Conditions: COPD Exacerbation
Keywords: COPD Exacerbations ST2 MAb RG6149 MSTT1041A Anti-ST2 Phase IIa Placebo controlled
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 81
Healthy volunteers: no

Brief summary:
Chronic obstructive pulmonary disease (COPD) is a significant cause of morbidity and mortality worldwide. In contrast to other chronic diseases, COPD is increasing in prevalence and is projected to be the third-leading cause of death and disability worldwide by 2030. The costs to society for treating COPD are high, accounting for approximately 3.4% of the total health care budget of the European Union. Acute exacerbations of COPD (AECOPD) are responsible for a large portion of the economic burden of COPD. More than 500,000 hospitalisations and 100,000 deaths are attributed to AECOPD in the US each year. In addition to a substantial economic burden, AECOPD is also responsible for much of the morbidity and mortality from COPD.

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. Both eosinophilic inflammation and viral infection drive COPD exacerbations and therefore targeting the IL33/ST2 axis might reduce COPD exacerbations.

The main aim of this trial is to evaluate whether anti-ST2 will impact on airway inflammation in COPD and therefore reduce the frequency of exacerbations. For the purposes of this trial, exacerbations are defined as flare-ups of symptoms involving the use of healthcare resulting in treatment with steroids and/or antibiotics and/or hospitalisation or death due to COPD.

Detailed description:
This is a single-centre, double-blind, placebo- controlled, parallel group, randomised controlled trial to assess the efficacy and safety of anti-ST2 compared to placebo, in patients with moderate to very severe COPD (GOLD II-IV). Anti-ST2 will be administered via subcutaneous injection once every 4 weeks (Week 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44) during the 48-week treatment period. Participants will be 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 exacerbation events presenting prior to treatment initiation.

After signing the informed consent at the initial visit, patients will enter a screening period which should last for up to 2 weeks unless extension of the screening period is necessary under certain circumstances. Patients who qualify to participate in the study will be randomised into a 48-week treatment period in which they will receive either 490 mg anti-ST2 or a matching placebo. Patients will be evaluated for an additional 12 weeks following completion of the randomised treatment period. Treatment groups will remain blinded until the 60-week follow-up period is completed, and trial database is locked.

This trial is sponsored by the University of Leicester, coordinated by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) - Respiratory and Leicester Clinical Trials Unit (LCTU) and funded by Genentech, Inc.

The primary objective of the study is 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 or hospitalisation, respectively) as add-on to standard of care.

Secondary objectives: another key objective is to assess the safety and tolerability of subcutaneous (SC) doses of anti-ST2 compared to placebo in adult patients with moderate to very severe COPD.

Additionally, to assess the effects of anti-ST2 versus placebo both during stable visits and at the exacerbation events on the following:

1. Symptoms
2. Health status
3. Lung function
4. Inflammatory cell differentials i. Sputum cell count ii. Blood cell count
5. Airway morphometry
6. Pharmacogenomics

Exploratory objectives include:

1. Systemic inflammation
2. Upper airway inflammation
3. Airway infection and ecology
4. Breath volatile organic compound profiling
5. Quantitative airway geometry and densitometry
6. Pharmacogenomics
7. Pharmacokinetics and ADA level
8. Pharmacogenomics response analysis in subgroups determined by SNPs for alleles associated with the IL33/ST2 axis.

Subgroup objectives: to evaluate the efficacy of anti-ST2 versus placebo on the outcome rate of protocol-defined COPD exacerbations through 48 weeks treatment period, patient reported outcomes (PROs) \[SGRQ-c\], and lung function \[FEV1\] in subgroups defined by baseline blood eosinophil count.

Arms:
arm 1: Anti-ST2 (MSTT1041A) received as subcutaneous injection by infusion pump at 490mg every 4 weeks over a 48 week treatment period. arm 2: Placebo (no active component) received as subcutaneous injection by infusion pump at 490mg every 4 weeks over a 48 week treatment period.

Interventions: intervention 1: MSTT1041A intervention 2: Placebo
Intervention descriptions: intervention 1: MSTT1041A (RO7187807; formerly made by Amgen \[AMG\] and referred to as AMG 282) is a novel biopharmaceutical that blocks signaling of interleukin (IL)-33, an inflammatory cytokine of the IL-1 family and member of the newly discovered "alarmin" class of molecules. IL-33 is released from airway epithelial cells in response to allergens, irritants, and infection. IL-33 release can trigger acute exacerbations in both asthma and COPD. MSTT1041A has the ability to block inflammation,prevent exacerbations, and improve lung function and quality of life.

Anti-ST2 is presented as sterile, clear, and colourless to slightly yellow liquid. Each sterile vial is filled with a 1 mL deliverable volume of 70 mg/mL. It is formulated with 15 mM sodium acetate, 9.0% (w/v) sucrose, 0.01% (w/v) polysorbate 20, pH 5.2. intervention 2: Placebo for Anti-ST2 (MSTT1041A) is formulated with 10 mM sodium acetate, 9.0% (w/v) sucrose, 0.004% (w/v) polysorbate 20, pH 5.2, and is supplied in an identical vial configuration.

Protocol document:
ICF_002.pdf: 
 
A randomised placebo-
controlled trial of anti-ST2 
in COPD (COPD-ST2OP)  
 
 
 
 
 
 
 
 
NCT 03615040 
 
 
Informed consent form 
V2.1, 1st April 2019 


Anti-ST2 in COPD Informed Consent     Version 2.1; 01-04-2019       IRAS No: 244758 
      EudraCT: 2018-000919-24     Page 1 of 2 
 
 
Sponsor Reference: 0671 
Screening Number: SN
TITLE: A randomised placebo-controlled trial of anti-ST2 in COPD (COPD-ST2OP) 
1.
I confirm that I have read and understand the participant information sheet (V2.2, 01/04/2019) for
the above trial. I have had the opportunity to consider the information, ask questions and have had
these answered satisfactorily.
2.
I understand that my participation is voluntary and that I am free to withdraw at any time, without
giving any reason, without my medical care or legal rights being affected. I understand that should I
withdraw then the information collected so far will still be used in the trial analysis.
3.
I understand that relevant sections of my medical notes, GP records and/or trial data may be
looked at by responsible individuals from the trial team, the sponsor, the Leicester Clinical Trials
Unit (LCTU), NHS Trust, Host Organisation, Funder, GP Practice or from regulatory authorities
where it is relevant to my taking part in the research. I give permission for these individuals to
access my records.
4.
I understand that I am consenting for my samples and anonymised data, including previous clinical
data, to be used in research along with anonymised data by Glenfield Hospital, LCTU, academic and
industry partners at routine visits and whilst in hospital.
5.
I understand and agree that my anonymised trial data may be shared with our research
collaborators in other academic institutions, industry partners, LCTU and pharmaceutical
companies and that this data may be used for other ethically approved research.
6.
I consent to the research team contacting my GP for additional information about my medical
history, COPD exacerbations and medications if required.
7.
I agree to undergo the tests and investigations as described in the participant information sheet.
The nature of the tests and investigations and any possible risks have been explained to me.
8.
I agree to my GP or any doctor treating me to be informed that I am taking part in this trial.
9.
I agree to take part in the above trial.
Please initial box 
Name of Chief Investigator:  Professor C Brightling 
CONSENT FORM 
(Mandatory section) 
THIS IS A DOUBLE SIDED DOCUMENT. 
PLEASE TURN OVER TO SIGN AND FOR ADDITIONAL SECTION. 


 
Anti-ST2 in COPD Informed Consent     Version 2.1; 01-04-2019       IRAS No: 244758 
      EudraCT: 2018-000919-24     Page 1 of 2 
 
 
 
 
 
 
 
Sponsor Reference: 0671 
 
Screening Number: SN 
 
 
 
TITLE: A randomised placebo-controlled trial of anti-ST2 in COPD (COPD-ST2OP) 
 
 
 
 
1. I agree to being contacted with details of future research and for my contact details to be stored 
securely on a computer database by the local trial team.  
 
2. I agree for my postcode to be used for future studies that will link the outcomes of this trial with 
environmental exposure such as pollution and weather. 
 
3. I agree to being re-called for further tests based upon results of this trial, including but not 
restricted to, your genetics and response to therapy. 
 
4. I consent for a genetic sample (DNA) to be taken for the purpose of research into COPD and to be 
stored (at the Respiratory BRC Tissue Bank) for this trial and future studies. 
 
