Tralo 300 mg Q2W	Placebo	Biomarker positive - Tralo 300 mg Q2W	Biomarker positive - Placebo	Biomarker negative - Tralo 300 mg Q2W	Biomarker negative - Placebo
Number of subjects analysed	420	417	108	121	308	290
Units: Events/year
number (confidence interval 95%)	0.08 (0.06 to 0.12)	0.12 (0.09 to 0.18)	0.06 (0.03 to 0.14)	0.16 (0.09 to 0.29)	0.09 (0.06 to 0.14)	0.11 (0.07 to 0.17)

AAER w ER/UC/hospitalisation: Biomarker positive

Statistical analysis description

Comparison of AAER associated with an ER/UC visit or hospitalisation: Biomarker positive population; Tralo 300 mg Q2W vs placebo. A variable for the biomarker population (positive, negative) as well as a treatment-by-biomarker population interaction term was included in the analysis model.

Comparison groups

Biomarker positive - Tralo 300 mg Q2W v Biomarker positive - Placebo

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

superiority ^[18]

P-value

= 0.0576

Method

Negative binomial

Parameter type

Rate ratio

Point estimate

0.39

Confidence interval

level

95%

sides

2-sided

lower limit

0.15

upper limit

1.03

Notes
[18] - Covariates in the model included treatment group, geographical region, age group, periostin group at baseline and number of exacerbations resulting in hospitalisation or ER treatment (yes/no) in the year before the study.

AAER w ER/UC/hospitalisation: Biomarker negative

Statistical analysis description

Comparison of AAER associated with an ER/UC visit or hospitalisation: Biomarker negative population; Tralo 300 mg Q2W vs placebo. A variable for the biomarker population (positive, negative) as well as a treatment-by-biomarker population interaction term was included in the analysis model.

Comparison groups

Biomarker negative - Tralo 300 mg Q2W v Biomarker negative - Placebo

Number of subjects included in analysis

598

Analysis specification

Pre-specified

Analysis type

superiority ^[19]

P-value

= 0.5249

Method

Negative binomial

Parameter type

Rate ratio

Point estimate

0.83

Confidence interval

level

95%

sides

2-sided

lower limit

0.46

upper limit

1.48

Notes
[19] - Covariates in the model included treatment group, geographical region, age group, periostin group at baseline and number of exacerbations resulting in hospitalisation or ER treatment (yes/no) in the year before the study.

AAER w ER/UC/hospitalisation: FAS

Statistical analysis description

Comparison of AAER associated with an ER/UC visit or hospitalisation: FAS population; Tralo 300 mg Q2W vs placebo.

Comparison groups

Tralo 300 mg Q2W v Placebo

Number of subjects included in analysis

837

Analysis specification

Pre-specified

Analysis type

superiority ^[20]

P-value

= 0.1155

Method

Negative binomial

Parameter type

Rate ratio

Point estimate

0.67

Confidence interval

level

95%

sides

2-sided

lower limit

0.41

upper limit

1.1

Notes
[20] - Covariates in the model included treatment group, geographical region, age group, periostin group at baseline and number of exacerbations resulting in hospitalisation or ER treatment (yes/no) in the year before the study.

Secondary: Change from baseline in European Quality of Life - 5 Dimension 5 Levels (EQ-5D-5L) visual analogue scale (VAS) scores at Week 52

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End point title

Change from baseline in European Quality of Life - 5 Dimension 5 Levels (EQ-5D-5L) visual analogue scale (VAS) scores at Week 52

End point description

The EQ-5D-5L questionnaire assesses 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response options (no problems, slight problems, moderate problems, severe problems and extreme problems) that reflect increasing levels of difficulty. The patient was asked to indicate his/her current health state by selecting the most appropriate level in each of the 5 dimensions. The questionnaire also included a VAS, where the patient was asked to rate current health status on a scale of 0 to 100, with 0 being the worst imaginable health state. The mean change from baseline in EQ-5D-5L VAS scores at Week 52 is presented. Only patients with data available at the timepoints of testing were included in the analysis.

End point type

Secondary

End point timeframe

Baseline (Week 0) and Week 52

End point values	Tralo 300 mg Q2W	Placebo	Biomarker positive - Tralo 300 mg Q2W	Biomarker positive - Placebo	Biomarker negative - Tralo 300 mg Q2W	Biomarker negative - Placebo
Number of subjects analysed	317	313	81	85	233	224
Units: Scores on a scale
arithmetic mean (standard deviation)	12.46 ± 16.67	11.66 ± 17.41	14.58 ± 15.21	11.58 ± 17.26	11.67 ± 17.18	12.01 ± 17.43

No statistical analyses for this end point

Secondary: Change from baseline in total asthma rescue medication use at Week 52 (bi-weekly means)

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End point title

Change from baseline in total asthma rescue medication use at Week 52 (bi-weekly means)

End point description

Salbutamol, albuterol or levalbuterol were used as rescue medication during the study in the event of a worsening of asthma symptoms. Rescue medication use was measured by the bi-weekly mean number of inhalations (puffs) per day, calculated as: total morning puffs + total evening puffs + 2*(total morning nebuliser use + total evening nebuliser use)/ total number of days with data in bi-weekly period. The change from baseline in bi-weekly mean total asthma rescue medication use at Week 52 is presented. Only patients with data available at the timepoints of testing were included in the analysis.

