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Clinical Trial Results:
A randomised placebo-controlled trial of anti-ST2 in COPD (COPD-ST2OP)

Summary
EudraCT number	2018-000919-24
Trial protocol	GB
Global end of trial date	31 Dec 2020

Results information
Results version number	v1(current)
This version publication date	28 Jan 2022
First version publication date	28 Jan 2022
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

0671

ISRCTN number

US NCT number

NCT03615040

WHO universal trial number (UTN)

U1111-1210-1335

Other trial identifiers

IRAS ID: 244758, REC reference: 18/EM/0189, Funder reference: GB40568

Sponsor organisation name

University of Leicester

Sponsor organisation address

Research Ethics, Governance and Integrity Office, Leicester General Hospital, Leicester, United Kingdom, LE5 4PW

Public contact

COPD-ST2OP Trial Manager, Leicester Clinical Trials Unit, University of Leicester, COPD-ST2OP@leicester.ac.uk

Scientific contact

Prof Christopher Brightling, Chief Investigator, Department of Respiratory Sciences, University of Leicester, +44 (0)116 250 2704 , ceb17@leicester.ac.uk

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

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

17 Jun 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

11 Aug 2020

Global end of trial reached?

Yes

Global end of trial date

31 Dec 2020

Was the trial ended prematurely?

Main objective of the trial

1) To evaluate the efficacy of anti-ST2 versus placebo on frequency of moderate-to-severe exacerbations (health care utilisation resulting in treatment with systemic corticosteroids and/or antibiotics) in 48 weeks as an add-on to standard of care. 2) To assess the safety and tolerability of subcutaneous doses of anti-ST2 compared to placebo in adult patients with moderate to very severe COPD. 3) To assess the effects of anti-ST2 versus placebo both during stable visits and at the exacerbation events on the following: (a) Symptoms (b) Health status (c) Lung function (d) Inflammatory cell differentials: (i) Sputum cell count and (ii) Blood cell count (e) Airway morphometry (f) Pharmacogenomics

Protection of trial subjects

Eligibility criteria for this trial were carefully considered to ensure the safety of the participants. Patients with active or unstable recent cardiovascular disease (CVD) were excluded from the trial. Cardiac safety was evaluated with monitoring of vital signs, ECG assessments, the collection of relevant AEs, and other assessments described in the protocol. Lastly, to monitor other factors that may impact upon cardiovascular risk, HbA1c, fasting glucose, and lipid panels were monitored to observe for indication of possible atherogenic and metabolic effects of MSTT1041A exposure. In populations at high risk for pre-existing CVD, additional monitoring strategies including echocardiography and cardiac biomarkers (e.g., NTproBNP) were also used. Serious Adverse Events (SAEs), Suspected Unexpected Serious Adverse Reaction (SUSARs) and deaths were subject to expedited reporting by the site to the Sponsor. Leicester CTU and the Sponsor provided monthly safety updates to the Data Safety Monitoring Committee (DSMC) and Genentech (funder and supplier of the trial drug and placebo), who reviewed the trial data periodically. In order to comply with the Medicines for Human Use (Clinical Trials) Regulations 2004, an accurate record of all Adverse Events (AEs) reported was maintained throughout the trial. Safety reviews occurred at monthly Trial Management Group (TMG) meetings and quarterly meetings with Genentech. Safety and tolerability (i.e. SAE/AE rate in the 48 weeks of the trial from first dose) was a key secondary outcome. Participants were evaluated for an additional 12 weeks following completion of the efficacy endpoint (visit 13, week 48). A procedure for unblinding was available 24/7 via a validated web-based randomisation system (Sealed Envelope).

Background therapy

Standard-of-care drug therapy as per British Thoracic Society (BTS) guidance for Chronic Obstructive Pulmonary Disease (COPD).

Evidence for comparator

Interleukin-33 (IL-33) is an alarmin released from the epithelium following damage. IL-33 is an IL-1 family alarmin cytokine constitutively expressed at epithelial barrier surfaces where it is rapidly released from cells during tissue injury. IL-33 signals through a receptor complex of IL-1 receptor-like 1 (IL1RL1) (known as ST2) and IL-1 receptor accessory protein (IL1RAcP) to initiate MyD88-dependent inflammatory pathways. The role of the IL33/ST2 axis in COPD is uncertain. IL33 has been implicated in eosinophil recruitment to the airway and maturation in the bone marrow largely via its effects upon innate lymphoid cells. IL33 increased following experimental cold in asthma and thus might play a role in the consequent inflammatory response and possible susceptibility to secondary bacterial infection in obstructive lung disease. MSTT1041A (official USAN name now astegolimab) 490mg subcutaneous or matched placebo was given every 4 weeks for a total of 12 doses. Participants were followed up for 60 weeks (i.e. 48 week treatment period and 12 week follow-up), with secondary outcome measures at baseline, 4, 12, 24, 36, 48 and 60 weeks and at exacerbations events presenting prior to treatment initiation. The dose and dosing interval was derived from an earlier PK/PD modelling and was the highest dose included in a phase IIb asthma study. The primary outcome measure was exacerbation frequency. Exacerbation events are relatively infrequent and can be affected by season, therefore a 48 week treatment duration with follow-up out to 12 months was chosen. Astegolimab has been investigated in 3 completed phase I studies. Additionally, a phase IIb study in patients with severe asthma and a phase II study in patients with atopic dermatitis have been completed. One phase II study in patients with severe COVID-19 pneumonia is ongoing, with patients having completed dosing. Astegolimab has been generally well tolerated and its safety profile remains favourable at this time.

Actual start date of recruitment

11 Oct 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 81

Worldwide total number of subjects

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)

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

Recruitment at a single centre. Potential participants were identified by the research team using a variety of methods: database of previous COPD trial participants who consented to be contacted for future trials; respiratory outpatient clinics/acute admission unit; self-referrals; GP practices. Recruitment ran between 11 Oct 2018 and 05 Jul 2019.

Screening details

Potential participants were assessed according to eligibility criteria at initial screening and provided written informed consent before commencing any trial-related procedures. Participants then entered a screening period for 7-14 days before randomisation. Those eligible were randomised into a 48-week treatment period (anti-ST2/placebo).

Number of subjects started

97 ^[1]

Intermediate milestone: Number of subjects

Subjects consented: 97

Intermediate milestone: Number of subjects

Subjects randomised: 81

Number of subjects completed

Reason: Number of subjects

Screen failure: 16

Notes
[1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: 97 patients consented to the trial and completed a screening visit (week 0). However, 16 of these were screen fails. Therefore, 81 participants were randomised (and thus enrolled) in the trial.

Period 1 title

Overall trial

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Assessor

Blinding implementation details

Participants, investigators, the trial management team and those involved in trial conduct remained blinded to treatment allocations until after database lock. Unblinded personnel included the trial statistician; pharmacy team; personnel responsible for trial drug preparation and reconstitution; trial monitor/Sponsor (one entity); and the DSMC in order to periodically review trial data. No emergency unblinding was required during the trial.