5. I agree for my health records in primary (GP) and secondary (hospital) to be linked to this study 
 
 
 
 
 
 
___________________________ 
______________                 _________________________ 
Name of Patient 
 
Date (dd/mm/yyyy)            Signature 
 
 
 
 
 
___________________________ 
______________                 _________________________ 
Name of Person taking consent 
Date (dd/mm/yyyy)            Signature 
 
 
 
 
Please indicate 
Yes  
 No 
 
 
CONSENT FORM 
(Optional section) 
 
 
Name of Chief Investigator:  Professor C Brightling 
 
 

Prot_000.pdf: 
 
A randomised placebo-
controlled trial of anti-ST2 
in COPD (COPD-ST2OP)  
 
 
 
 
 
 
 
 
NCT 03615040 
 
 
Study protocol  
V7.0, 7th July 2020 


 
Page 1 of 60 
Anti-ST2 in COPD Protocol      Version 7.0, 07/07/2020       IRAS No: 244758      EudraCT: 2018-000919-24 
 
 
 
 
 
 
 
 
 
 
 
A randomised placebo-controlled 
trial of anti-ST2 in COPD 
(COPD-ST2OP) 
 
 
 
Trial Protocol Version 7.0; 07-July-2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Page 2 of 60 
Anti-ST2 in COPD Protocol       Version 7.0, 07/07/2020         IRAS No: 244758        EudraCT: 2018-000919-24 
RESEARCH REFERENCE NUMBERS 
 
IRAS Number: 
244758 
EudraCT Number: 
WHO UTN Number: 
REC Reference Number: 
2018-000919-24 
U1111-1210-1335 
18/EM/0189 (East Midlands-Leicester South) 
SPONSOR: 
University of Leicester (ref: 0671) 
FUNDER: 
Genentech 
 
 
This protocol has regard for the HRA guidance and order of content, in line with Version 
1.2 (March 2016) of the HRA CTIMP Protocol Development Tool. 
 
 
Confidentiality Statement 
All information contained within this protocol is regarded as, and must be kept confidential.  No 
part of it may be disclosed to anyone other than the Sponsor, the Investigator Team, host NHS 
Trust, regulatory authorities and members of the Research Ethics Committee, by any Receiving 
Party to any Third Party, at any time, or in any form without the express written permission from 
the Chief Investigator and/or Sponsor. 
 


 
Page 3 of 60 
Anti-ST2 in COPD Protocol       Version 7.0, 07/07/2020         IRAS No: 244758        EudraCT: 2018-000919-24 
SIGNATURE PAGE 
The undersigned confirm that the following protocol has been agreed and accepted and that the Chief 
Investigator agrees to conduct the trial in compliance with the approved protocol and will adhere to the 
principles outlined in the Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031), 
amended regulations (SI 2006/1928) and any subsequent amendments of the clinical trial regulations, 
GCP guidelines, the Sponsor’s (and any other relevant) SOPs, and other regulatory requirements as 
amended. 
I agree to ensure that the confidential information contained in this document will not be used for any 
other purpose other than the evaluation or conduct of the clinical investigation without the prior written 
consent of the Sponsor 
I also confirm that I will make the findings of the trial publicly available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent account 
of the trial will be given; and that any discrepancies and serious breaches of GCP from the trial as 
planned in this protocol will be explained. 
 
 
 
 
 
 
 
PROTOCOL: A randomised placebo-controlled trial of anti-ST2 in COPD (COPD-ST2OP) 
  
VERSION:  Version 7.0; 07/07/2020              
 
 
 
 
 
 
 
 
 
 
For and on behalf of the Trial Sponsor: 
Signature:  
...................................................................................................... 
 
Date: 
....../....../...... 
Name (please print): 
...................................................................................................... 
 
 
Position: 
...................................................................................................... 
 
 
 
 
Chief Investigator: 
Signature:  
 
 
Date:10/09/2020 
Name: (please print): 
Professor Chris Brightling 
 
 
 
 
 
Dr Cat Taylor
Research Governance Manager
 11     09      2020


 
Page 4 of 60 
Anti-ST2 in COPD Protocol       Version 7.0, 07/07/2020         IRAS No: 244758        EudraCT: 2018-000919-24 
KEY TRIAL CONTACTS 
Chief Investigator 
Prof Chris Brightling 
Leicester Biomedical Research Centre 
Glenfield Hospital 
Groby Road 
Leicester, UK 
LE3 9QP 
Email: ceb17@leicester.ac.uk 
Trial Manager 
Niamh Quann 
Leicester Clinical Trials Unit 
Email: niamh.quann@leicester.ac.uk  
Phone: 0116 229 7243 
Sponsor 
University of Leicester 
Research Governance Office 
Academic Departments 
Leicester General Hospital 
Leicester, LE5 4PW 
Email: rgosponsor@leicester.ac.uk 
Phone: 0116 258 4099/258 4867/258 4393 
Funder 
Genentech, Inc. 
1 DNA Way 
South San Francisco 
California, CA 94080 
USA 
Email: Cheung.dorothy@gene.com 
Phone: +16508667684 
Clinical Trials Unit 
Leicester Clinical Trials Unit 
University of Leicester, College of Life Sciences 
Maurice Shock Building 
University Road 
Leicester, LE1 7RH 
Email: ctu@leicester.ac.uk 
Phone: 0116 229 7246 
Trial Statistician 
Seid Mohammed 
Leicester Clinical Trials Unit 
Email: sm974@leicester.ac.uk 
Phone: 0116 229 7276 
Trials Pharmacist 
 
Stephen Coleman 
Pharmacy Department 
Glenfield Hospital 
Groby Road 
Leicester, UK 
LE3 9QP 
Email: stephen.coleman@uhl-tr.nhs.uk 
Phone: 0116 258 3708 
 


 
Page 5 of 60 
Anti-ST2 in COPD Protocol       Version 7.0, 07/07/2020         IRAS No: 244758        EudraCT: 2018-000919-24 
i. LIST of CONTENTS 
GENERAL INFORMATION 
Page No. 
TITLE PAGE  
1 
RESEARCH REFERENCE NUMBERS 
 
2 
SIGNATURE PAGE 
3 
KEY TRIAL CONTACTS 
 
4 
i. LIST of CONTENTS 
5 
ii. LIST OF ABBREVIATIONS 
6 
iii. TRIAL SUMMARY  
8 
iv. FUNDING  
9 
v. ROLE OF SPONSOR AND FUNDER 
9 
vi. ROLES & RESPONSIBILITIES OF TRIAL MANAGEMENT COMMITTEES, 
GROUPS AND INDIVIDUALS  
 
9 
vii. PROTOCOL CONTRIBUTORS 
10 
viii. KEYWORDS 
10 
ix. TRIAL FLOW CHART 
 
10 
SECTION  
1. BACKGROUND 
 
11 
2. ASSESSMENT AND MANAGEMENT OF RISK  
11 
3. OBJECTIVES AND OUTCOME MEASURES  
12 
4. TRIAL DESIGN 
15 
5. TRIAL SETTING 
15 
6. PARTICIPANT ELIGIBILITY CRITERIA 
15 
7. TRIAL PROCEDURES 
16 
8. TRIAL TREATMENTS 
23 
9. PHARMACOVIGILANCE 
26 
10. STATISTICS AND DATA ANALYSIS 
34 
11. DATA MANAGEMENT  
37 
12. MONITORING, AUDIT & INSPECTION 
40 
13  ETHICAL AND REGULATORY CONSIDERATIONS 
41 
14. DISSEMINATION POLICY 
46 
15. REFERENCES 
47 
16. APPENDICES 
47 
 
 
 


 
Page 6 of 60 
Anti-ST2 in COPD Protocol       Version 7.0, 07/07/2020         IRAS No: 244758        EudraCT: 2018-000919-24 
ii. LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AR 
Adverse Reaction 
CA 
Competent Authority 
CI 
Chief Investigator 
COPD 
Chronic Obstructive Pulmonary Disease 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CRN 
Clinical Research Network 
CTA 
Clinical Trial Authorisation 
CTIMP  
Clinical Trial of Investigational Medicinal Product  
DSMC 
Data Safety Monitoring Committee 
DSUR 
Development Safety Update Report 
EC 
European Commission 
EMEA 
European Medicines Agency 
EUCTD 
European Clinical Trials Directive 
EudraCT 
European Clinical Trials Database 
EudraVIGILANCE 
European database for Pharmacovigilance 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice  
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of technical 
requirements for registration of pharmaceuticals for human use. 
IMP 
Investigational Medicinal Product 
IMPD 
Investigational Medicinal Product Dossier 
ISF 
Investigator Site File (This forms part of the TMF) 
ISRCTN 
International 
Standard 
Randomised 
Controlled 
Trials 
 
Number 
LCTU 
Leicester Clinical Trials Unit  
MA 
Marketing Authorisation 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MS 
Member State 
NHS R&D 
National Health Service Research & Development   
NIMP 
Non-Investigational Medicinal Product 