End point type

Secondary

End point timeframe

Baseline (Week 0) and Week 52

End point values	Tralo 300 mg Q2W	Placebo	Biomarker positive - Tralo 300 mg Q2W	Biomarker positive - Placebo	Biomarker negative - Tralo 300 mg Q2W	Biomarker negative - Placebo
Number of subjects analysed	297	309	79	81	215	223
Units: Puffs/day
arithmetic mean (standard deviation)	-2.25 ± 3.03	-1.97 ± 4.34	-2.86 ± 3.26	-1.73 ± 4.59	-2.01 ± 2.93	-2.08 ± 4.28

Rescue medication use: Biomarker positive

Statistical analysis description

Comparison of mean change from baseline in rescue medication use at Week 52: Biomarker positive population; Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis. A variable for the biomarker population (positive, negative) as well as a treatment-by-biomarker population interaction term and a 3-way biomarker population-by-treatment-by-visit interaction term was included in the analysis model.

Comparison groups

Biomarker positive - Tralo 300 mg Q2W v Biomarker positive - Placebo

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority ^[21]

P-value

= 0.036

Method

Repeated measures analysis

Parameter type

LS Mean difference

Point estimate

-0.95

Confidence interval

level

95%

sides

2-sided

lower limit

-1.85

upper limit

-0.06

Notes
[21] - Fixed categorical effects of baseline rescue medication use, treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

Rescue medication use: Biomarker negative

Statistical analysis description

Comparison of mean change from baseline in rescue medication use at Week 52: Biomarker negative population; Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis. A variable for the biomarker population (positive, negative) as well as a treatment-by-biomarker population interaction term and a 3-way biomarker population-by-treatment-by-visit interaction term was included in the analysis model.

Comparison groups

Biomarker negative - Tralo 300 mg Q2W v Biomarker negative - Placebo

Number of subjects included in analysis

438

Analysis specification

Pre-specified

Analysis type

superiority ^[22]

P-value

= 0.5864

Method

Repeated measures analysis

Parameter type

LS Mean difference

Point estimate

0.15

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

0.7

Notes
[22] - Fixed categorical effects of baseline rescue medication use, treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

Rescue medication use: FAS

Statistical analysis description

Comparison of mean change from baseline in rescue medication use at Week 52: FAS population; Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis.

Comparison groups

Tralo 300 mg Q2W v Placebo

Number of subjects included in analysis

606

Analysis specification

Pre-specified

Analysis type

superiority ^[23]

P-value

= 0.4689

Method

Repeated measures analysis

Parameter type

LS Mean difference

Point estimate

-0.17

Confidence interval

level

95%

sides

2-sided

lower limit

-0.63

upper limit

0.29

Notes
[23] - Fixed categorical effects of baseline rescue medication use, treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

Secondary: Change from baseline in home peak expiratory flow (PEF) (morning and evening) at Week 52

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End point title

Change from baseline in home peak expiratory flow (PEF) (morning and evening) at Week 52

End point description

Home PEF testing was performed by the patient using an electronic, hand-held spirometer (peak flow meter) and was performed in the morning upon awakening (prior to taking their morning asthma controller) and in the evening at bedtime (prior to taking their evening asthma controller). The mean change from baseline in home PEF values at Week 52 are presented separately for morning and evening. Only patients with data available at the timepoints of testing were included in the analysis for each individual category.

End point type

Secondary

End point timeframe

Baseline (Week 0) and Week 52

End point values	Tralo 300 mg Q2W	Placebo	Biomarker positive - Tralo 300 mg Q2W	Biomarker positive - Placebo	Biomarker negative - Tralo 300 mg Q2W	Biomarker negative - Placebo
Number of subjects analysed	322	313	86	86	233	222
Units: L/min
arithmetic mean (standard deviation)
Morning PEF (n=318, 308, 84, 81, 231, 222)	10.66 ± 73.88	9.43 ± 76.01	22.35 ± 74.00	18.80 ± 86.24	6.72 ± 73.82	6.10 ± 72.28
Evening PEF (n=322, 313, 86, 86, 233, 222)	5.72 ± 77.01	2.91 ± 74.94	18.15 ± 69.20	8.88 ± 79.72	1.72 ± 79.58	0.17 ± 73.66

Morning PEF: Biomarker positive

Statistical analysis description

Comparison of mean change from baseline in morning PEF at Week 52: Biomarker positive population; Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis. A variable for the biomarker population (positive, negative) as well as a treatment-by-biomarker population interaction term and a 3-way biomarker population-by-treatment-by-visit interaction term was included in the analysis model.

Comparison groups

Biomarker positive - Tralo 300 mg Q2W v Biomarker positive - Placebo

Number of subjects included in analysis

172

Analysis specification

Pre-specified

Analysis type

superiority ^[24]

P-value

= 0.5094

Method

Repeated measures analysis

Parameter type

LS Mean difference

Point estimate

6.15

Confidence interval

level

95%

sides

2-sided

lower limit

-12.13

upper limit

24.43

Notes
[24] - Fixed categorical effects of baseline PEF (morning), treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

Morning PEF: Biomarker negative

Statistical analysis description

Comparison of mean change from baseline in morning PEF at Week 52: Biomarker negative population; Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis. A variable for the biomarker population (positive, negative) as well as a treatment-by-biomarker population interaction term and a 3-way biomarker population-by-treatment-by-visit interaction term was included in the analysis model.