Are arms mutually exclusive

Yes

Anti-ST2

Arm description

Participants randomised to 490mg MSTT1041A via subcutaneous infusion every 4 weeks for 12 visits.

Arm type

Experimental

Investigational medicinal product name

MSTT1041A

Investigational medicinal product code

Other name

Astegolimab

Pharmaceutical forms

Solution for infusion

Routes of administration

Subcutaneous use

Dosage and administration details

MSTT1041A was administered by the blinded research personnel in the form of a 490mg subcutaneous infusion over 48 weeks (every 4 weeks for 12 months – maximum 12 doses). We therefore estimate a cumulative maximum exposure per participant of approximately 5.88g, with a total study cumulative maximum exposure across all participants (n=81) of 445.9g. This calculation takes into account the 14 participants withdrawn from the trial treatment.

Placebo

Arm description

Participants randomised to 490mg matched placebo via subcutaneous infusion every 4 weeks for 12 visits.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo was administered by the blinded research personnel in the form of a 490mg subcutaneous infusion over 48 weeks (every 4 weeks for 12 months – maximum 12 doses).

Number of subjects in period 1	Anti-ST2	Placebo
Started	42	39
Completed	42	39

Period 2 title

Week-4

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Assessor, Subject

Blinding implementation details

Are arms mutually exclusive

Yes

Anti-ST2

Arm description

Participants randomised to 490mg MSTT1041A via subcutaneous infusion every 4 weeks for 12 visits.

Arm type

Experimental

Investigational medicinal product name

MSTT1041A

Investigational medicinal product code

Other name

Astegolimab

Pharmaceutical forms

Solution for infusion

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo

Arm description

Participants randomised to 490mg matched placebo via subcutaneous infusion every 4 weeks for 12 visits.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo was administered by the blinded research personnel in the form of a 490mg subcutaneous infusion over 48 weeks (every 4 weeks for 12 months – maximum 12 doses).

Number of subjects in period 2	Anti-ST2	Placebo
Started	42	39
Completed	42	39

Period 3 title

Week-12

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Assessor

Blinding implementation details

Are arms mutually exclusive

Yes

Anti-ST2

Arm description

Participants randomised to 490mg MSTT1041A via subcutaneous infusion every 4 weeks for 12 visits.

Arm type

Experimental

Investigational medicinal product name

MSTT1041A

Investigational medicinal product code

Other name

Astegolimab

Pharmaceutical forms

Solution for infusion

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo

Arm description

Participants randomised to 490mg matched placebo via subcutaneous infusion every 4 weeks for 12 visits.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo was administered by the blinded research personnel in the form of a 490mg subcutaneous infusion over 48 weeks (every 4 weeks for 12 months – maximum 12 doses).

Number of subjects in period 3	Anti-ST2	Placebo
Started	42	39
Completed	41	38
Not completed	1	1
Death	-	1
Clinical diagnosis of lung cancer	1	-

Period 4 title

Week-24

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Assessor

Blinding implementation details

Are arms mutually exclusive

Yes

Anti-ST2

Arm description

Participants randomised to 490mg MSTT1041A via subcutaneous infusion every 4 weeks for 12 visits.

Arm type

Experimental

Investigational medicinal product name

MSTT1041A

Investigational medicinal product code

Other name

Astegolimab

Pharmaceutical forms

Solution for infusion

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo

Arm description

Participants randomised to 490mg matched placebo via subcutaneous infusion every 4 weeks for 12 visits.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo was administered by the blinded research personnel in the form of a 490mg subcutaneous infusion over 48 weeks (every 4 weeks for 12 months – maximum 12 doses).

Number of subjects in period 4	Anti-ST2	Placebo
Started	41	38
Completed	40	38
Not completed	1	0
Participant decision	1	-

Period 5 title

Week-36

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Assessor

Blinding implementation details

Are arms mutually exclusive

Yes

Anti-ST2

Arm description

Participants randomised to 490mg MSTT1041A via subcutaneous infusion every 4 weeks for 12 visits.

Arm type

Experimental

Investigational medicinal product name

MSTT1041A

Investigational medicinal product code

Other name

Astegolimab

Pharmaceutical forms

Solution for infusion

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo

Arm description

Participants randomised to 490mg matched placebo via subcutaneous infusion every 4 weeks for 12 visits.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo was administered by the blinded research personnel in the form of a 490mg subcutaneous infusion over 48 weeks (every 4 weeks for 12 months – maximum 12 doses).

Number of subjects in period 5	Anti-ST2	Placebo
Started	40	38
Completed	40	36
Not completed	0	2
Participant decision	-	2

Period 6 title

Week-48

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Assessor

Blinding implementation details

Are arms mutually exclusive

Yes

Anti-ST2

Arm description

Participants randomised to 490mg MSTT1041A via subcutaneous infusion every 4 weeks for 12 visits.

Arm type

Experimental

Investigational medicinal product name

MSTT1041A

Investigational medicinal product code

Other name

Astegolimab

Pharmaceutical forms

Solution for infusion

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo

Arm description

Participants randomised to 490mg matched placebo via subcutaneous infusion every 4 weeks for 12 visits.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo was administered by the blinded research personnel in the form of a 490mg subcutaneous infusion over 48 weeks (every 4 weeks for 12 months – maximum 12 doses).

Number of subjects in period 6	Anti-ST2	Placebo
Started	40	36
Completed	37	33
Not completed	3	3
Clinical diagnosis of Oesophageal cancer	1	-
Physician decision	2	2
Death	-	1

Baseline characteristics

Top of page

Reporting group title

Anti-ST2

Reporting group description

Participants randomised to 490mg MSTT1041A via subcutaneous infusion every 4 weeks for 12 visits.

Reporting group title

Placebo

Reporting group description

Participants randomised to 490mg matched placebo via subcutaneous infusion every 4 weeks for 12 visits.

Reporting group values	Anti-ST2	Placebo	Total
Number of subjects	42	39	81
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)	0	0	0
Adults (18-64 years)	12	4	16
From 65-84 years	30	35	65
85 years and over	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	67.6 ± 8.2	70.8 ± 6.2	-
Gender categorical
Units: Subjects
Female	17	13	30
Male	25	26	51
Smoking status
Units: Subjects
Current smoker	10	6	16
Ex smoker	32	33	65
Ethnicity
Units: Subjects
White	41	39	80
Indian	1	0	1
COPD GOLD stage
Units: Subjects
COPD GOLD stage I	1	0	1
COPD GOLD stage II	18	16	34
COPD GOLD stage III	14	16	30
COPD GOLD stage IV	9	7	16

Subject analysis set title

Over 48 Week (repeated measures)

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

The modified intention-to-treat will be comprised all the participants randomised to the trial (regardless of whether they received trial drug), analysed in their allocated group, where data is available. Therefore participants with missing outcome data will be excluded from the analysis (i.e complete case analysis). No imputation will be carried out for the missing data. Measurements are taken at week-4, week-12, week-24, week-36 and week-48

Subject analysis sets values	Over 48 Week (repeated measures)
Number of subjects	81
Age categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age continuous
Units: years
arithmetic mean (standard deviation)	69.1 ± 7.5
Gender categorical
Units: Subjects
Female
Male
Smoking status
Units: Subjects
Current smoker
Ex smoker
Ethnicity
Units: Subjects
White
Indian
COPD GOLD stage
Units: Subjects
COPD GOLD stage I
COPD GOLD stage II
COPD GOLD stage III
COPD GOLD stage IV

End points

Top of page

Reporting group title

Anti-ST2

Reporting group description

Participants randomised to 490mg MSTT1041A via subcutaneous infusion every 4 weeks for 12 visits.