 
Page 7 of 60 
Anti-ST2 in COPD Protocol       Version 7.0, 07/07/2020         IRAS No: 244758        EudraCT: 2018-000919-24 
PI 
Principal Investigator 
PIC 
Participant Identification Centre 
PIS 
Participant Information Sheet 
QA 
Quality Assurance 
QC 
Quality Control 
QP 
Qualified Person  
RCT 
Randomised Control Trial 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SDV 
Source Data Verification 
SOP 
Standard Operating Procedure  
SmPC 
Summary of Product Characteristics  
SSI 
Site Specific Information 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TMF 
Trial Master File 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
VOC 
Volatile Organic Compound 
WOCBP 
Woman of Child Bearing Potential 
 
 


 
Page 8 of 60 
Anti-ST2 in COPD Protocol       Version 7.0, 07/07/2020         IRAS No: 244758        EudraCT: 2018-000919-24 
iii. TRIAL SUMMARY 
This will be a single-centre, double-blinded, placebo- controlled, parallel group, randomised 
controlled trial comparing MSTT1041A (anti-ST2 antibody) versus placebo in COPD. MSTT1041A 
490mg subcutaneous (s/c) or matched placebo dosed every 4 weeks for a total of 12 doses. 
Patients will be 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. (Trial schedule and assessments are detailed in 
Appendix 1). The dose and dosing interval has been derived from an earlier PK/PD modelling and 
is the highest dose included in an ongoing phase 2b asthma study. The primary outcome measure 
is exacerbation frequency. Exacerbation events are relatively infrequent and can be affected by 
season, therefore we have chosen a 48 week treatment duration with follow-up out to 12 months. 
 
Trial Title 
A randomised placebo-controlled trial of anti-ST2 in COPD  
Short Title 
Anti-ST2 in COPD 
Trial Acronym 
COPD-ST2OP 
Clinical Phase  
IIa 
Trial Design 
Single-centre, double-blinded, placebo-controlled, parallel group, 
randomised controlled trial 
Trial Participants 
Moderate to very severe COPD (GOLD II to IV) 
Planned Sample Size 
80 
Treatment duration 
48 weeks 
Follow up duration 
12 weeks 
Planned Trial Period 
60 weeks (+/- 2 weeks) 
Planned Recruitment Period Up to 9 months 
Investigational 
Medicinal 
Product(s) 
Anti-ST2 
Formulation, Dose, Route of 
Administration 
Injectable, 490mg, subcutaneous 
Primary Objective 
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 add-on to standard of care 
Primary Outcome Measures Annual/48 week COPD exacerbation frequency where an exacerbation 
is defined by symptomatic worsening of COPD requiring: 
• 
use of systemic corticosteroids for at least 3 days;  
• 
a single depot injectable dose of corticosteroids will be considered 
equivalent to a 3-day course of systemic corticosteroids;  
• 
and/or use of antibiotics;  
• 
and/or an inpatient hospitalisation or death due to COPD 
Secondary Objectives 
Safety and tolerability, patient related outcomes (PROs), lung function 
and inflammatory cell differentials in sputum and blood.  
Exploratory Objectives 
Systemic inflammation, upper airway inflammation, airway infection and 
ecology, breath volatile organic compound profiling, quantitative airway 
geometry and densitometry, mediators, cell subset analysis and 
pharmacogenomics. 
Subgroup Objectives 
Rate of protocol defined COPD exacerbation through 48 week treatment 
period, SGRQ-c and FEV1 in subgroups defined by baseline blood 
eosinophil count.  


 
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Anti-ST2 in COPD Protocol       Version 7.0, 07/07/2020         IRAS No: 244758        EudraCT: 2018-000919-24 
iv. FUNDING AND SUPPORT IN KIND 
FUNDER(S) 
FINANCIAL AND NON-FINANCIAL SUPPORT 
GIVEN 
Genentech 
South San Francisco 
California 
USA 
Financial support and provision of the drug and 
placebo 
 
NIHR Biomedical Research Centre (BRC) and 
Clinical Research Facility (CRF) 
Local infrastructure support 
 
v. ROLE OF TRIAL SPONSOR AND FUNDER 
The trial sponsor, University of Leicester, will be responsible for all aspects of the trial as per 
ICH-GCP, apart from where these duties have been delegated to the Leicester Clinical Trials 
Unit.  The funder, Genentech, will be responsible for funding the trial, supplying the drug and 
placebo, performing certain sample analysis not available at Leicester. Data and samples will 
be shared between the Sponsor and Funder and the Funder will be provided with all Protocols 
and SOPs for their comment and input.  
  
vi. ROLES AND RESPONSIBILITIES OF TRIAL MANAGEMENT COMMITEES/GROUPS &    
INDIVIDUALS 
 
Trial Management Committees 
The TMG will comprise of the trial Chief Investigator, Trial Clinical Co-ordinators, Trial Manager, 
Database Developer (as required), Trial Statistician and a Research Nurse. The TMG will be 
responsible for the day-to-day management of the trial. The TMG is responsible for all aspects 
of the trial (including recruitment rate, budget management, safety reporting, protocol 
compliance etc.) and for ensuring appropriate action is taken to safeguard trial participants and 
the quality of the trial. 
Trial Steering Committee (TSC) 
The TSC will comprise of an Independent Chairperson, Chief Investigator, Funder 
Representative and other Independent Members including Patient Representative. The TSC 
will provide oversight of the trial and monitor the progress of the trial to ensure it is being 
conducted in accordance with the protocol, relevant regulations and the principles of GCP.  
Data Safety Management Committee (DSMC) 
The DSMC will consist of independent experts who will assess the progress, conduct, 
participant safety and critical endpoints of a clinical trial. The DSMC will adopt a DAMOCLES 
charter to define its terms of reference and operation and will make recommendations to the 
TSC. The DSMC will meet on a regular basis as specified in the DSMC charter to review the 


 
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Anti-ST2 in COPD Protocol       Version 7.0, 07/07/2020         IRAS No: 244758        EudraCT: 2018-000919-24 
trial information and accruing data during the conduct of the trial and make recommendations 
to the TSC.  
 
vii. Protocol contributors 
• Prof Chris Brightling and Dr Ahmed Yousuf, Respiratory BRC- trial design and protocol 
write up. 
• Cassey Brookes, Dr Shaun Barber and Seid Mohammed, Leicester Clinical Trials Unit –
sample size, statistical analysis & randomisation. 
• Dr Sarah Edwards and Niamh Quann, Leicester Clinical Trials Unit – trial management, 
safety reporting & pharmacovigilance, randomisation, data management, quality 
assurance.  
 
viii. KEY WORDS: 
anti-ST2, moderate to very severe COPD, safety and efficacy, 
randomised trial 
 
ix.TRIAL FLOW CHART  
(See Appendix 3) 
 
Fig 1: Schematic of Trial Design for anti-ST2 
 


 
Page 11 of 60 
Anti-ST2 in COPD Protocol      Version 7.0, 07/07/2020       IRAS No: 244758      EudraCT: 2018-000919-24 
1 
BACKGROUND and rationale for conducting this trial 
Chronic obstructive pulmonary disease (COPD) is a significant cause of morbidity and mortality 
worldwide[1]. In contrast to other chronic diseases, COPD is increasing in prevalence and is 
projected to be the third-leading cause of death and disability worldwide by 2030[2]. The costs 
to society for treating COPD are high, accounting for approximately 3.4% of the total health 
care budget of the European Union.   
Acute exacerbations of COPD (AECOPD) are responsible for a large portion of the economic 
burden of COPD. More than 500,000 hospitalisations and 100,000 deaths are attributed to 
AECOPD in the US each year [3]. In addition to a substantial economic burden, AECOPD is 
also responsible for much of the morbidity and mortality from COPD.  
Interleukin-33 (IL-33) is an alarmin released from the epithelium following damage [4].  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[5]. 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[6]. 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 
[7]. Both eosinophilic inflammation and viral infection drive COPD exacerbations and therefore 
targeting the IL33/ST2 axis might reduce COPD exacerbations. 
2 
Assessment and management of risk 
Beyond standard of care the participants will undergo additional blood tests, breathing tests, 
airway sampling, and a non-contrast CT scan and a SC IMP. These are all common routine 
tests. The blood, breath and airway sampling has minimal risk and mild discomfort. The non-
contrast CT scan will involve radiation but the increased risk of cancer from radiation in an 
elderly population with a significant smoking history will have a high lifetime risk and therefore 
the radiation exposure will present a very small increase in this risk. The IMP both placebo and 
drug can potentially cause local reactions. Anti-ST2 has been tested in healthy volunteers and 
a phase 2b trial in asthma is currently ongoing.  The target is anticipated to reduce exacerbation 
risk and symptoms and therefore might reduce risk in those individuals. Based on the three 
completed Phase I clinical trials and the ongoing Phase IIb trial in patients with uncontrolled 
severe asthma, the safety profile for anti-ST2 remains favourable at this time. We will also 
monitor and analyse all potential cases of anaphylaxis and major adverse cardiac events 
(MACE). 
 