Comparison groups

Biomarker negative - Tralo 300 mg Q2W v Biomarker negative - Placebo

Number of subjects included in analysis

455

Analysis specification

Pre-specified

Analysis type

superiority ^[25]

P-value

= 0.5984

Method

Repeated measures analysis

Parameter type

LS Mean difference

Point estimate

3.02

Confidence interval

level

95%

sides

2-sided

lower limit

-8.22

upper limit

14.26

Notes
[25] - Fixed categorical effects of baseline PEF (morning), treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

Evening PEF: Biomarker positive

Statistical analysis description

Comparison of mean change from baseline in evening PEF at Week 52: Biomarker positive population; Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis. A variable for the biomarker population (positive, negative) as well as a treatment-by-biomarker population interaction term and a 3-way biomarker population-by-treatment-by-visit interaction term was included in the analysis model.

Comparison groups

Biomarker positive - Tralo 300 mg Q2W v Biomarker positive - Placebo

Number of subjects included in analysis

172

Analysis specification

Pre-specified

Analysis type

superiority ^[26]

P-value

= 0.3971

Method

Repeated measures analysis

Parameter type

LS Mean difference

Point estimate

7.84

Confidence interval

level

95%

sides

2-sided

lower limit

-10.32

upper limit

Notes
[26] - Fixed categorical effects of baseline PEF (evening), treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

Evening PEF: Biomarker negative

Statistical analysis description

Comparison of mean change from baseline in evening PEF at Week 52: Biomarker negative population; Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis. A variable for the biomarker population (positive, negative) as well as a treatment-by-biomarker population interaction term and a 3-way biomarker population-by-treatment-by-visit interaction term was included in the analysis model.

Comparison groups

Biomarker negative - Tralo 300 mg Q2W v Biomarker negative - Placebo

Number of subjects included in analysis

455

Analysis specification

Pre-specified

Analysis type

superiority ^[27]

P-value

= 0.531

Method

Repeated measures analysis

Parameter type

LS Mean difference

Point estimate

3.59

Confidence interval

level

95%

sides

2-sided

lower limit

-7.65

upper limit

14.83

Notes
[27] - Fixed categorical effects of baseline PEF (evening), treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

Morning PEF: FAS

Statistical analysis description

Comparison of mean change from baseline in morning PEF at Week 52: FAS population; Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis.

Comparison groups

Tralo 300 mg Q2W v Placebo

Number of subjects included in analysis

635

Analysis specification

Pre-specified

Analysis type

superiority ^[28]

P-value

= 0.4764

Method

Repeated measures analysis

Parameter type

LS Mean difference

Point estimate

3.46

Confidence interval

level

95%

sides

2-sided

lower limit

-6.06

upper limit

12.97

Notes
[28] - Fixed categorical effects of baseline PEF (morning), treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

Evening PEF: FAS

Statistical analysis description

Comparison of mean change from baseline in evening PEF at Week 52: FAS population; Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis.

Comparison groups

Tralo 300 mg Q2W v Placebo

Number of subjects included in analysis

635

Analysis specification

Pre-specified

Analysis type

superiority ^[29]

P-value

= 0.4221

Method

Repeated measures analysis

Parameter type

LS Mean difference

Point estimate

3.88

Confidence interval

level

95%

sides

2-sided

lower limit

-5.6

upper limit

13.37

Notes
[29] - Fixed categorical effects of baseline PEF (evening), treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

Secondary: Change from baseline in night-time awakenings due to asthma requiring rescue medication use at Week 52 (bi-weekly means [percentage])

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End point title

Change from baseline in night-time awakenings due to asthma requiring rescue medication use at Week 52 (bi-weekly means [percentage])

End point description

The patient captured night-time awakenings (yes/no) and the use of rescue medication during these awakenings (yes/no) each morning in the Asthma Daily Diary. Night-time awakenings (percentage) was defined as the number of nights with awakenings due to asthma and requiring rescue medication divided by number of nights with data. The change from baseline in bi-weekly means (percentage) night-time awakenings due to asthma requiring rescue medication use at Week 52 is presented. Only patients with data available at the timepoints of testing were included in the analysis.

End point type

Secondary

End point timeframe

Baseline (Week 0) and Week 52

End point values	Tralo 300 mg Q2W	Placebo	Biomarker positive - Tralo 300 mg Q2W	Biomarker positive - Placebo	Biomarker negative - Tralo 300 mg Q2W	Biomarker negative - Placebo
Number of subjects analysed	368	348	94	96	270	247
Units: Night-time awakenings (percentage)
arithmetic mean (standard deviation)	-35.60 ± 35.40	-35.05 ± 36.63	-37.86 ± 38.36	-34.06 ± 34.96	-34.65 ± 34.34	-35.67 ± 37.37

Night-time awakenings: Biomarker positive

Statistical analysis description

Comparison of mean change from baseline in number (%) of awakenings at Week 52: Biomarker positive population; Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis. A variable for the biomarker population (positive, negative) as well as a treatment-by-biomarker population interaction term and a 3-way biomarker population-by-treatment-by-visit interaction term was included in the analysis model.