Reporting group title

Placebo

Reporting group description

Participants randomised to 490mg matched placebo via subcutaneous infusion every 4 weeks for 12 visits.

Reporting group title

Anti-ST2

Reporting group description

Participants randomised to 490mg MSTT1041A via subcutaneous infusion every 4 weeks for 12 visits.

Reporting group title

Placebo

Reporting group description

Participants randomised to 490mg matched placebo via subcutaneous infusion every 4 weeks for 12 visits.

Reporting group title

Anti-ST2

Reporting group description

Participants randomised to 490mg MSTT1041A via subcutaneous infusion every 4 weeks for 12 visits.

Reporting group title

Placebo

Reporting group description

Participants randomised to 490mg matched placebo via subcutaneous infusion every 4 weeks for 12 visits.

Reporting group title

Anti-ST2

Reporting group description

Participants randomised to 490mg MSTT1041A via subcutaneous infusion every 4 weeks for 12 visits.

Reporting group title

Placebo

Reporting group description

Participants randomised to 490mg matched placebo via subcutaneous infusion every 4 weeks for 12 visits.

Reporting group title

Anti-ST2

Reporting group description

Participants randomised to 490mg MSTT1041A via subcutaneous infusion every 4 weeks for 12 visits.

Reporting group title

Placebo

Reporting group description

Participants randomised to 490mg matched placebo via subcutaneous infusion every 4 weeks for 12 visits.

Reporting group title

Anti-ST2

Reporting group description

Participants randomised to 490mg MSTT1041A via subcutaneous infusion every 4 weeks for 12 visits.

Reporting group title

Placebo

Reporting group description

Participants randomised to 490mg matched placebo via subcutaneous infusion every 4 weeks for 12 visits.

Subject analysis set title

Over 48 Week (repeated measures)

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Primary: Exacerbation rate in 48 weeks

Top of page

End point title

Exacerbation rate in 48 weeks

End point description

End point type

Primary

End point timeframe

The rate of moderate to severe exacerbations each participant had over the course of observed time period for each participant (maximum trial duration for a patient was 49 weeks (48 weeks + 7 days))

End point values	Anti-ST2	Placebo
Number of subjects analysed	42	39
Units: Exacerbation rate in 48 weeks
arithmetic mean (standard deviation)	2.21 ± 2.04	2.67 ± 2.14

ITT analysis of exacerbation frequency in 48 weeks

Statistical analysis description

A generalised linear model (assuming neg. binomial distribution) was used. The model includes the number of exacerbations during the 48 week treatment as an outcome with explanatory variables of treatment arm & number of exacerbations in the 12 months prior to the trial (stratification factor), and log-time on trial (in weeks) as an offset. The offset, allows for different lengths of time in the trial. Only observed exacerbations were used alongside the corresponding time period in the offset.

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.195

Method

t-test, 2-sided

Parameter type

Incidence Rate Ratio

Point estimate

0.78

Confidence interval

level

95%

sides

2-sided

lower limit

0.53

upper limit

1.14

Variability estimate

Standard error of the mean

Dispersion value

0.15

Secondary: Adverse Event Rate in the 48 Weeks of the Trial From First Dose

Top of page

End point title

Adverse Event Rate in the 48 Weeks of the Trial From First Dose

End point description

End point type

Secondary

End point timeframe

0-60 weeks (i.e. at any point during trial post randomisation)

End point values	Anti-ST2	Placebo
Number of subjects analysed	42	39
Units: Individuals at least 1 (non-serious) AE
At least one (non-serious) AE	34	28
No (non-serious) AEs	8	11

No statistical analyses for this end point

Secondary: Serious Adverse Event Rate in the 48 Weeks of the Trial From First Dose

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End point title

Serious Adverse Event Rate in the 48 Weeks of the Trial From First Dose

End point description

End point type

Secondary

End point timeframe

0-60 weeks (i.e. at any point during trial post randomisation)

End point values	Anti-ST2	Placebo
Number of subjects analysed	42	39
Units: Individuals with at least 1 SAE in trial
At least 1 SAE during trial	12	16
No SAEs during trial	30	23

No statistical analyses for this end point

Secondary: St George’s Respiratory Questionnaire for COPD Patients (SGRQ-C)

Top of page

End point title

St George’s Respiratory Questionnaire for COPD Patients (SGRQ-C)

End point description

SGRQ-c total score

End point type

Secondary

End point timeframe

(Week 0 and) Week-4, Week-12, Week-24, Week-36 & Week-48

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Number of subjects analysed

Units: SGRQ-c total score

arithmetic mean (standard deviation)

60.1 ± 13.7

58.4 ± 17.6

56.7 ± 13.5

58.9 ± 16.5

56.9 ± 15.2

59.9 ± 18.2

56.6 ± 15.3

59.6 ± 17.9

59.5 ± 14.6

59.5 ± 17.0

57.7 ± 15.7

63.3 ± 17.2

SGRQ-c total score - mixed effect linear model

Statistical analysis description

Mixed effect linear model with explanatory variables treatment, number of exacerbations in the 12 months prior to the trial (stratification), visit time point (as categorical variable) and baseline score as fixed effects. Participant ID as a random effect to take in to account the repeated measurement (i.e inter-class correlation). Analysed using the modified intention-to-treat population (all the participants randomised to the trial analysed in their allocated group, where data is available).