•  Risk Type C = Markedly higher than the risk of standard medical care 
 
 


 
Page 12 of 60 
Anti-ST2 in COPD Protocol       Version 7.0, 07/07/2020         IRAS No: 244758        EudraCT: 2018-000919-24 
3 
OBJECTIVES AND OUTCOME MEASURES 
3.1 
Primary objective 
We hypothesise that anti-ST2 will impact on airway inflammation in COPD and consequently 
will reduce COPD exacerbation frequency.  
The primary objective of the trial is 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 or hospitalisation or death due to COPD, 
respectively) in 48 weeks as add-on to standard of care.  
3.2 Secondary Objectives 
Another key objective is to assess the safety and tolerability of SC doses of anti-ST2 compared 
to placebo in adult patients with moderate to very severe COPD. 
 
Additionally, to assess the effects of anti-ST2 versus placebo both during stable visits and at 
the exacerbation events on the following: 
 
1. Symptoms 
2. Health status 
3. Lung function 
4. Inflammatory cell differentials 
i. 
Sputum cell count 
ii. 
Blood cell count 
5. Airway morphometry  
6.  Pharmacogenomics 
 
3.3 Exploratory Objectives 
1. Systemic inflammation 
2. Upper airway inflammation 
3. Airway infection and ecology 
4. Breath volatile organic compound profiling 
5. Quantitative airway geometry and densitometry 
6. Pharmacogenomics 
7. Pharmacokinetics and ADA level 
8. Pharmacogenomics response analysis in subgroups determined by SNPs for alleles 
associated with the IL33/ST2 axis. 


 
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Anti-ST2 in COPD Protocol       Version 7.0, 07/07/2020         IRAS No: 244758        EudraCT: 2018-000919-24 
3.4 Subgroup Objectives 
• To evaluate the efficacy of anti-ST2 versus placebo on the outcome rate of protocol-
defined COPD exacerbations through 48 weeks treatment period, patient reported 
outcomes (PROs) [SGRQ-c], and lung function [FEV1] in subgroups defined by baseline 
blood eosinophil count. 
3.5 
Outcome measures 
3.5.1 Primary outcome 
The primary outcome is: Frequency of moderate to severe exacerbation (defined as requiring 
treatment with systemic corticosteroids and/or antibiotics in the community or hospital or 
hospitalisation) in 48 weeks. 
*where a COPD exacerbation is defined by symptomatic worsening of COPD requiring: 
• Use of systemic corticosteroids for at least 3 days; a single depot injectable dose of 
corticosteroids will be considered equivalent to a 3-day course of systemic 
corticosteroids; 
and/or 
 Use of antibiotics;  
and/or 
 An inpatient hospitalisation or death due to COPD 
For a detailed layout of the timeline for all visit procedures please refer to Appendix 1 
Schedule of Procedures. 
 
3.5.2 Secondary outcomes (*indicates this data is held on Macro database) 
1. Safety and tolerability 
• AE event rate in the 48 weeks of the trial from first dose* 
• SAE event rate in the 48 weeks of the trial from first dose* 
 
2. Patient related outcomes (PROs) (weeks 0, 4, 12, 24, 36 and 48)* 
• St George’s Respiratory Questionnaire for COPD patients (SGRQ-c) 
- Total 
• COPD Assessment Test (CAT) 
• mMRC Dyspnoea Scale  
• Visual analogue score (VAS) 
- Dyspnoea 
- Cough  
- Sputum production  
• Sputum purulence colour card 
 


 
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3. Lung function (Weeks 0 and 48) 
• Pre and post BD spirometry* 
- FEV1 
- FEV1 % predicted 
- FVC 
- FEV1/FVC % 
- BD reversibility % 
 
• Whole body plethysmography (body box)*  
- TLC 
- RV 
- RV/TLC % 
 
4. Inflammation (Weeks 0, 4, 12, 24, 36) 
• Cell count 
- Blood inflammatory cell differentials* 
o WBC 
o Eosinophils 
o Neutrophils 
- Sputum inflammatory cell differentials  
o Eosinophils 
o Neutrophils 
o Macrophages 
o Lymphocytes 
o Epithelial cells 
o Total 
 
3.5.3 Exploratory outcomes 
• Quantitative measures of airway geometry and densitometry (Weeks 0 and 48, non-
contrast thoracic CT-derived outcomes) 
- MLD E/I (small airway) 
- % WA 
- LA (larger airways) 
 
• Mediators 
- Sputum mediator profiling (biomarkers) 
- Blood biomarkers 
 
• Cell subset analysis including but not restricted to exploration of ILC2 cells  
• Urine biomarkers of inflammation 
• Mediator profiling (biomarkers) 
• Upper airway inflammation:  
- nasosorption  
- nasal epithelial sampling  (optional) 
• Airway infection and ecology: 


 
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- targeted qPCR (bacteria and viruses) for common airway pathogens 
- microbiomics 
• Breath volatile organic compound (VOC) profiling (PTR-MS & ADVION) – breathomics 
• Pharmacogenomics response analysis in subgroups determined by SNPs for alleles 
associated with the IL33/ST2 axis 
 
4 
TRIAL DESIGN 
This is a single-centre, double-blind, placebo- controlled, parallel group, randomised controlled 
trial to assess the efficacy and safety of anti-ST2 compared to placebo, in patients with 
moderate to very severe COPD (GOLD II-IV).  Anti-ST2 will be administered via subcutaneous 
injection once every 4 weeks (Week 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44) during the 
48-week treatment period. The treatment period will be followed by a 12-week follow-up period 
(i.e washout period). An overview of the trial design is presented in Figure 1. 
After signing the informed consent at the initial visit, patients will enter a screening period within 
7-14 days of randomisation. Patients who qualify to participate in the trial will be randomised 
into a 48-week treatment period in which they will receive either 490 mg anti-ST2 or a matching 
placebo. Patients will be evaluated for an additional 12 weeks following completion of the 
efficacy endpoint (visit 13, week 48). Treatment groups will remain blinded until the 60-week 
follow-up period is completed, and trial database is locked. Visit procedures will be performed 
as shown in Appendix 1.  
5 
TRIAL SETTING 
This trial will be a single centre RCT, sponsored by the University of Leicester and coordinated 
by the Leicester NIHR Respiratory BRC and Leicester Clinical Trials (LCTU).   
6 
PARTICIPANT ELIGIBILITY CRITERIA 
Eligibility criteria for this trial have been carefully considered to ensure the safety of the patients 
included in the trial and that the results of the trial can be used. It is important the participants 
meet all the inclusion criteria and none of the exclusion criteria. 
6.1 
Inclusion criteria 
1. Symptoms typical of COPD when stable (baseline mMRC dyspnoea score ≥ 2) 
2. GOLD COPD stage 2-4   
3. Smoking pack years ≥ 10 years 
4. Age > 40 years 
5. Receiving standard-of-care drug therapy as per BTS guidance for COPD 
6. A history of ≥ 2 moderate-to-severe exacerbations in the last 12 months.  
7. Be able to give valid written consent; compliant with trial procedures and trial visits. 
8. Able to understand written and spoken English. 
 