Comparison groups

Biomarker positive - Tralo 300 mg Q2W v Biomarker positive - Placebo

Number of subjects included in analysis

190

Analysis specification

Pre-specified

Analysis type

superiority ^[30]

P-value

= 0.1099

Method

Repeated measures analysis

Parameter type

LS Mean difference

Point estimate

-5.04

Confidence interval

level

95%

sides

2-sided

lower limit

-11.21

upper limit

1.14

Notes
[30] - Fixed categorical effects of baseline number (%) of awakenings, treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

Night-time awakenings: Biomarker negative

Statistical analysis description

Comparison groups

Biomarker negative - Placebo v Biomarker negative - Tralo 300 mg Q2W

Number of subjects included in analysis

517

Analysis specification

Pre-specified

Analysis type

superiority ^[31]

P-value

= 0.8112

Method

Repeated measures analysis

Parameter type

LS Mean difference

Point estimate

0.46

Confidence interval

level

95%

sides

2-sided

lower limit

-3.33

upper limit

4.25

Notes
[31] - Fixed categorical effects of baseline number (%) of awakenings, treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

Night-time awakenings: FAS

Statistical analysis description

Comparison of mean change from baseline in number (%) of awakenings at Week 52: FAS population; Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis.

Comparison groups

Tralo 300 mg Q2W v Placebo

Number of subjects included in analysis

716

Analysis specification

Pre-specified

Analysis type

superiority ^[32]

P-value

= 0.4645

Method

Repeated measures analysis

Parameter type

LS Mean difference

Point estimate

-1.19

Confidence interval

level

95%

sides

2-sided

lower limit

-4.4

upper limit

2.01

Notes
[32] - Fixed categorical effects of baseline number (%) of awakenings, treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

Secondary: Number of patients with ≥1 asthma exacerbation up to Week 52

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End point title

Number of patients with ≥1 asthma exacerbation up to Week 52

End point description

The number of patients with ≥1 asthma exacerbation up to Week 52 is presented.

End point type

Secondary

End point timeframe

Baseline (Week 0) up to Week 52

End point values	Tralo 300 mg Q2W	Placebo	Biomarker positive - Tralo 300 mg Q2W	Biomarker positive - Placebo	Biomarker negative - Tralo 300 mg Q2W	Biomarker negative - Placebo
Number of subjects analysed	420	417	108	121	308	290
Units: Participants	163	171	38	50	125	117

≥ 1 asthma exacerbation: Biomarker positive

Statistical analysis description

Comparison of number of patients with ≥ 1 asthma exacerbations up to Week 52: Biomarker positive population; Tralo 300 mg Q2W vs placebo.

Comparison groups

Biomarker positive - Tralo 300 mg Q2W v Biomarker positive - Placebo

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

superiority ^[33]

P-value

= 0.344

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.77

Confidence interval

level

95%

sides

2-sided

lower limit

0.44

upper limit

1.33

Notes
[33] - The estimate of each odds ratio was obtained from a Cochran-Mantel-Haenszel test controlling for geographical region, age group and periostin group at baseline.

≥ 1 asthma exacerbation: Biomarker negative

Statistical analysis description

Comparison of number of patients with ≥ 1 asthma exacerbations up to Week 52: Biomarker negative population; Tralo 300 mg Q2W vs placebo.

Comparison groups

Biomarker negative - Tralo 300 mg Q2W v Biomarker negative - Placebo

Number of subjects included in analysis

598

Analysis specification

Pre-specified

Analysis type

superiority ^[34]

P-value

= 0.7768

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

1.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.75

upper limit

1.46

Notes
[34] - The estimate of each odds ratio was obtained from a Cochran-Mantel-Haenszel test controlling for geographical region, age group and periostin group at baseline.

≥ 1 asthma exacerbation: FAS

Statistical analysis description

Comparison of number of patients with ≥ 1 asthma exacerbations up to Week 52: FAS population; Tralo 300 mg Q2W vs placebo.

Comparison groups

Tralo 300 mg Q2W v Placebo

Number of subjects included in analysis

837

Analysis specification

Pre-specified

Analysis type

superiority ^[35]

P-value

= 0.5276

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.91

Confidence interval

level

95%

sides

2-sided

lower limit

0.69

upper limit

1.21

Notes
[35] - The estimate of each odds ratio was obtained from a Cochran-Mantel-Haenszel test controlling for geographical region, age group and periostin group at baseline.

Secondary: Work Productivity and Activity Impairment Questionnaire and Classroom Impairment Questions (WPAI+CIQ): Productivity Loss at Week 52

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End point title

Work Productivity and Activity Impairment Questionnaire and Classroom Impairment Questions (WPAI+CIQ): Productivity Loss at Week 52

End point description

The WPAI+CIQ consists of questions about how asthma and asthma-related issues impact a patient’s ability to work, attend classes and perform regular daily activities. The questionnaire contains 10 questions relating to the patient’s experience over the previous 7 days. The WPAI+CIQ outcomes for productivity loss are presented separately for those currently employed and for those currently in school and are expressed as mean productivity loss (percentage) at Week 52, with higher numbers indicating less productivity. Work Productivity Loss = {Q2/(Q2+Q4)+[(1-Q2/(Q2+Q4))x(Q5/10)]}*100 (Absenteeism = Q2/(Q2+Q4)*100; Presenteeism = (Q5/10)*100). Class Productivity Loss = {Q7/(Q7+Q8) + [(1-Q7/(Q7+Q8))x(Q9/10)]}*100 (Absenteeism = Q7/(Q7+Q8)*100; Presenteeism = (Q9/10)*100). Note: QX refers to response to question number X on WPAI+CIQ questionnaire. Only patients with data available at the timepoints of testing were included in the analysis for each individual category.

