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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 1)

Summary
EudraCT number	2013-005614-35
Trial protocol	DE HU PL SK BG BE
Global end of trial date	18 Jul 2017

Results information
Results version number	v2(current)
This version publication date	21 Jun 2018
First version publication date	27 Jan 2018
Other versions	v1
Version creation reason

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

D2210C00007

ISRCTN number

US NCT number

NCT02161757

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

18 Jul 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

28 Feb 2017

Global end of trial reached?

Yes

Global end of trial date

18 Jul 2017

Was the trial ended prematurely?

Main objective of the trial

To evaluate the effect of tralokinumab 300 milligrams (mg) administered every 2 weeks compared with placebo on the annualised asthma exacerbation rate (AAER) in 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

13 Jun 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: 281

Country: Number of subjects enrolled

Bulgaria: 170

Country: Number of subjects enrolled

Poland: 166

Country: Number of subjects enrolled

Argentina: 119

Country: Number of subjects enrolled

Peru: 101

Country: Number of subjects enrolled

Ukraine: 80

Country: Number of subjects enrolled

Vietnam: 80

Country: Number of subjects enrolled

Korea, Republic of: 75

Country: Number of subjects enrolled

Hungary: 59

Country: Number of subjects enrolled

Germany: 32

Country: Number of subjects enrolled

Colombia: 15

Country: Number of subjects enrolled

Slovakia: 12

Country: Number of subjects enrolled

Belgium: 9

Country: Number of subjects enrolled

Spain: 3

Worldwide total number of subjects

1202

EEA total number of subjects

451

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)

963

From 65 to 84 years

196

85 years and over

Subject disposition

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Recruitment details

First patient enrolled: 13 Jun 2014; Week 52 cut-off: 28 Feb 2017; Last Patient Last Visit Week 72: 18 Jul 2017. Study performed at 254 sites in 14 countries. Patients were maintained on currently prescribed inhaled corticosteroid long-acting β2-agonist therapy + any additional maintenance asthma controller medications throughout the study period.

Screening details

2248 patients signed informed consent, 1669 entered screening/run-in period, 1207 patients were randomised to receive treatment with tralokinumab 300 mg, or placebo, every 2 weeks (Q2W) or every 4 weeks (Q4W). Of the 1207 patients randomised, 1202 received investigational product (IP).

Period 1 title

Randomised Through Start Treatment

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, investigational product (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). Follow-up visits were conducted at Weeks 56 and 72.

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 milligram/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.

Tralo 300 mg Q4W

Arm description

Tralokinumab 300 mg administered subcutaneously Q4W over a 52-week treatment period (up to 13 doses). Follow-up visits were conducted at Weeks 56 and 72.

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 was administered subcutaneously over a 52-week treatment period. The placebo treatment group is a pooled treatment group (placebo Q2W + placebo Q4W) where the 2 placebo cohorts were given weights proportional to the number of patients in each cohort. Follow-up visits were conducted at Weeks 56 and 72.

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	Tralo 300 mg Q4W	Placebo
Started	401	406	400
Completed	398	404	400
Not completed	3	2	0
Did not receive treatment	3	2	-

Period 2 title

Treatment Through Study Completion

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

Tralo 300 mg Q4W

Arm description

Tralokinumab 300 mg administered subcutaneously Q4W over a 52-week treatment period (up to 13 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

Placebo

Arm description

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 who received 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 IP. Period 2 is therefore the baseline period.