 
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6.2 
Exclusion criteria 
1. Significant known respiratory disorders other than COPD that in the view of the investigator 
will affect the trial 
2. Patients whose treatment is considered palliative (life expectancy <12 months) 
3. Known hypersensitivity to the active substance of IMP or any of the excipients 
4. Known history of anaphylaxis 
5. Patients with a COPD exacerbation and/or pneumonia within the 4 weeks prior to visit 1 
6. Have, in the opinion of investigator, uncontrolled co-morbid conditions, such as diabetes 
mellitus, hypertension and heart failure [e.g. NYHA class III (e.g. less than ordinary activity 
causes fatigue, palpitation, or dyspnoea) patients will be excluded if they have had 
exacerbation of their HF in previous 6 months, and class IV (e.g. Symptoms of heart failure 
at rest)] that will affect the trial. 
7. Myocardial infarction, unstable angina or stroke within 12 month prior to screening 
8. Diagnosis of malignancy within 5 years of visit 1 (except for excised localised carcinoma 
of skin not including malignant melanoma) 
9. Clinically significant ECG changes, which in the opinion of investigator warrants further 
investigations 
10. Laboratory abnormalities, which in the opinion of investigator warrants further 
investigations 
11. Have, in the opinion of the investigator, evidence of alcohol, drug or solvent abuse. 
12. Pregnant, breastfeeding, or lactating women. Women of child-bearing potential (see 
protocol section 9.7)) must have a negative blood serum pregnancy test performed at the 
screening visit and must agree to use two methods of birth control, (one of which must be 
a barrier method). 
13. Participation in an interventional clinical trial within 3 months of visit 1 or receipt of any 
investigational medicinal product within 3 months or 5 half-lives. 
14. Upon questioning the patient has blood born infection (e.g. HIV, hepatitis B or C). 
7 
TRIAL PROCEDURES  
See appendix 1 for detailed visit structure and trial procedures.  
7.1 
Participant Identification and Recruitment 
The trial will recruit in a single centre (NIHR Leicester BRC Respiratory) that has a previous 
track record of delivering randomised designed studies. The participants will be identified from 
a database which has the details of patients who have taken part in previous COPD related 
trials and have consented to be contacted for future trials. They will also be identified from 
respiratory outpatient clinics and acute admission unit.  
We will recruit members of the public who self-refer and who meet the inclusion/exclusion 
criteria. We will put posters advertising the study throughout the University Hospitals of 
Leicester NHS Trust and with permission in other community settings such as, pharmacies, GP 
practices and public notice boards. We will also make use of the NHS intranet, digital and social 
media (such as Facebook and Twitter) to help promote the study, whilst interest and patient 
feedback regarding the study will be generated via other media outlets (e.g. press releases, 
radio) where possible.  


 
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Patients will also be recruited from primary care. The Clinical Research Network (CRN) East 
Midlands will assist with identifying GP practices that are willing to identify potential participants 
for the trial. The practice will identify potential participants from the practice database for 
eligibility based on criteria supplied by the research team. Additionally, posters will be placed 
in the practice and clinical rooms, alerting staff and patients to the trial. The practice team will 
invite the patient to participate and the patient will respond to the research team if they wish to 
do so. Although this is a single centre trial, participants will be recruited from GP practices 
across Leicester, Leicestershire, Rutland (LLR) Clinical Commissioning Groups (CCGs).Once 
a participant has been identified as potentially eligible or requests further information, they will 
be sent a letter inviting them to express interest in the trial and return a reply slip which will 
contain the minimum amount of personal data. Alternatively they will be approached by a 
member of the clinical or research team and if interested their details passed onto the trial team 
for eligibility assessment. The trial team will contact the participant and arrange for a baseline 
screening visit (visit 0) and advise the participant to bring any concurrent medications with them.  
They may also discuss halting any current medication such as inhalers that would affect the 
baseline measures. For participants with long acting inhalers, i.e. taken once a day (e.g. Spiriva) 
we would recommend these be halted 24 hours before the visit. For medium acting inhalers i.e. 
taken twice a day (e.g. symbicort, seretide, fostair, eklira, Anoro ellipta, Duaklir genuair, and 
Duoresp spiromax), we would recommend halting 12 hours before the visit. All other inhalers 
we would recommend halting 4 hours before the visit. This information would also be stated in 
the letter generated by the trial team with the appointment details.   
Eligible participants will be offered trial entry at the baseline screening visit (visit 0) after they 
have had 24 hours to read the PIS and have understood the nature of trial. 
7.1.2 Screening 
Each potential participant will provide informed consent at screening before starting any trial 
related procedures. Participants will be assessed for eligibility as per inclusion/exclusion criteria 
at initial screening and at each subsequent follow up visit this will be checked for changes.  
All potential participants who submit a reply or who agree to be contacted by the trial team, will 
be assigned a screening number and will be reviewed by a member of the research team who 
will screen for eligibility using pre-specified inclusion/exclusion criteria prior to or at the 
consent/screening visit.  Participants who are deemed not to be eligible for the trial (even if this 
is prior to a screening visit 0), will be screen failed and their anonymised data (initials and year 
of birth) added to the screening log along with the details of their ineligibility. This will be 
maintained by the blinded trial staff with the Investigator Site File (ISF). 
A log of all participants enrolled in the trial (i.e. who have been randomised) will also be created 
and kept securely with the unblinded staff as it will contain the treatment information. 
7.1.3  Payment  
Participants will be reimbursed for travel expenses at the usual NHS Trust rate (up to a 
maximum of £50 per visit) payable on production of original receipts (if taxis are not provided) 
at all trial visits (including screening and exacerbation visits). Once randomised participants will 


 
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receive an additional £25 per completed scheduled visit to compensate for any inconvenience. 
The payment schedule will depend on the participant’s preference and will either be received 
after a series of visits have been completed, or at their final visit in a single lump sum.  
7.2 Consent  
Written version of the participant information sheet and consent form will be presented to the 
participants detailing the exact nature of the trial; what it will involve for the participant; the 
implication and constraints of the protocol; the potential side effects and any risks involved in 
taking part. It will be clearly stated that the participant is free to withdraw from the trial at any 
time for any reason, without prejudice to future care, and with no obligation to give the reason 
for withdrawal.   
The participant will be given a minimum of 24 hours to consider the information and have the 
opportunity to question the researcher, or other independent parties to decide whether they will 
participate in the trial.  The participant will attend an initial screening visit, where written informed 
consent will then be obtained by means of participant dated signature and dated signature of 
the person who presented and obtained the informed consent, which will contain information 
that conforms to current data sharing and handling requirements.  
7.3 
Blinding 
Participants, investigators, the Trial management team and everyone involved in trial conduct 
will remain blinded with regard to the randomised treatment assignments until after database 
lock.  
Unblinded personnel will include: 
• The trial statistician, in order for the unblinded DSMC to make safety decisions 
• The Pharmacy team, to take receipt of and dispense the IMP/placebo 
• The designated individuals from the Respiratory BRC responsible for reconstituting the 
IMP/placebo.  
• The trial monitor, in order to perform drug accountability and reconciliation. The Sponsor 
and the trial monitor are one entity; therefore it will not be possible to maintain the blind 
of the Sponsor. 
The IMP and placebo will be shipped by Genentech to the Hospital Pharmacy. Genentech will 
be responsible for QP release and the trial drug will arrive unblinded, pre-labelled with the 
approved trial outer labels. The entire Pharmacy team are unblinded and will take receipt of the 
IMP and placebo in accordance with their local SOPs and complete the necessary 
documentation including the accountability logs which will be maintained securely in the trial 
Pharmacy Site File. They will provide the IMP/placebo to the unblinded trial personnel only. The 
Unblinded trial personnel will collect and transfer the unprepared IMP/Placebo making sure that 
they are not visible to anyone during transport i.e. transferred in a closed non-transparent bag. 
The unblinded trial personnel are designated in the Delegation Log and will be responsible for 
randomisation and trial drug preparation and reconstitution, which will take place in Glenfield 
out of sight of blinded trial personnel or the participant with clear warning notices that unblinded 


 
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IMP is being prepared. All documentation of drug/placebo preparation (including a participant 
accountability log), randomisation CRF, prescription, and the enrolment log containing 
information about randomisation for each participant, will be kept in a folder in a sealed box and 
location will be unknown to blinded team. A yellow label will be added directly to the syringe 
containing only the participant ID, initials, a statement that it is ‘either drug or placebo within’, 
date, time of preparation, and the initials of the unblinded personnel preparing it. 
This ‘blinded yellow label syringe’ will be given to a Blinded trial personnel to be administered 
to the participant on site. The IMP and placebo will be identical in physical appearance within 
the syringe. 
The randomisation results will not be revealed until the Clinical Trial Unit perform final database 
lock.  
A DSMC will be reviewing the trial data periodically, to assess patient safety and will have 
access to unblinded data if necessary as outlined and agreed in the DSMC Charter. Data 
presented at the DSMC will be prepared by the unblinded trial statistician and take the format 
of an open blinded session followed by a closed unblinded session (as appropriate) to prevent 
unblinding of the CI, trial manager and the rest of the trial team. 
7.4 
Emergency Unblinding 
If it is deemed necessary by the clinical or research team to unblind the patient to the allocated 
treatment the CI must be contacted. Only the CI or delegated individual on the delegation log 
can decide to unblind. Emergency unblinding will be available to the investigator / pharmacist / 
Sponsor via the web based Sealed Envelope system. The username and password will be 
tested in advance of the first patient enrolled onto the trial. The Sealed Envelope system will be 
fully audit traceable until the end of the trial to ensure that blinding has not been compromised. 
Unblinding will only occur in the case of a medical emergency or if a patient experiences an 
unexpected serious reaction such as a SUSAR.  
Unblinding of all subjects will take place when the last patient has had their final visit 
assessments and data collection and validation is complete.  
To test the validity of the blinding both the patients and researchers will be asked if they were 
aware of treatment allocation. 
Unblinding before database lock must only be used in an emergency situation when the identity 
of the trial drug must be known to the Investigator in order to provide appropriate medical 
treatment or otherwise assure safety of trial participants. The reason for unblinding must be 
documented in the source documents and recorded on the web based randomisation system 
when unblinding along with the date and the initials of the person who broke the code. Reason 
for unblinding should also be recorded in the CRF, data collection tool, in the site file and 
medical notes. In the case of unblinding an individual participant for safety reasons, appropriate 
follow-up of safety related events is required. It will also be documented at the end of the trial 
in any final trial report and/or statistical report. The CI/Investigating team will notify the Sponsor 
and the LCTU in writing as soon as possible following the unblinding detailing the necessity. 