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.039

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-3.3

Confidence interval

level

95%

sides

2-sided

lower limit

-6.4

upper limit

-0.2

Secondary: COPD Assessment Test (CAT) (Questionnaire)

Top of page

End point title

COPD Assessment Test (CAT) (Questionnaire)

End point description

End point type

Secondary

End point timeframe

(Week 0 and) Week-4, Week-12, Week-24, Week-36, Week-48

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Number of subjects analysed

Units: CAT score

arithmetic mean (standard deviation)

22.1 ± 6.6

22.6 ± 5.7

22.2 ± 5.5

21.7 ± 5.8

22.0 ± 5.1

22.3 ± 6.9

22.7 ± 6.9

22.1 ± 5.5

22.7 ± 5.0

22.4 ± 6.0

23.4 ± 6.0

23.6 ± 7.8

CAT score-mixed effect linear model

Statistical analysis description

CAT score was analysed using mixed effect linear model with explanatory variables treatment, number of exacerbations in the 12 months prior to the trial (stratification), visit time point (as categorical variable) and baseline score as fixed effects. Participant ID as a random effect to take in to account the repeated measurement (i.e inter-class correlation). The modified ITT population was used (i.e. the available data the the outcomes for individuals in the ITT population)

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.469

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.53

Confidence interval

level

95%

sides

2-sided

lower limit

-0.91

upper limit

Secondary: Modified Medical Research Council (mMRC) Dyspnea Scale

Top of page

End point title

Modified Medical Research Council (mMRC) Dyspnea Scale

End point description

End point type

Secondary

End point timeframe

(Week 0 and) Weeks 4, 12, 24, 36, 48

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Number of subjects analysed

Units: mMRC dyspnoea score

median (inter-quartile range (Q1-Q3))

2.0 (2.0 to 3.0)

2.0 (1.0 to 3.0)

2.0 (2.0 to 3.0)

3.0 (2.0 to 3.0)

2.0 (2.0 to 3.0)

2.0 (1.5 to 3.5)

mMRC dyspnoea score Wilcoxon rank sum test Week 4

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9

Method

Wilcoxon (Mann-Whitney)

Confidence interval

mMRC dyspnoea score Wilcoxon rank sum test Week 12

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.95

Method

Wilcoxon (Mann-Whitney)

Confidence interval

mMRC dyspnoea score Wilcoxon rank sum test Week 24

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.78

Method

Wilcoxon (Mann-Whitney)

Confidence interval

mMRC dyspnoea score Wilcoxon rank sum test Week 36

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.88

Method

Wilcoxon (Mann-Whitney)

Confidence interval

mMRC dyspnoea score Wilcoxon rank sum test Week 48

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.78

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: Visual Analogue Score (VAS) Total

Top of page

End point title

Visual Analogue Score (VAS) Total

End point description

End point type

Secondary

End point timeframe

(Week 0 and) Weeks 4, 12, 24, 36, 48

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Number of subjects analysed

Units: Visual Analogue Score (VAS) Total

arithmetic mean (standard deviation)

142.7 ± 54.6

143.8 ± 53.8

129.3 ± 45.7

148.5 ± 61.2

139.5 ± 50.3

140.0 ± 65.1

131.0 ± 57.9

146.6 ± 55.1

146.9 ± 51.9

147.6 ± 59.6

140.7 ± 58.0

146.5 ± 70.0

VAS Total mixed effects model

Statistical analysis description

Using mixed effect linear model with explanatory variables treatment, number of exacerbations in the 12 months prior to the trial (stratification), visit time point (as categorical variable) and baseline score as fixed effects. Participant ID as a random effect to take in to account the repeated measurement (i.e inter-class correlation). In the modified ITT population.

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.236

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

-9.4

Confidence interval

level

95%

sides

2-sided

lower limit

-24.9

upper limit

6.2

Secondary: Sputum Purulence Colour Card

Top of page

End point title

Sputum Purulence Colour Card

End point description

End point type

Secondary

End point timeframe

(Week 0 and) Week 12, 24, 36, 48

End point values	Anti-ST2	Placebo	Anti-ST2	Placebo	Anti-ST2	Placebo	Anti-ST2	Placebo	Anti-ST2	Placebo
Number of subjects analysed	42	39	42	36	40	36	38	36	24	21
Units: sputum purulence colour card score
median (inter-quartile range (Q1-Q3))	3.0 (2.0 to 4.0)	3.0 (2.0 to 4.0)	3.0 (2.0 to 4.0)	3.0 (2.0 to 4.0)	3.0 (2.0 to 4.0)	3.0 (2.0 to 4.0)	3.0 (2.0 to 4.0)	3.0 (2.0 to 4.5)	4.0 (2.0 to 6.0)	4.0 (2.0 to 6.0)

sputum purulence colour card Week 12

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.84

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Sputum purulence colour card Week 24

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.52

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Sputum purulence colour card Week 36

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.82

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Sputum purulence colour card Week 48

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.95

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: Post BD Forced Expiratory Volume in 1 Second

Top of page

End point title

Post BD Forced Expiratory Volume in 1 Second

End point description

End point type

Secondary

End point timeframe

(Week 0 and) Week 4, 12, 24, 36, 48

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Number of subjects analysed

Units: FEV1,litre(s)

arithmetic mean (standard deviation)

1.21 ± 0.46

1.14 ± 0.48

1.21 ± 0.46

1.09 ± 0.46

1.22 ± 0.48

1.14 ± 0.52

1.17 ± 0.43

1.10 ± 0.50

1.23 ± 0.47

1.09 ± 0.52

1.30 ± 0.50

1.09 ± 0.57

Post-BD FEV1 mixed effects model

Statistical analysis description

A mixed effect linear model with explanatory variables of treatment arm, number of exacerbations in the 12 months prior to the trial (stratification factor), visit time point (as categorical variable), baseline score and patient identification as a random effect to account for repeated measures over time was fitted for each outcome. Adjusted mean difference between treatment arms with 95% confidence interval and p-value were reported. In the modified ITT population.

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.094

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.01

upper limit

0.09

Secondary: White Blood Cell Count

Top of page

End point title

White Blood Cell Count

End point description

End point type

Secondary

End point timeframe

(Week 0 and) Week 4, 12, 24, 36, 48

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Number of subjects analysed

Units: 10^9/L

geometric mean (standard error)

8.2 ± 0.045

8.0 ± 0.046

7.5 ± 0.035

7.5 ± 0.037

8.0 ± 0.043

7.7 ± 0.047

7.8 ± 0.047

7.6 ± 0.050

8.0 ± 0.046

7.3 ± 0.048

7.5 ± 0.058

8.0 ± 0.065

White Blood Cell Count

Statistical analysis description

A mixed effect linear model was fitted on the log transformed outcome with explanatory variables of treatment arm, number of exacerbations in the 12 months prior to the trial (stratification factor), log baseline value, visit time point (as categorical variable) and patient identification as a random effect to account for repeated measures over time. As a result adjusted geometric mean ratio alongside two sided 95%CI and p-value were reported

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.736

Method

Mixed models analysis

Parameter type

Geometric mean ratio

Point estimate

1.01

Confidence interval

level

95%

sides

2-sided

lower limit

0.95

upper limit

1.07

Secondary: Eosinophil Count

Top of page

End point title

Eosinophil Count

End point description

End point type

Secondary

End point timeframe

(Week 0 and) Week 4, 12, 24, 36, 48

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Number of subjects analysed

Units: 10^9/L

geometric mean (standard error)