Number of subjects in period 2	Tralo 300 mg Q2W	Tralo 300 mg Q4W	Placebo
Started	398	404	400
Completed treatment for Week 52 cut-off	332 ^[2]	355 ^[3]	360 ^[4]
Completed	341	361	361
Not completed	57	43	39
Adverse event, serious fatal	2	1	1
Consent withdrawn by subject	27	19	20
Adverse event, non-fatal	1	1	-
Unspecified	20	19	12
Lost to follow-up	7	2	4
Protocol deviation	-	1	2

Notes
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The Milestone field reports the number of patients who completed treatment up to the Week 52 data cut-off, whereas the Completed field reports the number of patients who completed the study up to Week 72. The results are correctly stated for the Placebo arm that more patients completed the study overall compared to those completing treatment up to Week 52 since the latter also included patients who discontinued treatment but who completed study assessments.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The Milestone field reports the number of patients who completed treatment up to the Week 52 data cut-off, whereas the Completed field reports the number of patients who completed the study up to Week 72. The results are correctly stated for the Tralo 300 mg Q2W arm that more patients completed the study overall compared to those completing treatment up to Week 52 since the latter also included patients who discontinued treatment but who completed study assessments.
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The Milestone field reports the number of patients who completed treatment up to the Week 52 data cut-off, whereas the Completed field reports the number of patients who completed the study up to Week 72. The results are correctly stated for the Tralo 300 mg Q4W arm that more patients completed the study overall compared to those completing treatment up to Week 52 since the latter also included patients who discontinued treatment but who completed study assessments.

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

Tralo 300 mg Q4W

Reporting group description

Tralokinumab 300 mg administered subcutaneously Q4W over a 52-week treatment period (up to 13 doses).

Reporting group title

Placebo

Reporting group description

Reporting group values	Tralo 300 mg Q2W	Tralo 300 mg Q4W	Placebo	Total
Number of subjects	398	404	400	1202
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	14	15	14	43
Adults (18-64 years)	332	322	309	963
From 65-84 years	52	67	77	196
85 years and over	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	49.4 ( 14.3 )	51.1 ( 13.9 )	51.4 ( 14.3 )	-
Sex: Female, Male
Units: Subjects
Female	252	281	265	798
Male	146	123	135	404
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	21	22	25	68
Asian	53	55	55	163
Native Hawaiian or Other Pacific Islander	1	0	0	1
Black or African American	21	16	14	51
White	285	297	288	870
More than one race	0	0	0	0
Unknown or Not Reported	17	14	18	49

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). Follow-up visits were conducted at Weeks 56 and 72.

Reporting group title

Tralo 300 mg Q4W

Reporting group description

Tralokinumab 300 mg administered subcutaneously Q4W over a 52-week treatment period (up to 13 doses). Follow-up visits were conducted at Weeks 56 and 72.

Reporting group title

Placebo

Reporting group description

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

Tralo 300 mg Q4W

Reporting group description

Tralokinumab 300 mg administered subcutaneously Q4W over a 52-week treatment period (up to 13 doses).

Reporting group title

Placebo

Reporting group description

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	Tralo 300 mg Q4W	Placebo
Number of subjects analysed	398	404	400
Units: Events/year
number (confidence interval 95%)	0.56 (0.46 to 0.67)	0.54 (0.45 to 0.65)	0.60 (0.50 to 0.72)

AAER: rate ratio

Statistical analysis description

Tralo 300 mg Q2W vs placebo. 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.

Comparison groups

Tralo 300 mg Q2W v Placebo

Number of subjects included in analysis

798

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.5859

Method

Negative binomial

Parameter type

Rate ratio

Point estimate

0.93

Confidence interval

level

95%

sides

2-sided

lower limit

0.72

upper limit

1.21

Notes
[1] - 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

Statistical analysis description

Tralo 300 mg Q4W vs placebo. 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.

Comparison groups

Tralo 300 mg Q4W v Placebo

Number of subjects included in analysis

804

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

= 0.4406

Method

Negative binomial

Parameter type

Rate ratio

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

0.7

upper limit

1.17

Notes
[2] - 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

Statistical analysis description

Comparison groups

Tralo 300 mg Q2W v Placebo

Number of subjects included in analysis

798

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.5859

Method

Negative binominal

Parameter type

Rate reduction

Point estimate

7.01

Confidence interval

level

95%

sides

2-sided

lower limit

-20.76

upper limit

28.39

Notes
[3] - 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

Statistical analysis description

Comparison groups

Tralo 300 mg Q4W v Placebo

Number of subjects included in analysis

804

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

P-value

= 0.4406

Method

Negative binominal

Parameter type

Rate reduction

Point estimate

9.76

Confidence interval

level

95%

sides

2-sided

lower limit

-17.16

upper limit

30.5

Notes
[4] - 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	Tralo 300 mg Q4W	Placebo
Number of subjects analysed	357	373	363
Units: Percent change from baseline
arithmetic mean (standard deviation)	16.366 ( 27.349 )	12.099 ( 26.253 )	10.136 ( 24.206 )