 
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7.5 
The randomisation scheme 
The LCTU will supply a web based randomisation system from a third party (Sealed Envelope 
Ltd.). Participants will be randomised in a 1:1 ratio to anti-ST2 or placebo, this will be set up as 
a blinded randomisation process.  Each participant will be given a unique screening number on 
consent, and a unique participant ID when they are randomised. This combination of unique 
screening number and participant ID will be linked on the enrolment log with the unique 
participant ID number being used to identify the individual participant throughout the trial 
following randomisation. Neither of these numbers will be re-assigned to any other subject. 
Participants will be assigned to trial treatment in accordance with the randomisation schedule.  
Randomisation will be stratified by frequency of exacerbation in the previous 12 months (Low 
[2 or 3] or High [4 or more]). Randomisation results will be printed out and signed as 
confirmation by the unblinded trial personnel performing the randomisation and a copy will be 
stored securely with the unblinded documentation and presented to pharmacy alongside the 
prescription. 
7.5.1 Method of implementing the randomisation/allocation sequence 
Once the participant has given written consent to the trial, a member of the trial team will assess 
the eligibility of the participant by completing a screening visit. If eligible, randomisation should 
occur immediately after the participant undergoes their baseline assessment where possible. 
The unblinded trial personnel (authorised and trained) will complete a randomisation form, enter 
the eligibility criteria data onto the online system and randomise the participant to a treatment 
allocation, this will generate a unique participant ID and a blinded randomisation code which 
relates either to the IMP (anti-ST2 or placebo). The linkage information between the 
randomisation code list(s) and the allocated treatment will be generated/held by the Sealed 
Envelope system and by the unblinded trial personnel.  
7.6 
Baseline data 
See Appendix 1 for detailed visit structure and trial procedures. 
7.7 
Trial assessments 
See Appendix 1 for detailed visit structure and trial procedures. For dosage schedules please 
see section 8.6. For Trial restrictions and missed windows please see Section 8.10. 
 
7.8 
Long term follow-up assessments 
See Appendix 1 for detailed visit structure and trial procedures.  
7.9 
Qualitative assessments  
There will be no qualitative assessment. 
 


 
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7.10 Withdrawal criteria  
The only specified withdrawal criteria for this study will be for participants that miss more than 
one dose of the study treatment, or who delay a scheduled study visit for >4 weeks. These 
participants will remain in follow-up for the trial duration. If a participant wishes to completely 
withdraw from the study, or is withdrawn for reasons other than a missed or delayed dose, the 
research team will encourage them to undertake the ‘withdrawal visit’ procedures and 
assessments which will signify the end of their participation. This will include participants who 
withdraw via telephone. It will be at the participant’s discretion whether or not they attend the 
withdrawal visit. Withdrawal visits should be completed as soon as possible, however the 
timeframe will be largely dependent on what the participants finds acceptable.  
Every effort should be made by the research team to keep the participants in the trial.  However, 
participants have the right to withdraw their consent to take part in the trial at any time without 
having to give a reason and this will not affect their future care.  Withdrawal details and reasons 
(if known) should be recorded on the withdrawal/loss to follow up CRF and in the medical notes.  
In addition, the investigator may discontinue a participant from the trial at any time if the 
investigator considers it necessary. The IMP will also be discontinued in the case of an adverse 
event which the investigator considers sufficient to jeopardise the safety of the trial participant. 
Participants who want to discontinue protocolled treatment should be encouraged to remain in 
the trial and continue to be followed-up as per protocol or as of routine care.   
Every effort should be made to keep the participant in the trial to collect important efficacy and 
safety data. Withdrawals from the trial should be discussed with the CI or their deputy and the 
Trial Manager. If a participant has withdrawn from the trial for any reason, then his/her screening 
and participant ID number(s) cannot be issued to another participant. 
Loss to follow-up will be minimised by diligent liaison with the participant, their medical team 
and if required the general practitioner. If a participant fails to attend the clinic for trial visit, the 
research team should contact the participant and re-schedule the missed visit within a week.  If 
the participant can’t be contacted or misses his/her next appointment, the research team should 
make every effort to contact the participant again by phone and letter. If the participant still 
cannot be contacted, then he/she can be withdrawn from the trial and the reason in the notes 
and eCRF can be recorded as ‘lost to follow-up’.   
A participant will be considered to have completed the trial if: 
• they continue to take trial treatment until Visit 12 (Week 44) and attend Visit 14 (Week 
60) 
• they continue to participate in the trial until Visit 13 (Week 48) regardless of whether they 
continue to take IP. 
As stated in section 3.3.2, participants will undergo a non-contrast CT scan at the beginning 
and end of the trial. Bearing in mind the average age of participants, diagnosis of COPD and 
smoking history, lung nodules are a very common finding in this population. Therefore 
participants will remain in the trial whilst they are followed up in the virtual nodule clinic, however 


 
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at the point where a suspicious nodule has led them into the cancer pathway, they will be 
withdrawn from the trial. 
7.11 Storage and analysis of clinical samples 
See Appendix 1 and trial procedures and laboratory manual for standard operating procedures 
(SOPs).  
The following blood samples will be processed by the University Hospitals of Leicester NHS 
Trust central pathology labs and will be collected at room temperature from the trial site:  
• Biochemistry Profile - Full (including U&E,s LFTs) 
• Full Blood Count (FBC/CBC) 
 
• NTproBNP 
 
• HbA1c 
 
• Lipid profile  
 
• Total IgE 
 
• RAST (HDM, Cat ,dog, grass pollen) 
 
• C-Reactive Protein 
The following samples will be analysed for research purposes by the research team and 
processed at the Respiratory BRC laboratories. Samples will be kept on ice or stored in 
monitored -20C or -80C freezers prior to analysis, unless contraindicated. 
• Urine sample (for inflammatory biomarkers and pregnancy)  
• Sputum sample (Sputum is collected on ice and processed at 4°C as soon as possible 
and within 2 hours of expectoration) 
• Nasal epithelial sample (optional) 
• Nasosorption 
• PK and ADA samples 
• Serum Plasma (for inflammatory biomarkers) 
• Pregnancy Testing (blood sample) 
• DNA sample 
• RNA sample 
The DNA and RNA samples taken during this study will be stored in a -80C temperature 
monitored freezer in the Respiratory BRC, all analysis on these samples will be carried out at 
the end of the study. The Respiratory BRC is a registered Tissue Bank. 
 
7.12 End of trial (ET) 
The end of the trial is defined as the last participant’s final visit. 
However, final trial closure will be when all final sample analysis has been completed or at the 
discretion of the TSC acting on the recommendation of the DSMC. Participants who discontinue 
the trial early will be asked to return to the trial centre and will undergo withdrawal or early 