End point type

Secondary

End point timeframe

At Week 52

End point values	Tralo 300 mg Q2W	Placebo	Biomarker positive - Tralo 300 mg Q2W	Biomarker positive - Placebo	Biomarker negative - Tralo 300 mg Q2W	Biomarker negative - Placebo
Number of subjects analysed	154	151	46	46	105	104
Units: Percent productivity loss
arithmetic mean (standard deviation)
Currently employed (n=137, 125, 43, 34, 92, 90)	23.43 ± 23.66	30.17 ± 27.08	22.51 ± 24.47	28.15 ± 27.39	23.36 ± 23.39	31.05 ± 27.20
Currently in school (n=17, 26, 3, 12, 13, 14)	28.03 ± 31.01	28.09 ± 29.80	28.89 ± 34.21	37.92 ± 28.72	25.99 ± 32.17	19.67 ± 29.06

No statistical analyses for this end point

Secondary: WPAI+CIQ: Activity Impairment at Week 52

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End point title

WPAI+CIQ: Activity Impairment at Week 52

End point description

The WPAI+CIQ consists of questions about how asthma and asthma-related issues impact a patient’s ability to work, attend classes and perform regular daily activities. The questionnaire contains 10 questions relating to the patient’s experience over the previous 7 days. The WPAI+CIQ outcomes for activity impairment are presented separately for those currently employed and for those currently in school and are expressed as mean impairment percentages at Week 52, with higher numbers indicating greater impairment. Activity impairment = (Q10/10)*100. Note: QX refers to response to question number X on WPAI+CIQ questionnaire. Only patients with data available at the timepoints of testing were included in the analysis for each individual category.

End point type

Secondary

End point timeframe

At Week 52

End point values	Tralo 300 mg Q2W	Placebo	Biomarker positive - Tralo 300 mg Q2W	Biomarker positive - Placebo	Biomarker negative - Tralo 300 mg Q2W	Biomarker negative - Placebo
Number of subjects analysed	169	160	50	49	116	110
Units: Percent impairment
arithmetic mean (standard deviation)
Currently employed (n=147, 131, 45, 36, 100, 94)	20.68 ± 19.82	26.11 ± 24.89	20.89 ± 18.81	25.28 ± 28.63	20.50 ± 20.42	26.49 ± 23.59
Currently in school (n=22, 29, 5, 13, 16, 16)	24.55 ± 27.38	27.93 ± 28.71	20.00 ± 18.71	33.85 ± 26.63	26.88 ± 30.49	23.13 ± 30.27

No statistical analyses for this end point

Secondary: Asthma-related healthcare encounters by type up to Week 52

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End point title

Asthma-related healthcare encounters by type up to Week 52

End point description

Broad-based healthcare utilisation asthma-related event information was collected by the Investigator/authorised delegate at each visit. At Visit 1, healthcare resource utilisation information was collected with a 1-year recall period; subsequent visits collected information with a recall period of ‘since the last scheduled visit’. Total number of times the healthcare encounter occurred was calculated across all patients for each of the following categories: • Ambulance transport, • Emergency room visits, • Unscheduled outpatient visits (visit to specialist and/or visit to primary healthcare physician and/or other healthcare visit), • Home visits (home visit, physician and/or other healthcare professional), • Telephone calls (telephone calls to physician and/or nurse), and • Advanced pulmonary function test.

End point type

Secondary

End point timeframe

Baseline (Week 0) up to Week 52

End point values	Tralo 300 mg Q2W	Placebo	Biomarker positive - Tralo 300 mg Q2W	Biomarker positive - Placebo	Biomarker negative - Tralo 300 mg Q2W	Biomarker negative - Placebo
Number of subjects analysed	420	417	108	121	308	290
Units: Number of times
Ambulance transport	35	41	14	21	21	20
Emergency room visits	87	99	20	28	65	70
Unscheduled outpatient visits	1798	1834	513	579	1274	1216
Home visits	59	44	10	18	49	26
Telephone calls	163	196	51	76	112	117
Advanced pulmonary function test	51	46	16	20	35	26

No statistical analyses for this end point

Secondary: Asthma-related healthcare encounters by type up to Week 52: Hospitalisations

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End point title

Asthma-related healthcare encounters by type up to Week 52: Hospitalisations

End point description

End point type

Secondary

End point timeframe

Baseline (Week 0) up to Week 52

End point values	Tralo 300 mg Q2W	Placebo	Biomarker positive - Tralo 300 mg Q2W	Biomarker positive - Placebo	Biomarker negative - Tralo 300 mg Q2W	Biomarker negative - Placebo
Number of subjects analysed	420	417	108	121	308	290
Units: Days	417	590	82	175	334	414

No statistical analyses for this end point

Secondary: Asthma-related healthcare encounters by type up to Week 52: Spirometry