Percent change from baseline in pre-BD FEV1

Statistical analysis description

Tralo 300 mg Q2W vs placebo. Restricted maximum likelihood (REML) based repeated measures analysis performed 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

720

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

Method

Parameter type

Least square (LS) Mean difference

Point estimate

6.03

Confidence interval

level

95%

sides

2-sided

lower limit

2.34

upper limit

9.73

Notes
[5] - 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.

Percent change from baseline in pre-BD FEV1

Statistical analysis description

Tralo 300 mg Q4W vs placebo. REML based repeated measures analysis performed on patients with a baseline pre-dose/pre-BD FEV1 assessment.

Comparison groups

Tralo 300 mg Q4W v Placebo

Number of subjects included in analysis

736

Analysis specification

Pre-specified

Analysis type

superiority ^[6]

Method

Parameter type

LS Mean difference

Point estimate

2.1

Confidence interval

level

95%

sides

2-sided

lower limit

-1.58

upper limit

5.77

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.

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	Tralo 300 mg Q4W	Placebo
Number of subjects analysed	313	313	312
Units: Scores on a scale
arithmetic mean (standard deviation)	-1.09 ( 1.22 )	-1.00 ( 1.11 )	-1.03 ( 1.13 )

Change from baseline in total asthma symptom score

Statistical analysis description

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

625

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

Method

Parameter type

LS Mean difference

Point estimate

-0.09

Confidence interval

level

95%

sides

2-sided

lower limit

-0.23

upper limit

0.04

Notes
[7] - 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.

Change from baseline in total asthma symptom score

Statistical analysis description

Tralo 300 mg Q4W vs placebo. REML based repeated measures analysis.

Comparison groups

Tralo 300 mg Q4W v Placebo

Number of subjects included in analysis

625

Analysis specification

Pre-specified

Analysis type

superiority ^[8]

Method

Parameter type

LS Mean difference

Point estimate

-0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.15

upper limit

0.12

Notes
[8] - 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	Tralo 300 mg Q4W	Placebo
Number of subjects analysed	304	321	315
Units: Scores on a scale
arithmetic mean (standard deviation)	1.18 ( 1.17 )	1.16 ( 1.14 )	1.03 ( 1.24 )

Change in mean score from baseline for AQLQ(S)+12

Statistical analysis description

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

619

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

Method

Parameter type

LS Mean difference

Point estimate

0.15

Confidence interval

level

95%

sides

2-sided

lower limit

-0.01

upper limit

0.31

Notes
[9] - 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.

Change in mean score from baseline for AQLQ(S)+12

Statistical analysis description

Tralo 300 mg Q4W vs placebo. REML based repeated measures analysis.

Comparison groups

Tralo 300 mg Q4W v Placebo

Number of subjects included in analysis

636

Analysis specification

Pre-specified

Analysis type

superiority ^[10]

Method

Parameter type

LS Mean difference

Point estimate

0.12

Confidence interval

level

95%

sides

2-sided

lower limit

-0.03

upper limit

0.28

Notes
[10] - 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	Tralo 300 mg Q4W	Placebo
Number of subjects analysed	324	344	329
Units: Scores on a scale
arithmetic mean (standard deviation)	-1.19 ( 1.06 )	-1.12 ( 1.03 )	-1.02 ( 1.14 )

Change in mean score from baseline for ACQ-6

Statistical analysis description

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

653

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

Method

Parameter type

LS Mean difference

Point estimate

-0.16

Confidence interval

level

95%

sides

2-sided

lower limit

-0.29

upper limit

-0.02

Notes
[11] - 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.