 
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termination (ET) visit procedures listed in Appendix 1 under ‘withdrawal’. The withdrawal visit 
will include all procedures to be done at end of trial visit as well as any other laboratory 
assessment planned at the originally scheduled follow-up visit. 
8 
TRIAL TREATMENTS 
8.1 
Name and description of investigational medicinal product(s) 
See IB for more details.  MSTT1041A (anti-ST2) is a first-in-class, fully human, IgG2 
monoclonal antibody (mAb) being developed for use in the treatment of asthma and COPD. 
Anti-ST2 binds with high affinity to the human receptor for IL-33/ST2, and blocks IL-33 binding, 
thus inhibiting association with the IL-1R accessory protein (AcP) co-receptor and formation of 
an activated receptor complex.  
Anti-ST2 is presented as sterile, clear, and colourless to slightly yellow liquid. Each sterile vial 
is filled with a 1 mL deliverable volume of 70 mg/mL. It is formulated with 15 mM sodium acetate, 
9.0% (w/v) sucrose, 0.01% (w/v) polysorbate 20, pH 5.2.   
Placebo for Anti-ST2 (MSTT1041A) is formulated with 10 mM sodium acetate, 9.0% (w/v) 
sucrose, 0.004% (w/v) polysorbate 20, pH 5.2, and is supplied in an identical vial configuration. 
8.2 
Regulatory status of the drug  
Anti-ST2 is currently in development and has not been granted marketing approval in any 
country yet. The drug and placebo will be supplied by Genentech, South San Francisco, 
California, USA.  
8.3 
Product Characteristics  
See Investigator’s Brochure (IB).   
8.4 
Drug storage and supply 
The Anti-ST2 and placebo will be supplied by Genentech free of charge.  They will be provided 
as open-label product to unblinded pharmacist and trial staff. Unblinded staff will be responsible 
for the receipt, storage, and labelling.   
Both the Anti-ST2 (MSTT1041A) and Placebo should be stored at 2oC to 8oC in a secured 
location, protected from light, and according to the storage and expiration information (where 
required) provided on the label that is affixed to the package containing the investigational 
product(s). The drug product(s) should not be shaken.  
The Anti-ST2 and placebo contain no preservatives and are suitable for single use only. Anti-
ST2 should be prepared per the instructions provided in the Pharmacy Guide or trial drug 
preparation instructions. Vials should be checked for cracks or damage that may have occurred. 
Damaged product should not be administered and should be returned to Genentech. Any 
temperature deviations will be recorded and reported for evaluation to Genentech, LCTU and 
the Sponsor. Stock that has been exposed to a temperature deviation will be quarantined at 


 
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the correct temperature pending Genentech’s response on outcome and authorisation from the 
Sponsor to use or destroy the affected stock. 
8.5  
Preparation and labelling of Investigational Medicinal Product and Placebo 
Anti-ST2 and the placebo will be provided by Genentech to the Pharmacy in packaged vials 
with unblinded outer labels. Both the IMP and placebo will be ready for use and will not need 
to be diluted prior to administration. Allocation of trial medication (Anti-ST2 or placebo) will be 
managed by Sealed Envelope (web based randomisation system). The Anti-ST2 and placebo 
will be prepared and a blinded yellow label applied to the syringe by unblinded trial personnel 
(see section 7.3-7.5 on Blinding and Randomisation). All information will be documented on an 
unblinded participant accountability log and the enrolment log by the unblinded trial personnel, 
the pharmacist will maintain their own unblinded accountability logs. 
8.6 
Dosage schedules 
See figure 1 for dosing schedule.  In animal trial and phase I human studies both, intravenous and 
subcutaneous (SC) routes were used, with no significant difference in safety. For ease of 
administration we will be using the SC route in this trial. The drug dose is fixed at 490mg every 4 
weeks for 12 visits.  
A window of up to 4 weeks will be allowed within which a participant will be able to delay or miss 
taking a scheduled dose. A delay will then be carried through to all their subsequent study visits.  
If the participant misses a dose it will be recorded in the notes and the next scheduled dose will 
be administered.  Participants will be allowed to miss a single dose of the study drug (See Section 
7.7) and are permitted up to a 4 week treatment delay. 
8.7 
Dosage modifications  
There will not be any dose modification during the trial (see Section 8.10 for non IMP medication 
changes). 
If a participant has an anaphylactic reaction to the drug or placebo, they will discontinue from 
protocolled treatment but remain in follow-up. If the drug was stopped due to a clinical reason 
such as allergic reaction, we will err on side of caution and not restart the drug in the same 
participant. 
No information on overdose, maximum-tolerated dose, or dose-limiting toxicities has been 
established at this time. 
 
8.8 
Known drug reactions and interaction with other therapies 
There are no known drug reactions and interactions with other therapies. See Section 13.6.1 
Possible Side Effects of the Trial Medication and the Placebo. 


 
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8.9 
Concomitant medication 
There are no restrictions on concomitant use of other medications.   
8.10 Trial restrictions  
There is no scope in this study for dose reduction of the IMP, however participants are permitted 
to miss a single dose. The dose for the patients' standard of care therapy(s) for COPD will be 
maintained where possible, however this will be left up to the clinician’s discretion. The clinician 
will also have discretion to alter any concomitant medication(s) that are unrelated to their COPD 
as required.  
Participants are required to complete the scheduled clinic visits within the time windows allowed 
in the protocol. As the administration of trial medication is only at the clinic, and the need to 
maintain the required intervals between dosing, it is very important to adhere to the time 
windows for each visit.  
All study visits have been given a window of +/- 7days to allow for flexibility, apart from visit 14 
which will have a window of +/- 14 days. Any visits completed outside of this window will be 
logged as protocol deviations. Participants will be permitted where required, up to a 4 week 
treatment delay of a scheduled dosing visit, to allow for adverse events, holidays or other 
unexpected events. The participant can miss a dose and receive their next dose at the 
scheduled visit, or they can receive a delayed dose when available and their subsequent visit 
schedule would be altered accordingly to incorporate the delay (see Section 8.6). Depending 
on the nature of the AE/SAE it will be left to the clinician’s discretion to determine if the patient 
should be withdrawn from the study. Participants that are delayed more than 4 weeks (more 
than a single dose) will be withdrawn. 
Persistent deviations would indicate potential non-compliance and will have to be discussed 
with the Chief Investigator and the Sponsor regarding possible withdrawal. Those participants 
who are planning to take more than a 4 week consecutive holiday would not be included in the 
study, this will be asked at screening. 
Participants should be compliant in taking their daily COPD medications during the course of 
the trial. Dose and regimen of routine medications should not be changed during the course of 
the trial (screening, treatment, and follow-up periods) except for treatment of an exacerbation 
or unless absolutely medically necessary. Baseline treatment should be maintained at the same 
dose and regimen at it was at the time of entry to the trial.  
If changes are absolutely necessary for reasons other than to treat the participant for COPD 
exacerbation, this should be discussed with the Local Clinical Monitor, and documented in the 
participant source data including the medical rationale for the change from the treating 
physician. The follow-up period is also an important part of the study to assess therapeutic 
efficacy and changes following the last dose of anti-ST2 should be avoided. After the participant 
completes the final clinic visit at week-48, investigator may adjust the dose or change the COPD 
medications without consequence to the trial objectives. 
 


 
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8.11 Assessment of compliance with treatment  
All doses of the trial treatment will be administered SC at the investigational site by blinded 
research staff.  The prescribed dosage, and mode of administration should not be changed. If 
a participant misses a dose, the missed dose can be given within 1 week.  Any changes from 
the intended regimen must be recorded in the CRF. Infusion start date/time and infusion end 
date/time should be documented in the patient’s CRF.  
Drug dispensing/accountability logs will be maintained by a designated unblinded member of 
the site staff and by the Pharmacy team. 
 
9 
PHARMACOVIGILANCE 
9.1 
Operational definitions for (S)AEs  
An Adverse Event (AE) is any untoward medical occurrence in a patient, associated with the 
use of a medicinal product, whether or not considered related to the medicinal product. 
Events meeting the definition of an AE include: 
• Exacerbation of a chronic condition (except COPD)  
• New conditions detected or diagnosed after trial treatment administration even though it 
may have been present prior to the start of the trial 
• Signs, symptoms, or the clinical sequelae of a suspected interaction 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of trial treatment  
• Any unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product 
• Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• Any deterioration in a laboratory value or other clinical test (e.g., ECG, X ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• Adverse events that are related to a protocol mandated intervention, including those that 
occur prior to assignment of study treatment (e.g., screening invasive procedures such 
as biopsies) 
Events that do not meet the definition of an AE include: 
• Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that  
leads to the procedure is an AE 
• Situations where an untoward medical occurrence did not occur (social admission to a 
hospital) 
• COPD exacerbation, progression, signs and symptoms (unless they are considered to 
be related to the trial drug by the investigator; then they would constitute a reaction) 


 
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An adverse reaction (AR) is an untoward and unintended response(s) related to the study 
treatment. All cases judged by either the reporting medically qualified professional or the 
sponsor as having a reasonable suspected causal relationship to the study treatment qualify 
as adverse reactions.   
A Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) is defined as any adverse 
event or adverse reaction in a trial participant that: 
• Results in death 
• Is life threatening (the subject was at risk of death at the time of event) 
• Requires hospitalisation or prolongation of an existing hospitalisation 
• Results in persistent or significant disability or incapacity 
• Consists of a congenital anomaly or birth defect 
• Other serious Important Medical Event - an event that may not be immediately life 
threatening or result in death or hospitalisation but may jeopardise the subject or may 
require intervention to prevent one of the outcomes listed above should be considered. 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is defined as an adverse reaction 
that is both unexpected (not consistent with the Reference Safety Information) and also meets the 
definitions of a Serious Adverse Reaction. 
9.2 
Safety Assessments 
All Adverse events (AEs) will be recorded throughout the study whether serious or not. Members 
of the research team will ask the participants about AEs at each study time point (see Appendix 
1) and will complete the participant AE form, which will be a continuous log so as to capture end 
dates, and the study serious adverse event (SAE) log. This will be evaluated and classed 
according to the definitions in sections 9.1. 
9.2.1 Reference Safety Information and Expectedness 
For the purposes of this trial the Reference Safety Information for determining expectedness of 
any SAR will be Table 12 (section 6.4.1) of the Investigator’s Brochure.  
All fatal SAEs will be considered unexpected. No SADRs have been identified for Anti-ST2 as of 
March 2017 and updated in March 2018. Therefore there are no serious expected Adverse Drug 
Reactions (ADRs). Any treatment-emergent SAE deemed related to Anti-ST2 treatment during 
this study will be reported as a SUSAR. There are also a number of expected Serious Adverse 
Events associated with this disease population, these would be reported as SAEs, but may also 
be captured as part of the outcome measures exacerbations.   
• Administration of MSTT1041A, a protein therapeutic, may lead to the development of anti-
MSTT1041A antibodies which could lead to adverse events and/or decreased exposure. 
 