0.21 ± 0.107

0.20 ± 0.111

0.15 ± 0.105

0.22 ± 0.111

0.13 ± 0.105

0.20 ± 0.116

0.12 ± 0.096

0.21 ± 0.099

0.11 ± 0.106

0.20 ± 0.111

0.10 ± 0.143

0.17 ± 0.160

Eosinophil Count mixed effects model

Statistical analysis description

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed models analysis

Parameter type

Geometric mean ratio

Point estimate

0.59

Confidence interval

level

95%

sides

2-sided

lower limit

0.51

upper limit

0.69

Secondary: Neutrophil Count

Top of page

End point title

Neutrophil Count

End point description

End point type

Secondary

End point timeframe

(Week 0 and) Week 4, 12, 24, 36, 48

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Number of subjects analysed

Units: 10^9/L

geometric mean (standard error)

5.6 ± 0.062

5.1 ± 0.064

4.9 ± 0.046

4.9 ± 0.049

5.4 ± 0.053

5.2 ± 0.059

5.4 ± 0.059

5.0 ± 0.061

5.6 ± 0.056

4.9 ± 0.059

5.3 ± 0.079

5.5 ± 0.089

Neutrophil Count mixed effects model

Statistical analysis description

Comparison groups

Placebo v Anti-ST2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.668

Method

Mixed models analysis

Parameter type

Geometric mean ratio

Point estimate

1.02

Confidence interval

level

95%

sides

2-sided

lower limit

0.93

upper limit

1.13

Secondary: Macrophage count in sputum

Top of page

End point title

Macrophage count in sputum

End point description

End point type

Secondary

End point timeframe

(Week 0 and) Week 4, 12, 24, 36, 48

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Number of subjects analysed

Units: Macrophage count (%)

geometric mean (standard error)

8.9 ± 0.205

9.6 ± 0.196

8.6 ± 0.211

11.0 ± 0.208

9.0 ± 0.190

9.8 ± 0.216

9.2 ± 0.222

12.3 ± 0.244

8.1 ± 0.213

9.7 ± 0.237

6.9 ± 0.286

11.4 ± 0.300

Macrophage count in sputum mixed effects model

Statistical analysis description

A mixed effect linear model of the log outcome with explanatory variables treatment, number of exacerbations in the 12 months prior to the trial (stratification), visit time point (as categorical variable) and log baseline score as fixed effects. Participant ID as a random effect to take in to account the repeated measurement (i.e inter-class correlation)

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.114

Method

Mixed models analysis

Parameter type

Geometric mean ratio

Point estimate

0.75

Confidence interval

level

95%

sides

2-sided

lower limit

0.52

upper limit

1.07

Secondary: Epithelium count in sputum

Top of page

End point title

Epithelium count in sputum

End point description

End point type

Secondary

End point timeframe

(Week 0 and) Week 4, 12, 24, 36, 48

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Number of subjects analysed

Units: Epithelium count (%)

geometric mean (standard error)

1.51 ± 0.255

1.59 ± 0.243

1.34 ± 0.257

2.06 ± 0.253

1.14 ± 0.243

1.91 ± 0.276

1.56 ± 0.284

1.44 ± 0.311

1.03 ± 0.266

1.26 ± 0.296

1.56 ± 0.435

1.21 ± 0.456

Epithelium count in sputum mixed effects model

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.215

Method

Mixed models analysis

Parameter type

Geometric mean ratio

Point estimate

0.79

Confidence interval

level

95%

sides

2-sided

lower limit

0.54

upper limit

1.15

Secondary: Eosinophil count in sputum

Top of page

End point title

Eosinophil count in sputum

End point description

End point type

Secondary

End point timeframe

(Week 0 and) Week 4, 12, 24, 36, 48

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Number of subjects analysed

Units: Eosinophil count (%)

geometric mean (standard error)

1.42 ± 0.254

1.63 ± 0.242

0.43 ± 0.188

1.69 ± 0.185

0.41 ± 0.168

1.67 ± 0.190

0.44 ± 0.191

1.69 ± 0.209

0.47 ± 0.212

1.94 ± 0.236

0.33 ± 0.232

1.24 ± 0.243

Eosinophil count in sputum mixed effects model

Statistical analysis description

A mixed effect linear model with dependent variable of the log outcome at baseline and follow-up time points; explanatory variables of treatment arm, number of exacerbations in the 12 months prior to the trial (stratification factor), visit time point (as categorical variable), log baseline score; an interaction term between treatment and visit as fixed effects; and patient identification as a random effect.

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed models analysis

Parameter type

Geometric mean ratio

Point estimate

0.25

Confidence interval

level

95%

sides

2-sided

lower limit

0.19

upper limit

0.33

Secondary: Pre BD FEV1 (litres)

Top of page

End point title

Pre BD FEV1 (litres)

End point description

End point type

Secondary

End point timeframe

(Week 0 and) Week 48

End point values	Anti-ST2	Placebo	Anti-ST2	Placebo
Number of subjects analysed	8	5	8	5
Units: litre(s)
arithmetic mean (standard deviation)	1.43 ± 0.43	0.94 ± 0.33	1.43 ± 0.49	0.86 ± 0.15

Pre BD FVC (litre)

Statistical analysis description

Analysis of covariance (ANCOVA) adjusting for the baseline value

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.362

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.11

Confidence interval

level

95%

sides

2-sided

lower limit

-0.14

upper limit

0.35

Secondary: Pre BD FEV1 predicted (%)

Top of page

End point title

Pre BD FEV1 predicted (%)

End point description

End point type

Secondary

End point timeframe

(Week 0 and) Week 48

End point values	Anti-ST2	Placebo	Anti-ST2	Placebo
Number of subjects analysed	8	5	8	5
Units: FEV1 predicted (%)
arithmetic mean (standard deviation)	55.9 ± 17.1	39.6 ± 10.4	56.5 ± 19.9	38.2 ± 8.3

Pre BD FEV1 predicted

Statistical analysis description

Analysis of covariance (ANCOVA) adjusting for the baseline value

Comparison groups

Placebo v Anti-ST2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.711

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

1.78

Confidence interval

level

95%

sides

2-sided

lower limit

-8.63

upper limit

12.2

Secondary: Pre BD FVC (litre)

Top of page

End point title

Pre BD FVC (litre)

End point description

End point type

Secondary

End point timeframe

(Week 0 and) Week 48

End point values	Anti-ST2	Placebo	Anti-ST2	Placebo
Number of subjects analysed	8	5	8	5
Units: litre(s)
arithmetic mean (standard deviation)	2.97 ± 0.89	2.17 ± 0.34	2.88 ± 0.94	2.20 ± 0.36

Pre BD FVC (litre)

Statistical analysis description

Analysis of covariance (ANCOVA) adjusting for the baseline value

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.713

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.09

Confidence interval

level

95%

sides

2-sided

lower limit

-0.61

upper limit

0.44

Secondary: Pre BD FVC predicted

Top of page

End point title

Pre BD FVC predicted

End point description

End point type

Secondary

End point timeframe

(Week 0 and) Week 48

End point values	Anti-ST2	Placebo	Anti-ST2	Placebo
Number of subjects analysed	8	5	8	5
Units: FVC predicted (%)
arithmetic mean (standard deviation)	88.5 ± 16.6	75.6 ± 16.7	85.8 ± 22.8	79.2 ± 28.5