Change in mean score from baseline for ACQ-6

Statistical analysis description

Tralo 300 mg Q4W vs placebo. REML based repeated measures analysis.

Comparison groups

Tralo 300 mg Q4W v Placebo

Number of subjects included in analysis

673

Analysis specification

Pre-specified

Analysis type

superiority ^[12]

Method

Parameter type

LS Mean difference

Point estimate

-0.12

Confidence interval

level

95%

sides

2-sided

lower limit

-0.26

upper limit

0.01

Notes
[12] - 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	Tralo 300 mg Q4W	Placebo
Number of subjects analysed	398	404	400
Units: Events/year
number (confidence interval 95%)	0.04 (0.02 to 0.06)	0.06 (0.04 to 0.09)	0.07 (0.05 to 0.11)

AAER associated with ER/UC visit / hospitalisation

Statistical analysis description

Tralo 300 mg Q2W vs placebo.

Comparison groups

Tralo 300 mg Q2W v Placebo

Number of subjects included in analysis

798

Analysis specification

Pre-specified

Analysis type

superiority ^[13]

P-value

= 0.0369

Method

Negative binomial

Parameter type

Rate ratio

Point estimate

0.54

Confidence interval

level

95%

sides

2-sided

lower limit

0.3

upper limit

0.96

Notes
[13] - 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 associated with ER/UC visit / hospitalisation

Statistical analysis description

Tralo 300 mg Q4W vs placebo.

Comparison groups

Tralo 300 mg Q4W v Placebo

Number of subjects included in analysis

804

Analysis specification

Pre-specified

Analysis type

superiority ^[14]

P-value

= 0.3603

Method

Negative binomial

Parameter type

Rate ratio

Point estimate

0.78

Confidence interval

level

95%

sides

2-sided

lower limit

0.46

upper limit

1.33

Notes
[14] - 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	Tralo 300 mg Q4W	Placebo
Number of subjects analysed	306	319	324
Units: Scores on a scale
arithmetic mean (standard deviation)	10.68 ( 20.33 )	9.00 ( 18.99 )	10.06 ( 18.92 )

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	Tralo 300 mg Q4W	Placebo
Number of subjects analysed	313	313	312
Units: Puffs/day
arithmetic mean (standard deviation)	-2.18 ( 3.46 )	-2.15 ( 3.69 )	-2.04 ( 3.84 )

Mean change from baseline in rescue medication use

Statistical analysis description

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

625

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

Method

Parameter type

LS Mean difference

Point estimate

-0.11

Confidence interval

level

95%

sides

2-sided

lower limit

-0.51

upper limit

0.29

Notes
[15] - 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.

Mean change from baseline in rescue medication use

Statistical analysis description

Tralo 300 mg Q4W vs placebo. REML based repeated measures analysis.

Comparison groups

Tralo 300 mg Q4W v Placebo

Number of subjects included in analysis

625

Analysis specification

Pre-specified

Analysis type

superiority ^[16]

Method

Parameter type

LS Mean difference

Point estimate

-0.16

Confidence interval

level

95%

sides

2-sided

lower limit

-0.56

upper limit

0.24

Notes
[16] - 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.

End point type

Secondary

End point timeframe

Baseline (Week 0) and Week 52

End point values	Tralo 300 mg Q2W	Tralo 300 mg Q4W	Placebo
Number of subjects analysed	321	326	329
Units: L/min
arithmetic mean (standard deviation)
Morning PEF (n=320,326,329)	12.95 ( 85.66 )	7.55 ( 74.97 )	5.23 ( 74.10 )
Evening PEF (n=321,319,326)	8.89 ( 83.02 )	0.68 ( 73.19 )	-0.28 ( 76.05 )

Mean change from baseline in morning PEF

Statistical analysis description

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

650

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

Method

Parameter type

LS Mean difference

Point estimate

6.25

Confidence interval

level

95%

sides

2-sided

lower limit

-3.53

upper limit

16.03

Notes
[17] - 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.