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End point title

Asthma-related healthcare encounters by type up to Week 52: Spirometry

End point description

End point type

Secondary

End point timeframe

Baseline (Week 0) up to Week 52

End point values	Tralo 300 mg Q2W	Placebo	Biomarker positive - Tralo 300 mg Q2W	Biomarker positive - Placebo	Biomarker negative - Tralo 300 mg Q2W	Biomarker negative - Placebo
Number of subjects analysed	420	417	108	121	308	290
Units: Number of assessments	434	426	148	151	284	270

No statistical analyses for this end point

Secondary: Serum trough concentration (Ctrough) of tralokinumab during the treatment period up to Week 72

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End point title

Serum trough concentration (Ctrough) of tralokinumab during the treatment period up to Week 72

End point description

To evaluate the PK, pre-dose blood samples were collected at each visit and tralokinumab concentrations in serum were determined. Mean Ctrough concentrations are presented at each indicated visit up to Week 72. All patients in the FAS who received tralokinumab and who had PK blood samples were included in the PK analysis set. Results are reported for patients in the biomarker positive, biomarker negative and 'total' PK groups. PK analyses were not performed on samples taken from patients in the placebo Q2W group. Only patients with data available at the timepoints of testing were included in the analysis.

End point type

Secondary

End point timeframe

Blood samples were collected pre-dose at Baseline (Week 0), and at Week 2, Week 8, Week 26, Week 56 (follow-up) and Week 72 (follow-up)

End point values	Biomarker positive - Tralo 300 mg Q2W	Biomarker negative - Tralo 300 mg Q2W	Total - Tralo 300 mg Q2W
Number of subjects analysed	108 ^[36]	302 ^[37]	410 ^[38]
Units: micrograms/millilitre
geometric mean (geometric coefficient of variation)
Baseline (n=108, 302, 410)	99999999 ± 99999999	99999999 ± 99999999	99999999 ± 99999999
Week 2 (n=103, 293, 396)	24.049 ± 172.475	20.916 ± 280.452	21.690 ± 248.876
Week 8 (n=105, 280, 385)	55.887 ± 206.478	52.324 ± 226.298	53.272 ± 220.301
Week 26 (n=99, 274, 373)	58.375 ± 145.256	47.707 ± 319.456	50.332 ± 264.686
Week 56 (follow-up) (n=96, 275, 371)	12.363 ± 591.282	12.513 ± 707.267	12.474 ± 671.922
Week 72 (follow-up) (n=92, 264, 356)	0.325 ± 251.436	0.384 ± 242.035	0.368 ± 244.398

Notes
[36] - 99999999 denotes that the value was not calculable since below level of detection.
[37] - 99999999 denotes that the value was not calculable since below level of detection.
[38] - 99999999 denotes that the value was not calculable since below level of detection.

No statistical analyses for this end point

Secondary: Incidence rate of positive anti-drug antibodies (ADAs) including the characterization of their neutralizing potential

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End point title

Incidence rate of positive anti-drug antibodies (ADAs) including the characterization of their neutralizing potential

End point description

ADA assessments performed using a tiered approach (screening, confirmatory and titering assays). Confirmed ADA positive samples were also tested for neutralising antibodies (nAb). ADA prevalence defined as proportion of study population with drug-reactive antibodies at any point in time. ADA incidence (treatment-emergent ADA) defined as sum of treatment-induced (post-baseline ADA positive only) and treatment-boosted ADA. Persistently positive defined as positive at ≥2 post-baseline assessments (with ≥16 weeks between first and last positive) or positive at last post-baseline assessment. Transiently positive defined as having ≥1 post-baseline ADA positive assessment and not fulfilling conditions of persistently positive. Treatment-boosted ADA defined as baseline positive ADA titer boosted to a 4-fold or higher level following drug administration. In some category titles 'positive' is denoted by 'pos'. Only patients with data available at timepoints of testing included in the analysis.

End point type

Secondary

End point timeframe

Baseline (Week 0), Week 26, Week 56 (follow-up) and Week 72 (follow-up)

End point values	Tralo 300 mg Q2W	Placebo
Number of subjects analysed	405	394
Units: Participants
ADA prevalence	7	8
ADA incidence	5	3
ADA positive at baseline	2	5
ADA positive post-baseline	5	6
ADA pos post-baseline & pos at baseline	0	3
ADA pos post-baseline & not detected at baseline	5	3
ADA not detected post-baseline & pos at baseline	2	2
Persistent Positive	3	6
Transient Positive	2	0
Treatment-boosted ADA	0	0
nAB positive at any visit	5	2

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Serious and non-serious adverse event (AE) data reported for the treatment period, from baseline (Week 0) to end of treatment (Week 52). Deaths (all causes) is reported for the overall study period (including the extended follow-up period), up to Week 72.

Adverse event reporting additional description

Treatment-emergent AEs were defined with an onset date ≥ the first day of IP and ≤ (the last day of IP + 2 weeks). Patient population was the safety analysis set which included all patients who received at least one dose of IP.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Tralo 300 mg Q2W

Reporting group description

Tralokinumab 300 mg administered subcutaneously Q2W over a 52-week treatment period (up to 26 doses).

Reporting group title

Placebo

Reporting group description

Placebo administered subcutaneously Q2W over a 52-week treatment period (up to 26 doses).