Pre BD FVC predicted

Statistical analysis description

Analysis of covariance (ANCOVA) adjusting for the baseline value

Comparison groups

Placebo v Anti-ST2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.214

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-10.4

Confidence interval

level

95%

sides

2-sided

lower limit

-27.9

upper limit

7.1

Secondary: Pre BD FEV1/FVC ratio

Top of page

End point title

Pre BD FEV1/FVC ratio

End point description

End point type

Secondary

End point timeframe

(Week 0 and) Week 48

End point values	Anti-ST2	Placebo	Anti-ST2	Placebo
Number of subjects analysed	8	5	8	5
Units: FEV1/FVC ratio
arithmetic mean (standard deviation)	49.0 ± 14.1	46.6 ± 18.6	51.0 ± 15.5	40.2 ± 9.6

Pre BD FVC1/FVC ratio

Statistical analysis description

Analysis of covariance (ANCOVA) adjusting for the baseline value

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.069

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

9.06

Confidence interval

level

95%

sides

2-sided

lower limit

-0.83

upper limit

18.97

Secondary: Body Plethysmography TLC

Top of page

End point title

Body Plethysmography TLC

End point description

End point type

Secondary

End point timeframe

(Baseline and) Week 48

End point values	Anti-ST2	Placebo	Anti-ST2	Placebo
Number of subjects analysed	19	16	19	16
Units: litre(s)
arithmetic mean (standard deviation)	7.5 ± 1.6	7.5 ± 1.4	7.6 ± 1.5	7.6 ± 1.5

Body plethysmography TLC

Statistical analysis description

To compare change from baseline to 48 weeks (pre and post treatment measurements), analysis of covariance (ANCOVA) model with baseline value as a covariate was fitted. Adjusted mean difference with 95% confidence interval and p-value were reported.

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.905

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.46

upper limit

0.52

Secondary: Body Plethysmography RV

Top of page

End point title

Body Plethysmography RV

End point description

End point type

Secondary

End point timeframe

(Baseline and) Week 48

End point values	Anti-ST2	Placebo	Anti-ST2	Placebo
Number of subjects analysed	19	16	19	16
Units: litre(s)
arithmetic mean (standard deviation)	4.5 ± 1.5	4.7 ± 1.5	4.8 ± 1.6	5.0 ± 1.4

Body plethysmography RV

Statistical analysis description

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.775

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-0.62

upper limit

0.47

Secondary: Body Plethysmography RV/TLC (%)

Top of page

End point title

Body Plethysmography RV/TLC (%)

End point description

End point type

Secondary

End point timeframe

(Baseline and) Week 48

End point values	Anti-ST2	Placebo	Anti-ST2	Placebo
Number of subjects analysed	19	16	19	16
Units: RV/TLC ratio (%)
arithmetic mean (standard deviation)	59.8 ± 9.5	61.3 ± 11.5	61.1 ± 11.2	65.2 ± 9.7

Body plethysmography RV/TLC

Statistical analysis description

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.201

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-2.95

Confidence interval

level

95%

sides

2-sided

lower limit

-7.53

upper limit

1.65

Secondary: VAS dyspnoea score

Top of page

End point title

VAS dyspnoea score

End point description

End point type

Secondary

End point timeframe

(Week 0 and) Week 4, 12, 24, 36, 48

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Number of subjects analysed

Units: VAS score

arithmetic mean (standard deviation)

60.1 ± 13.7

58.4 ± 17.6

56.7 ± 13.5

58.9 ± 16.5

56.9 ± 15.2

59.9 ± 18.2

56.6 ± 15.3

59.6 ± 17.9

59.5 ± 14.6

59.5 ± 17.0

57.7 ± 15.7

63.3 ± 17.2

VAS Dyspnoea mixed effects model

Statistical analysis description

A number of exacerbations in the 12 months prior to the trial (stratification), visit time point (as categorical variable) and baseline score as fixed effects. Participant ID as a random effect to take in to account the repeated measurement (i.e inter-class correlation)

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.083

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-4.9

Confidence interval

level

95%

sides

2-sided

lower limit

-10.6

upper limit

0.7

Secondary: VAS Cough

Top of page

End point title

VAS Cough

End point description

End point type

Secondary

End point timeframe

(Week 0 and) Week 4, 12, 24, 36, 48

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Number of subjects analysed

Units: VAS score

arithmetic mean (standard deviation)

49.7 ± 23.7

47.5 ± 22.7

41.3 ± 19.6

45.9 ± 25.5

44.2 ± 22.3

45.1 ± 24.6

47.6 ± 23.7

45.2 ± 21.9

48.4 ± 20.4

46.0 ± 25.1

40.4 ± 24.7

47.0 ± 29.6

VAS Cough mixed effects model

Statistical analysis description

A mixed effect linear model with explanatory variables treatment, number of exacerbations in the 12 months prior to the trial (stratification), visit time point (as categorical variable) and baseline score as fixed effects. Participant ID as a random effect to take in to account the repeated measurement (i.e inter-class correlation)

Comparison groups

Anti-ST2 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.546

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-2.1

Confidence interval

level

95%

sides

2-sided

lower limit

-8.9

upper limit

4.7

Secondary: VAS Sputum production

Top of page

End point title

VAS Sputum production

End point description

End point type

Secondary

End point timeframe

(Week 0 and) Week 4, 12, 24, 36, 48

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Anti-ST2

Placebo

Number of subjects analysed

Units: VAS score

arithmetic mean (standard deviation)

40.5 ± 25.5

42.8 ± 24.5

37.9 ± 24.5

44.7 ± 27.0

40.1 ± 25.7

40.2 ± 28.7

36.9 ± 26.3

43.5 ± 24.3

42.6 ± 27.3

44.0 ± 26.2

41.5 ± 26.5

39.0 ± 27.6

VAS Sputum production mixed effects model

Statistical analysis description

Comparison groups

Placebo v Anti-ST2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.527

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-1.9

Confidence interval

level

95%

sides

2-sided

lower limit

-7.8

upper limit

Adverse events

Top of page

Timeframe for reporting adverse events

AEs: recorded at each study timepoint SAEs/SUSARs: reported to Sponsor and Leicester CTU within 24 hours of research staff learning of the event AEs of special interest: reported to Sponsor within 24 hours of research staff learning of the event

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Anti-ST2

Reporting group description

Participants randomised to 490mg MSTT1041A via subcutaneous infusion every 4 weeks for 12 visits.

Reporting group title

Placebo

Reporting group description

Participants randomised to 490mg matched placebo via subcutaneous infusion every 4 weeks for 12 visits.