Mean change from baseline in morning PEF

Statistical analysis description

Tralo 300 mg Q4W vs placebo. REML based repeated measures analysis.

Comparison groups

Tralo 300 mg Q4W v Placebo

Number of subjects included in analysis

655

Analysis specification

Pre-specified

Analysis type

superiority ^[18]

Method

Parameter type

LS Mean difference

Point estimate

1.77

Confidence interval

level

95%

sides

2-sided

lower limit

-7.99

upper limit

11.53

Notes
[18] - 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.

Mean change from baseline in evening PEF

Statistical analysis description

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

650

Analysis specification

Pre-specified

Analysis type

superiority ^[19]

Method

Parameter type

LS Mean difference

Point estimate

7.14

Confidence interval

level

95%

sides

2-sided

lower limit

-2.6

upper limit

16.87

Notes
[19] - 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.

Mean change from baseline in evening PEF

Statistical analysis description

Traco 300 mg Q4W vs placebo. REML based repeated measures analysis.

Comparison groups

Tralo 300 mg Q4W v Placebo

Number of subjects included in analysis

655

Analysis specification

Pre-specified

Analysis type

superiority ^[20]

Method

Parameter type

LS Mean difference

Point estimate

0.61

Confidence interval

level

95%

sides

2-sided

lower limit

-9.13

upper limit

10.35

Notes
[20] - 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	Tralo 300 mg Q4W	Placebo
Number of subjects analysed	346	357	357
Units: Percentage of nights with awakenings
arithmetic mean (standard deviation)	-37.63 ( 37.27 )	-35.17 ( 37.49 )	-36.00 ( 36.69 )

Mean change from baseline in % of awakenings

Statistical analysis description

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

703

Analysis specification

Pre-specified

Analysis type

superiority ^[21]

Method

Parameter type

LS Mean difference

Point estimate

-1.8

Confidence interval

level

95%

sides

2-sided

lower limit

-5.29

upper limit

1.69

Notes
[21] - 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.

Mean change from baseline in % of awakenings

Statistical analysis description

Tralo 300 mg Q4W vs placebo. REML based repeated measures analysis.

Comparison groups

Tralo 300 mg Q4W v Placebo

Number of subjects included in analysis

714

Analysis specification

Pre-specified

Analysis type

superiority ^[22]

Method

Parameter type

LS Mean difference

Point estimate

-2.36

Confidence interval

level

95%

sides

2-sided

lower limit

-5.84

upper limit

1.12

Notes
[22] - 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	Tralo 300 mg Q4W	Placebo
Number of subjects analysed	398	404	400
Units: Participants	128	124	133

Proportion of patients ≥ 1 asthma exacerbations

Statistical analysis description

Tralo 300 mg Q2W vs placebo.

Comparison groups

Tralo 300 mg Q2W v Placebo

Number of subjects included in analysis

798

Analysis specification

Pre-specified

Analysis type

superiority ^[23]

P-value

= 0.732

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.95

Confidence interval

level

95%

sides

2-sided

lower limit

0.71

upper limit

1.28

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

Proportion of patients ≥ 1 asthma exacerbations

Statistical analysis description

Tralo 300 mg Q4W vs placebo.

Comparison groups

Tralo 300 mg Q4W v Placebo

Number of subjects included in analysis

804

Analysis specification

Pre-specified

Analysis type

superiority ^[24]

P-value

= 0.421

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.88

Confidence interval

level

95%

sides

2-sided

lower limit

0.65

upper limit

1.19

Notes
[24] - The estimate of each odds ratio was obtained from two separate models, 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.