Serious adverse events	Tralo 300 mg Q2W	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	35 / 425 (8.24%)	39 / 422 (9.24%)
number of deaths (all causes)	1	4
number of deaths resulting from adverse events	1	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Rectal cancer
subjects affected / exposed	0 / 425 (0.00%)	1 / 422 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Oedema peripheral
subjects affected / exposed	1 / 425 (0.24%)	0 / 422 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Eosinophilic granulomatosis with polyangiitis
subjects affected / exposed	0 / 425 (0.00%)	1 / 422 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Adnexa uteri pain
subjects affected / exposed	0 / 425 (0.00%)	1 / 422 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ovarian cyst
subjects affected / exposed	1 / 425 (0.24%)	0 / 422 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Uterine haemorrhage
subjects affected / exposed	0 / 425 (0.00%)	1 / 422 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	17 / 425 (4.00%)	23 / 422 (5.45%)
occurrences causally related to treatment / all	0 / 17	0 / 30
deaths causally related to treatment / all	0 / 0	0 / 1
Bronchitis chronic
subjects affected / exposed	1 / 425 (0.24%)	0 / 422 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nasal polyps
subjects affected / exposed	0 / 425 (0.00%)	1 / 422 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Suicidal ideation
subjects affected / exposed	1 / 425 (0.24%)	0 / 422 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 425 (0.24%)	0 / 422 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 425 (0.24%)	0 / 422 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Humerus fracture
subjects affected / exposed	1 / 425 (0.24%)	0 / 422 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	1 / 425 (0.24%)	0 / 422 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	1 / 425 (0.24%)	0 / 422 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 425 (0.00%)	1 / 422 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	0 / 425 (0.00%)	1 / 422 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 425 (0.24%)	0 / 422 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cardiac failure
subjects affected / exposed	0 / 425 (0.00%)	1 / 422 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 425 (0.24%)	0 / 422 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Vascular headache
subjects affected / exposed	0 / 425 (0.00%)	1 / 422 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Colitis ulcerative
subjects affected / exposed	0 / 425 (0.00%)	1 / 422 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 425 (0.00%)	1 / 422 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspepsia
subjects affected / exposed	1 / 425 (0.24%)	0 / 422 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematochezia
subjects affected / exposed	0 / 425 (0.00%)	1 / 422 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal ulcer
subjects affected / exposed	0 / 425 (0.00%)	1 / 422 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	0 / 425 (0.00%)	1 / 422 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Umbilical hernia
subjects affected / exposed	0 / 425 (0.00%)	1 / 422 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	1 / 425 (0.24%)	0 / 422 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Vitiligo
subjects affected / exposed	1 / 425 (0.24%)	0 / 422 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Urinary incontinence
subjects affected / exposed	0 / 425 (0.00%)	1 / 422 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Patellofemoral pain syndrome
subjects affected / exposed	1 / 425 (0.24%)	0 / 422 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 425 (0.00%)	1 / 422 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis A
subjects affected / exposed	0 / 425 (0.00%)	1 / 422 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Laryngitis viral
subjects affected / exposed	0 / 425 (0.00%)	1 / 422 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	1 / 425 (0.24%)	0 / 422 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Otitis media acute
subjects affected / exposed	1 / 425 (0.24%)	0 / 422 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	4 / 425 (0.94%)	3 / 422 (0.71%)
occurrences causally related to treatment / all	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	1 / 425 (0.24%)	0 / 422 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tracheobronchitis
subjects affected / exposed	1 / 425 (0.24%)	0 / 422 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 425 (0.00%)	1 / 422 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	1 / 425 (0.24%)	0 / 422 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Metabolism and nutrition disorders
Obesity
subjects affected / exposed	0 / 425 (0.00%)	1 / 422 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Type 2 diabetes mellitus
subjects affected / exposed	1 / 425 (0.24%)	0 / 422 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Tralo 300 mg Q2W	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	159 / 425 (37.41%)	152 / 422 (36.02%)
Nervous system disorders
Headache
subjects affected / exposed	40 / 425 (9.41%)	32 / 422 (7.58%)
occurrences all number	76	49
General disorders and administration site conditions
Injection site reaction
subjects affected / exposed	23 / 425 (5.41%)	3 / 422 (0.71%)
occurrences all number	93	5
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	35 / 425 (8.24%)	47 / 422 (11.14%)
occurrences all number	51	79
Infections and infestations
Bronchitis
subjects affected / exposed	34 / 425 (8.00%)	31 / 422 (7.35%)
occurrences all number	59	50
Upper respiratory tract infection
subjects affected / exposed	29 / 425 (6.82%)	31 / 422 (7.35%)
occurrences all number	49	39
Viral upper respiratory tract infection
subjects affected / exposed	50 / 425 (11.76%)	52 / 422 (12.32%)
occurrences all number	71	80

More information

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Were there any global substantial amendments to the protocol? Yes

17 Nov 2014

- Change in Forced Vital Capacity and Forced Expiratory Flow 25-75% were added as exploratory variables. - Death events were included in the adjudication process. - Inclusion criteria were amended for the following reasons: to clarify what constitutes acceptable documentation to support patient eligibility; to make the protocol consistent with standard of care across included regions; to clarify the washout period for BD prior to the pre-BD FEV1 test and the reversibility test. - To add clarifications to the study plan and timing of procedures table. - To clarify the timing and procedures for an IP discontinuation (IPD) visit for those patients discontinuing IP prematurely. - To clarify that urinalysis will be completed at all unscheduled visits. - To include the haematology/haemostasis assessment schedule for the IPD visit. - To include the urinalysis schedule for the IPD visit and unscheduled visit, and to clarify the local dipstick test procedure. - Evaluation of cardiovascular and malignancy AEs occurring after randomisation were added to the adjudication committee responsibilities as a result of sponsor decision to proactively implement independent adjudication of these across all Phase 3 studies conducted with human antibodies in patients with severe asthma. - To amend the asthma medications restrictions, including clarification for prophylactic use of short-acting β2-agonists, clarification of use of once daily asthma medications, to clarify the restrictions on bronchodilators prior to run-in visit and during the treatment period, and required rescheduling of the FEV1 visit if the indicated washout times are not adhered to. - To clarify the immunotherapy restrictions. - Testing strategy for primary and key secondary objectives was revised.