Serious adverse events	Anti-ST2	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	12 / 42 (28.57%)	16 / 39 (41.03%)
number of deaths (all causes)	0	2
number of deaths resulting from adverse events	0	0
Cardiac disorders
Descending aorta thrombosis
subjects affected / exposed	0 / 42 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Heart failure
subjects affected / exposed	0 / 42 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Right thrombosed popliteal aneurysm
subjects affected / exposed	0 / 42 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Syncopal episode
subjects affected / exposed	0 / 42 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	0 / 42 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Blood transfusion (anaemia)
subjects affected / exposed	1 / 42 (2.38%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 42 (2.38%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Adenoma of the bowel
subjects affected / exposed	0 / 42 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal symptoms
subjects affected / exposed	1 / 42 (2.38%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal cancer
subjects affected / exposed	1 / 42 (2.38%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Epididymo-orchitis
subjects affected / exposed	0 / 42 (0.00%)	1 / 39 (2.56%)
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
Chest infection/infective exacerbation of bronchiectasis
subjects affected / exposed	0 / 42 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Clinical diagnosis of lung cancer
subjects affected / exposed	1 / 42 (2.38%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Community acquired pneumonia
subjects affected / exposed	3 / 42 (7.14%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Flu-like illness (viral infection)
subjects affected / exposed	1 / 42 (2.38%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hospital acquired pneumonia
subjects affected / exposed	0 / 42 (0.00%)	2 / 39 (5.13%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Infective exacerbation of bronchiectasis
subjects affected / exposed	0 / 42 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 42 (0.00%)	4 / 39 (10.26%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia and type 2 respiratory failure
subjects affected / exposed	0 / 42 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Right pneumothorax
subjects affected / exposed	0 / 42 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Shortness of breath
subjects affected / exposed	0 / 42 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Type 2 respiratory failure
subjects affected / exposed	1 / 42 (2.38%)	0 / 39 (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
Elective surgery (transurethral resection of the prostate)
subjects affected / exposed	1 / 42 (2.38%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Prostatitis
subjects affected / exposed	0 / 42 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Resection of prostate
subjects affected / exposed	1 / 42 (2.38%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Small bowel obstruction
subjects affected / exposed	1 / 42 (2.38%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Suspected UTI
subjects affected / exposed	0 / 42 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 42 (0.00%)	1 / 39 (2.56%)
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
Fractured neck of femur
subjects affected / exposed	0 / 42 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gout
subjects affected / exposed	1 / 42 (2.38%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Left scaphoid fracture
subjects affected / exposed	0 / 42 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 3%

Non-serious adverse events	Anti-ST2	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	34 / 42 (80.95%)	28 / 39 (71.79%)
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 42 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	3
Vascular disorders
Hypertension
subjects affected / exposed	3 / 42 (7.14%)	1 / 39 (2.56%)
occurrences all number	3	1
Nervous system disorders
Headache
subjects affected / exposed	10 / 42 (23.81%)	5 / 39 (12.82%)
occurrences all number	20	9
General disorders and administration site conditions
Chest pain
subjects affected / exposed	5 / 42 (11.90%)	4 / 39 (10.26%)
occurrences all number	5	4
Lethargy
subjects affected / exposed	2 / 42 (4.76%)	2 / 39 (5.13%)
occurrences all number	2	2
Malaise
subjects affected / exposed	2 / 42 (4.76%)	1 / 39 (2.56%)
occurrences all number	2	1
Oedema peripheral
subjects affected / exposed	1 / 42 (2.38%)	2 / 39 (5.13%)
occurrences all number	1	2
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	5 / 42 (11.90%)	1 / 39 (2.56%)
occurrences all number	7	1
Dyspepsia
subjects affected / exposed	1 / 42 (2.38%)	2 / 39 (5.13%)
occurrences all number	1	2
Nausea
subjects affected / exposed	2 / 42 (4.76%)	1 / 39 (2.56%)
occurrences all number	2	1
Oral pain
subjects affected / exposed	1 / 42 (2.38%)	2 / 39 (5.13%)
occurrences all number	1	2
Toothache
subjects affected / exposed	4 / 42 (9.52%)	1 / 39 (2.56%)
occurrences all number	4	1
Vomiting
subjects affected / exposed	5 / 42 (11.90%)	1 / 39 (2.56%)
occurrences all number	5	2
Respiratory, thoracic and mediastinal disorders
Haemoptysis
subjects affected / exposed	0 / 42 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	2
Oropharyngeal pain
subjects affected / exposed	2 / 42 (4.76%)	1 / 39 (2.56%)
occurrences all number	2	2
Pulmonary mass
subjects affected / exposed	3 / 42 (7.14%)	2 / 39 (5.13%)
occurrences all number	3	2
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 42 (4.76%)	1 / 39 (2.56%)
occurrences all number	3	1
Back pain
subjects affected / exposed	4 / 42 (9.52%)	3 / 39 (7.69%)
occurrences all number	5	4
Neck pain
subjects affected / exposed	4 / 42 (9.52%)	0 / 39 (0.00%)
occurrences all number	5	0
Pain in extremity
subjects affected / exposed	1 / 42 (2.38%)	2 / 39 (5.13%)
occurrences all number	1	2
Infections and infestations
Cellulitis
subjects affected / exposed	0 / 42 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	2
Skin infection
subjects affected / exposed	0 / 42 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	2
Urinary tract infection
subjects affected / exposed	6 / 42 (14.29%)	1 / 39 (2.56%)
occurrences all number	11	2
Viral upper respiratory tract infection
subjects affected / exposed	3 / 42 (7.14%)	4 / 39 (10.26%)
occurrences all number	5	6

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Were there any global substantial amendments to the protocol? Yes

01 Apr 2019

1. Amendment to CTU trial manager and trial statistician contact details. 2. Change to Genentech (funder) main contact. 3. Nasal epithelial sample changed to optional. Differentiation between epithelial sample and nasosorption. 4. Reduction of duration for visit 0. 5. Addition of transfer factor to lung function tests (Sponsor request for comprehensive overview of tests). 6. Research team to contact GP to obtain additional information/clarification related to medical history, COPD exacerbations and medications if required. 7. GP questionnaire withdrawn from use as not viable document. 8. Extension of recruitment period from 7 months to up to 9 months. 9. Addition of process for CT scans, lung nodules and follow-up. 10. Update to secondary outcomes (removal of physical examination, medical history, current medications and pregnancy testing) as these are descriptors rather than outcomes. 11. Clarification of LCTU’s data management responsibilities. 12. Amendment to recording and reporting of SAEs/SUSARs (from point of randomisation rather than from point of consent) and clarification on AESI reporting. 13. Clarification of withdrawal criteria. 14. Clarification of unblinded personnel and their roles. 15. Removal of FBC, U&Es, LFTs, CRP, RNA, serum/plasma inflammatory biomarkers, pharmacogenetics SNPs, and NTproBNP blood tests from visit 1. 16. Addition of participant identification centres (GP surgeries) with support from CRN East Midlands.