End point type

Secondary

End point timeframe

At Week 52

End point values	Tralo 300 mg Q2W	Tralo 300 mg Q4W	Placebo
Number of subjects analysed	123	130	137
Units: Percent productivity loss
arithmetic mean (standard deviation)
Currently employed (n=112,116,118)	27.71 ( 24.06 )	28.48 ( 25.11 )	31.25 ( 25.34 )
Currently in school (n=11,14,19)	33.13 ( 28.03 )	31.79 ( 34.28 )	32.31 ( 28.46 )

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.

End point type

Secondary

End point timeframe

At Week 52

End point values	Tralo 300 mg Q2W	Tralo 300 mg Q4W	Placebo
Number of subjects analysed	134	135	146
Units: Percent Impairment
arithmetic mean (standard deviation)
Currently employed (n=120,119,127)	23.25 ( 21.31 )	23.53 ( 22.57 )	27.01 ( 23.21 )
Currently in school (n=14,16,19)	29.29 ( 20.56 )	27.50 ( 29.55 )	28.95 ( 23.07 )

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	Tralo 300 mg Q4W	Placebo
Number of subjects analysed	398	404	400
Units: Encounters
Ambulance transport	5	15	16
Emergency room visits	59	87	64
Unscheduled outpatient visits	1750	1786	1705
Home visits	21	5	6
Telephone calls	515	463	198
Advanced pulmonary function test	84	70	67

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	Tralo 300 mg Q4W	Placebo
Number of subjects analysed	398	404	400
Units: Days	270	345	482

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	Tralo 300 mg Q4W	Placebo
Number of subjects analysed	398	404	400
Units: Assessments	489	520	502

No statistical analyses for this end point

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

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End point title

Serum trough concentration (Ctrough) of tralokinumab during the study period up to Week 72 ^[25]

End point description

To evaluate the pharmacokinetics (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 full analysis set who received tralokinumab and who had PK blood samples were included in the PK analysis set. 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 4, Week 8, Week 26, Week 52 and Week 72 (follow-up)

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The baseline period arms were ‘Tralo 300 mg Q2W’, ‘Tralo 300 mg Q4W’ and ‘Placebo’. Since this particular end point presents pharmacokinetic data of tralokinumab, it was not applicable to select the Placebo arm for the analysis.

End point values	Tralo 300 mg Q2W	Tralo 300 mg Q4W
Number of subjects analysed	394 ^[26]	401 ^[27]
Units: micrograms/millilitre
geometric mean (geometric coefficient of variation)
Baseline (n=394,401)	99999999 ( 99999999 )	99999999 ( 99999999 )
Week 4 (n=353,353)	34.690 ( 199.269 )	13.151 ( 188.026 )
Week 8 (n=358,366)	55.262 ( 159.824 )	19.243 ( 112.830 )
Week 26 (n=358,370)	52.766 ( 257.341 )	30.305 ( 255.039 )
Week 52 (n=354,373)	37.074 ( 675.764 )	14.290 ( 437.472 )
Week 72 (follow-up) (n=339,356)	0.419 ( 238.749 )	0.172 ( 171.973 )

Notes
[26] - 99999999 denotes that the value was not calculable.
[27] - 99999999 denotes that the value was not calculable.

No statistical analyses for this end point

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

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End point title

Incidence rate of positive anti-drug antibodies (ADAs) including the characterisation of their neutralising 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	Tralo 300 mg Q4W	Placebo
Number of subjects analysed	373	382	374
Units: Participants
ADA prevalence\|	7	7	9
ADA incidence	3	2	3
ADA positive at baseline	4	5	7
ADA positive post-baseline	3	3	8
ADA pos post-baseline & pos at baseline	0	1	6
ADA pos post-baseline & not detected at baseline	3	2	2
ADA not detected post-baseline & pos at baseline	4	4	1
Persistent Positive	2	2	7
Transient Positive	1	1	1
Treatment-boosted ADA	0	0	1
nAB positive at any visit	5	5	4

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 + dosing frequency). 'Dosing frequency’ was 2 or 4 weeks depending on whether patients were randomised to Q2W or Q4W dosing regimens. Patient population was safety analysis set which included all patients who received at least one dose of any 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). Follow-up visits were conducted at Weeks 56 and 72.