19 May 2015

- Global Impression of Change assessment was added to obtain an early indicator of patients’ response to treatment. - Evaluation of cardiovascular, cerebrovascular and malignancy adverse events occurring after randomisation were added to the adjudication committee responsibilities as a result of sponsor decision to proactively implement independent adjudication of these across all Phase 3 studies conducted with human antibodies in patients with severe asthma. A specialist in neurology was added to the adjudication committee. - An immunoglobulin E measurement was added during the treatment period to obtain an early indication of patients’ response to treatment. - The AE follow-up reporting period definition was amended to include the whole period up to 72 weeks for all patients.

08 Oct 2015

- The minimum interval of 7 days required between 2 dosing visits was clarified.

09 Jun 2017

- Based on the results of the pivotal Phase 3 study (D2210C00007), the primary and secondary populations, the biomarker strategy and the hierarchical testing strategy population were all clarified.

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Annualised asthma exacerbation rate (AAER) up to Week 52

Primary: Annualised asthma exacerbation rate (AAER) up to Week 52

Secondary: Percent change from baseline to Week 52 in pre-dose/pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV1)

Secondary: Percent change from baseline to Week 52 in pre-dose/pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV1)

Secondary: Change from baseline to Week 52 in total asthma symptom score (bi-weekly means)

Secondary: Change from baseline to Week 52 in total asthma symptom score (bi-weekly means)

Secondary: Change from baseline to Week 52 in Asthma Quality of Life Questionnaire for 12 Years and Older (AQLQ(S)+12) total score

Secondary: Change from baseline to Week 52 in Asthma Quality of Life Questionnaire for 12 Years and Older (AQLQ(S)+12) total score

Secondary: Change from baseline to Week 52 in Asthma Control Questionnaire-6 (ACQ-6) score

Secondary: Change from baseline to Week 52 in Asthma Control Questionnaire-6 (ACQ-6) score

Secondary: AAER associated with an ER/UC visit, or a hospitalisation up to Week 52

Secondary: AAER associated with an ER/UC visit, or a hospitalisation up to Week 52

Secondary: Change from baseline in European Quality of Life - 5 Dimension 5 Levels (EQ-5D-5L) visual analogue scale (VAS) scores at Week 52

Secondary: Change from baseline in European Quality of Life - 5 Dimension 5 Levels (EQ-5D-5L) visual analogue scale (VAS) scores at Week 52

Secondary: Change from baseline in total asthma rescue medication use at Week 52 (bi-weekly means)

Secondary: Change from baseline in total asthma rescue medication use at Week 52 (bi-weekly means)

Secondary: Change from baseline in home peak expiratory flow (PEF) (morning and evening) at Week 52

Secondary: Change from baseline in home peak expiratory flow (PEF) (morning and evening) at Week 52

Secondary: Change from baseline in night-time awakenings due to asthma requiring rescue medication use at Week 52 (bi-weekly means [percentage])

Secondary: Change from baseline in night-time awakenings due to asthma requiring rescue medication use at Week 52 (bi-weekly means [percentage])

Secondary: Number of patients with ≥1 asthma exacerbation up to Week 52

Secondary: Number of patients with ≥1 asthma exacerbation up to Week 52

Secondary: Work Productivity and Activity Impairment Questionnaire and Classroom Impairment Questions (WPAI+CIQ): Productivity Loss at Week 52

Secondary: Work Productivity and Activity Impairment Questionnaire and Classroom Impairment Questions (WPAI+CIQ): Productivity Loss at Week 52

Secondary: WPAI+CIQ: Activity Impairment at Week 52

Secondary: WPAI+CIQ: Activity Impairment at Week 52

Secondary: Asthma-related healthcare encounters by type up to Week 52

Secondary: Asthma-related healthcare encounters by type up to Week 52

Secondary: Asthma-related healthcare encounters by type up to Week 52: Hospitalisations

Secondary: Asthma-related healthcare encounters by type up to Week 52: Hospitalisations

Secondary: Asthma-related healthcare encounters by type up to Week 52: Spirometry

Secondary: Asthma-related healthcare encounters by type up to Week 52: Spirometry

Secondary: Serum trough concentration (Ctrough) of tralokinumab during the treatment period up to Week 72

Secondary: Serum trough concentration (Ctrough) of tralokinumab during the treatment period up to Week 72

Secondary: Incidence rate of positive anti-drug antibodies (ADAs) including the characterization of their neutralizing potential

Secondary: Incidence rate of positive anti-drug antibodies (ADAs) including the characterization of their neutralizing potential

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information