11 Mar 2020

1. Update to Sponsor’s email address. 2. Removal of reference to interim analysis throughout. This was agreed following discussions with Leicester CTU Statistics Team who did not feel an interim analysis was justified or warranted. No data will be made available until after final data lock and the end of trial report is finalised ahead of publication. 3. Removal of week 60 washout (visit 14). This will be superseded by a new observational follow-up study (REC ref: 20/LO/0268, IRAS ID: 275215). 4. Update to Schematic of Trial Design for anti-ST2, schedule of procedures and participant trial flow chart to reflect removal of week 60. 5. Clarification of secondary endpoints (text re-arranged in more logical manner but endpoints themselves have not changed). These endpoints were clarified to ensure consistency with the statistical analysis plan (SAP). 6. Clarification of subgroup objectives and analyses. 7. Addition of full BEAT-COPD study name for clarification purposes. 8. Update of wording in relation to the Investigator’s Brochure (IB) and Reference Safety Information (RSI) to be generic, to avoid further protocol amendments if the IB version changes.

11 May 2020

1. Week 60 washout (visit 14) reinstated following MHRA non-acceptance of its removal on medical grounds (Notice of Non-Acceptance dated 01/05/2020). 2. Original schematic of trial design and participant trial flow chart reinstated in accordance with the above. 3. Adaptions made to schedule of procedures as part of an Urgent Safety Measure (USM) due to COVID-19 restrictions (see footnote on page 50 for further information). 4. Clarification of time point of 12 week follow-up [12 weeks from visit 13 (week 48) rather than 12 weeks from end of treatment (visit 12, week 44)]. This was an error in the original protocol.

09 Jun 2020

1. Adaptions made to schedule of procedures. During the COVID-19 restriction period, participants will not be seen at the research clinic for unscheduled and withdrawal visits. 2. Update to Sponsor’s email address. 3. Removal of reference to interim analysis throughout. This was agreed following discussions with Leicester CTU Statistics Team who did not feel an interim analysis was justified or warranted. No data will be made available until after final data lock and the end of trial report is finalised ahead of publication. 4. Treatment groups will remain blinded until the 60 week follow-up period is completed and the trial database lock. This was originally stated as ’48 week follow-up period’ which was an error in the original protocol. 5. Clarification of secondary outcomes, exploratory outcomes and subgroup objectives/analyses. The text has been re-arranged in a more logical manner to ensure consistency with the statistical analysis plan (SAP). The outcomes themselves have not changed. 6. Addition of full BEAT-COPD study name for clarification purposes. 7. Update of wording in relation to the Investigator’s Brochure (IB) and Reference Safety Information (RSI) to be generic, to avoid further protocol amendments if the IB version changes.

07 Jul 2020

1. Pharmacogenomics response analysis in subgroups determined by single nucleotide polymorphism (SNP) for alleles associated with the IL33/ST2 axis and baseline thoracic CT-derived % wall area are to be changed from subgroup objectives to exploratory outcomes for the following reasons: • Due to COVID-19 there was a delay in transporting SNP samples to Genentech (San Francisco, California) and there were limitations for undertaking analyses in California and alternatively in Leicester. • From March-June 2020, California was on a mandated shelter-in-place and shipment of samples to the USA was restricted. Genentech was only accepting samples for projects predetermined to be business critical, and COPD-ST2OP samples were not deemed business critical. • Genentech was operating with a skeleton crew and therefore did not have adequate staff resource in place for sample testing and analysis, therefore causing a delay in obtaining the SNP data for the subgroup analyses. • A large proportion of participants were unable to undergo their visit 13 CT scan due to COVID-19, therefore the CT scan data will take a smaller role in the analysis than originally planned and analysis of the baseline CT scan is affected by access to the University of Leicester campus due to COVID-19. 2. The list of secondary and exploratory outcomes in the study summary has been tidied up to ensure consistency with the list of outcomes in section 3. 3. The Trial Statistician and Senior Trial Manager have been added to the list of protocol contributors. 4. For the subgroup objectives, it has been specified that the patient-reported outcome (PRO) and the lung function variable will be the St George’s Respiratory Questionnaire for COPD patients (SGRQ-c) and forced expiratory volume in one second (FEV1) respectively.

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.

Small sample size at a single site, therefore not powered to detect a reduction in exacerbation frequency that was observed. Collection of secondary/exploratory outcomes reduced and spirometry & sputum induction discontinued due to COVID-19.

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Clinical trials

Clinical Trial Results: A randomised placebo-controlled trial of anti-ST2 in COPD (COPD-ST2OP)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Exacerbation rate in 48 weeks

Primary: Exacerbation rate in 48 weeks

Secondary: Adverse Event Rate in the 48 Weeks of the Trial From First Dose

Secondary: Adverse Event Rate in the 48 Weeks of the Trial From First Dose

Secondary: Serious Adverse Event Rate in the 48 Weeks of the Trial From First Dose

Secondary: Serious Adverse Event Rate in the 48 Weeks of the Trial From First Dose

Secondary: St George’s Respiratory Questionnaire for COPD Patients (SGRQ-C)

Secondary: St George’s Respiratory Questionnaire for COPD Patients (SGRQ-C)

Secondary: COPD Assessment Test (CAT) (Questionnaire)

Secondary: COPD Assessment Test (CAT) (Questionnaire)

Secondary: Modified Medical Research Council (mMRC) Dyspnea Scale

Secondary: Modified Medical Research Council (mMRC) Dyspnea Scale

Secondary: Visual Analogue Score (VAS) Total

Secondary: Visual Analogue Score (VAS) Total

Secondary: Sputum Purulence Colour Card

Secondary: Sputum Purulence Colour Card

Secondary: Post BD Forced Expiratory Volume in 1 Second

Secondary: Post BD Forced Expiratory Volume in 1 Second

Secondary: White Blood Cell Count

Secondary: White Blood Cell Count

Secondary: Eosinophil Count

Secondary: Eosinophil Count

Secondary: Neutrophil Count

Secondary: Neutrophil Count

Secondary: Macrophage count in sputum

Secondary: Macrophage count in sputum

Secondary: Epithelium count in sputum

Secondary: Epithelium count in sputum

Secondary: Eosinophil count in sputum

Secondary: Eosinophil count in sputum

Secondary: Pre BD FEV1 (litres)

Secondary: Pre BD FEV1 (litres)

Secondary: Pre BD FEV1 predicted (%)

Secondary: Pre BD FEV1 predicted (%)

Secondary: Pre BD FVC (litre)

Secondary: Pre BD FVC (litre)

Secondary: Pre BD FVC predicted

Secondary: Pre BD FVC predicted

Secondary: Pre BD FEV1/FVC ratio

Secondary: Pre BD FEV1/FVC ratio

Secondary: Body Plethysmography TLC

Secondary: Body Plethysmography TLC

Secondary: Body Plethysmography RV

Secondary: Body Plethysmography RV

Secondary: Body Plethysmography RV/TLC (%)

Secondary: Body Plethysmography RV/TLC (%)

Secondary: VAS dyspnoea score

Secondary: VAS dyspnoea score

Secondary: VAS Cough

Secondary: VAS Cough

Secondary: VAS Sputum production

Secondary: VAS Sputum production

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A randomised placebo-controlled trial of anti-ST2 in COPD (COPD-ST2OP)