Reporting group title

Tralo 300 mg Q4W

Reporting group description

Tralokinumab 300 mg administered subcutaneously Q4W over a 52-week treatment period (up to 13 doses). Follow-up visits were conducted at Weeks 56 and 72.

Reporting group title

Placebo

Reporting group description

Serious adverse events	Tralo 300 mg Q2W	Tralo 300 mg Q4W	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	40 / 398 (10.05%)	39 / 404 (9.65%)	48 / 400 (12.00%)
number of deaths (all causes)	2	1	1
number of deaths resulting from adverse events	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	1 / 398 (0.25%)	1 / 404 (0.25%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cervix carcinoma
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Uterine cancer
subjects affected / exposed	0 / 398 (0.00%)	0 / 404 (0.00%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 398 (0.00%)	1 / 404 (0.25%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Eosinophilic granulomatosis with polyangiitis
subjects affected / exposed	0 / 398 (0.00%)	1 / 404 (0.25%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Ovarian cyst
subjects affected / exposed	0 / 398 (0.00%)	1 / 404 (0.25%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metrorrhagia
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostatitis
subjects affected / exposed	0 / 398 (0.00%)	0 / 404 (0.00%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	12 / 398 (3.02%)	19 / 404 (4.70%)	25 / 400 (6.25%)
occurrences causally related to treatment / all	0 / 15	0 / 23	0 / 39
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Atelectasis
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 398 (0.00%)	0 / 404 (0.00%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pharyngeal oedema
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hallucination
subjects affected / exposed	0 / 398 (0.00%)	1 / 404 (0.25%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Blood pressure increased
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Facial bones fracture
subjects affected / exposed	0 / 398 (0.00%)	0 / 404 (0.00%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	2 / 398 (0.50%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Limb injury
subjects affected / exposed	0 / 398 (0.00%)	1 / 404 (0.25%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	1 / 398 (0.25%)	1 / 404 (0.25%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Laceration
subjects affected / exposed	0 / 398 (0.00%)	0 / 404 (0.00%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Meniscus injury
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural complication
subjects affected / exposed	0 / 398 (0.00%)	1 / 404 (0.25%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post-traumatic pain
subjects affected / exposed	0 / 398 (0.00%)	0 / 404 (0.00%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	2 / 400 (0.50%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 398 (0.00%)	0 / 404 (0.00%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	0 / 398 (0.00%)	0 / 404 (0.00%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure acute
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 398 (0.00%)	0 / 404 (0.00%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sinus node dysfunction
subjects affected / exposed	0 / 398 (0.00%)	0 / 404 (0.00%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 398 (0.00%)	1 / 404 (0.25%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular disorder
subjects affected / exposed	0 / 398 (0.00%)	1 / 404 (0.25%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Radiculopathy
subjects affected / exposed	0 / 398 (0.00%)	0 / 404 (0.00%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	2 / 398 (0.50%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Carpal tunnel syndrome
subjects affected / exposed	0 / 398 (0.00%)	0 / 404 (0.00%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 398 (0.00%)	1 / 404 (0.25%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhagic stroke
subjects affected / exposed	0 / 398 (0.00%)	0 / 404 (0.00%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular encephalopathy
subjects affected / exposed	0 / 398 (0.00%)	1 / 404 (0.25%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vertebrobasilar insufficiency
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lymphadenopathy
subjects affected / exposed	0 / 398 (0.00%)	0 / 404 (0.00%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	0 / 398 (0.00%)	2 / 404 (0.50%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retinal detachment
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 398 (0.00%)	0 / 404 (0.00%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Erosive duodenitis
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 398 (0.00%)	0 / 404 (0.00%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Swollen tongue
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Umbilical hernia
subjects affected / exposed	0 / 398 (0.00%)	0 / 404 (0.00%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	2 / 398 (0.50%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Osteoarthritis
subjects affected / exposed	0 / 398 (0.00%)	2 / 404 (0.50%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ankylosing spondylitis
subjects affected / exposed	0 / 398 (0.00%)	1 / 404 (0.25%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	0 / 398 (0.00%)	0 / 404 (0.00%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteochondrosis
subjects affected / exposed	0 / 398 (0.00%)	1 / 404 (0.25%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rheumatoid arthritis
subjects affected / exposed	0 / 398 (0.00%)	0 / 404 (0.00%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal pain
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Synovitis
subjects affected / exposed	0 / 398 (0.00%)	1 / 404 (0.25%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Trigger finger
subjects affected / exposed	0 / 398 (0.00%)	0 / 404 (0.00%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Chronic sinusitis
subjects affected / exposed	0 / 398 (0.00%)	1 / 404 (0.25%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	0 / 398 (0.00%)	1 / 404 (0.25%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 398 (0.00%)	0 / 404 (0.00%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea infectious
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 398 (0.00%)	0 / 404 (0.00%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 398 (0.00%)	0 / 404 (0.00%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	3 / 398 (0.75%)	3 / 404 (0.74%)	4 / 400 (1.00%)
occurrences causally related to treatment / all	0 / 4	0 / 3	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia viral
subjects affected / exposed	0 / 398 (0.00%)	1 / 404 (0.25%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 398 (0.00%)	1 / 404 (0.25%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dyslipidaemia
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 398 (0.25%)	0 / 404 (0.00%)	0 / 400 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypovolaemia
subjects affected / exposed	0 / 398 (0.00%)	0 / 404 (0.00%)	1 / 400 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Tralo 300 mg Q2W	Tralo 300 mg Q4W	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	134 / 398 (33.67%)	145 / 404 (35.89%)	107 / 400 (26.75%)
Nervous system disorders
Headache
subjects affected / exposed	23 / 398 (5.78%)	31 / 404 (7.67%)	17 / 400 (4.25%)
occurrences all number	35	42	28
General disorders and administration site conditions
Injection site erythema
subjects affected / exposed	24 / 398 (6.03%)	12 / 404 (2.97%)	0 / 400 (0.00%)
occurrences all number	58	29	0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	35 / 398 (8.79%)	33 / 404 (8.17%)	28 / 400 (7.00%)
occurrences all number	55	43	45
Infections and infestations
Bronchitis
subjects affected / exposed	20 / 398 (5.03%)	23 / 404 (5.69%)	18 / 400 (4.50%)
occurrences all number	29	27	24
Upper respiratory tract infection
subjects affected / exposed	26 / 398 (6.53%)	48 / 404 (11.88%)	36 / 400 (9.00%)
occurrences all number	40	61	73
Viral upper respiratory tract infection
subjects affected / exposed	44 / 398 (11.06%)	48 / 404 (11.88%)	37 / 400 (9.25%)
occurrences all number	62	67	55

More information

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Were there any global substantial amendments to the protocol? Yes

30 Sep 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. - Additional samples were added for PK analysis to allow more extensive characterisation of the PK-pharmacodynamic relationship for tralokinumab. - Inclusion criteria were amended for the following reasons: to increase lower weight limit for adolescents to 40 kg; to clarify calculation of total daily ICS dose; 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 allow use of selective β-adrenergic antagonists. - Exclusion criteria were amended to include 5-lipoxygenase inhibitors (eg, Zileuton) and roflumilast as restricted medications and to disallow bronchial thermoplasty before study entry or during the study. - Asthma medication restrictions were amended to allow background asthma therapy according to local standard of care; to clarify the use of once daily asthma medications and to clarify the restrictions on BDs. - Safety analysis set definition was revised. - Testing strategy for primary and key secondary objectives was revised.

23 Feb 2015

- Clinical - Global Impression of Change assessment was added to obtain an early indicator of subjects’ 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.

08 Oct 2015

- Dosing requirements and restrictions were 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 study period up to Week 72

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

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

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

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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