• Hypersensitivity reactions and anaphylaxis have been described with SC administration of 
mAbs (Corominas et al. 2014). Signs and symptoms may include acute onset (minutes to 
several hours) of one or more of the following: respiratory compromise, reduced blood 


 
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pressure, skin-mucosal involvement, or gastrointestinal symptoms (Sampson et al. 2006). 
The potential for hypersensitivity to MSTT1041A in humans is unknown. However, as with 
any large-molecule, therapeutic administration of MSTT1041A may result in systemic 
reactions. 
 
• Systemic reactions to large-molecule therapeutics can be IgE or non-IgE mediated or due to 
the release of cytokines and are generally characterized by signs and symptoms such as 
skin rash, urticaria, pruritus, local or diffuse erythema, angioedema, fever, chills, cough, 
dyspnea, wheezing, bronchospasm, nausea, vomiting, diaphoresis, chest pain, tachycardia 
or bradycardia, and/or hypotension, which can be severe or life threatening. Effects typically 
occur during or within several hours after drug administration, but they may be delayed. 
 
• Injection-site reactions have been described with SC administration of mAbs (Corominas et 
al. 2014). Signs and symptoms may include pain, itching, erythema, and swelling at the 
injection site. The reaction may be immediate, although it usually appears within 24-48 hours 
with variable incidence according to the drug administered. 
 
• Patients with a history of anaphylaxis, hypersensitivities, or drug allergies are excluded from 
studies with MSTT1041A. 
 
• The intended mechanism of action of MSTT1041A suggests inhibitory effects on immune 
responses mediated by Th2 cells, leading to the possibility of a decrease in the protective 
response to infection, particularly helminthic infections (Molofsky et al. 2015). All trial 
participants will be monitored for signs and symptoms suggestive of infection by collection of 
vital signs, clinical laboratory tests, and AEs. 
 
• Evidence has shown that the sST2 receptor is a prognostic biomarker of cardiovascular 
disease outcome (Sabatine et al. 2008; Shah et al. 2009; Weir et al. 2010). Although 
published findings suggest a possible risk of exacerbation of existing cardiovascular disease 
in humans, there are no identified cardiovascular risks associated with inhibiting the IL-
33/ST2 axis in humans. Patients with active or unstable recent cardiovascular disease are 
excluded from the trial. Cardiac safety is 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 are monitored to observe for indication of possible 
atherogenic and metabolic effects of MSTT1041A exposure. In populations at high risk for 
pre-existing cardiovascular disease, such as patients with severe COPD, additional 
monitoring strategies including echocardiography and cardiac biomarkers (e.g., NTproBNP) 
may also be used. 
 
 
9.3 
Recording and reporting of SAEs, AESIs, SARs AND SUSARs  
All SAEs / SUSARs occurring from the point of randomisation until the final trial visit 
following follow-up (or 100 days post cessation of trial treatment (if discontinued early), 
must be recorded on the SAE Form and sent to the Sponsor and the Leicester Clinical 
Trials Unit (LCTU) within 24 hours of the research staff becoming aware of the event.  


 
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After informed consent has been obtained but prior to initiation of study drug, only serious 
adverse events caused by a protocol‑mandated intervention (e.g., invasive procedures 
such as biopsies, discontinuation of medications) should be reported. 
Accidental overdoses or medication errors must report to the Sponsor within 24 hours 
after learning of the event, regardless of relationship to study drug. 
Adverse events of special interest (AESIs) are required to be reported by the investigator 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event. 
Once all resulting queries have been resolved, the Sponsor will send an 
acknowledgement of the closure of the SAE, all correspondence and signed SAE forms 
will be retained by the site, within the Trial Master File and electronically on the Sponsor 
SAE database.  
For each SAEs / SUSARs the following information will be collected: 
• full details in medical terms and case description 
• event duration (start and end dates, if applicable) 
• action taken 
• outcome 
• seriousness criteria 
• causality (i.e. relatedness to trial drug / investigation), in the opinion of the investigator 
• whether the event would be considered anticipated. 
Any change of condition or other follow-up information should be faxed to the Sponsor as 
soon as it is available or at least within 24 hours of the information becoming available. 
Events will be followed up until the event has resolved or a final outcome has been 
reached.   
All SAEs assigned by the CI or delegate (or following central review) as both suspected 
to be related to IMP-treatment and unexpected will be classified as SUSARs and will be 
subject to expedited reporting to the Medicines and Healthcare Products Regulatory 
Agency (MHRA). The sponsor will inform the MHRA and the REC of SUSARs within the 
required expedited reporting timescales. Fatal or life-threatening SUSARs must be 
reported within 7 days and all other SUSARs within 15 days. 
 
9.4 
Responsibilities 
Principal Investigator (PI):  
1. Checking for AEs and ARs when participants attend for treatment / follow-up. 
2. Using medical judgement in assigning seriousness, causality and whether the 
event/reaction was anticipated using the Reference Safety Information approved 
for the trial. 


 
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3. Using medical judgement in assigning seriousness and causality and providing an 
opinion on whether the event/reaction was anticipated using the Reference Safety 
Information approved for the trial.  
4. Ensuring that all SAEs are recorded and reported to the sponsor within 24 hours 
of becoming aware of the event and provide further follow-up information as soon 
as available. Ensuring that SAEs are chased with Sponsor if a record of receipt is 
not received within 2 working days of initial reporting.  
5. Ensuring that AEs and ARs are recorded and reported to the sponsor in line with 
the requirements of the protocol. 
Chief Investigator (CI) / delegate or independent clinical reviewer: 
1. Clinical oversight of the safety of patients participating in the trial, including an 
ongoing review of the risk / benefit. 
2. Using medical judgement in assigning the SAEs seriousness, causality and 
whether the event was anticipated (in line with the Reference Safety Information) 
where it has not been possible to obtain local medical assessment. 
3. Using medical judgement in assigning whether and event/reaction was anticipated 
or expectedness in line with the Reference Safety Information. 
4. Immediate review of all SUSARs.  
5. Review of specific SAEs and SARs in accordance with the trial risk assessment 
and protocol as detailed in the Trial Monitoring Plan. 
6. Assigning Medical Dictionary for Regulatory Activities (MedDRA) or Body System 
coding to all SAEs and SARs. 
7. Preparing the clinical sections and final sign off of the Development Safety Update 
Report (DSUR). 
Sponsor: (NB: where relevant, these can be delegated to CI) 
1. Central data collection and verification of AEs, ARs, SAEs, SARs and SUSARs 
according to the trial protocol onto a database.  
2. Reporting safety information to the CI, delegate or independent clinical reviewer 
for the ongoing assessment of the risk / benefit according to the Trial Monitoring 
Plan. 
3. Reporting safety information to the independent oversight committees identified 
for the trial (Data Monitoring Committee (DMC) and / or Trial Steering Committee 
(TSC)) according to the Trial Monitoring Plan. 
4. Expedited reporting of SUSARs to the Competent Authority (MHRA in UK) and 
REC within required timelines. 
5. Notifying Investigators of SUSARs that occur within the trial. 
6. The unblinding of a participant for the purpose of expedited SUSAR reporting [For 
double blind trials only]. 
7. Checking for (annually) and notifying PIs of updates to the Reference Safety 
Information for the trial. 
8. Preparing standard tables and other relevant information for the DSUR in 
collaboration with the CI and ensuring timely submission to the MHRA and REC. 
 


 
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Trial Steering Committee (TSC):  
In accordance with the Trial Terms of Reference for the TSC, periodically reviewing any 
safety issues highlighted by the DSMC and acting upon them appropriately. 
Data Safety Monitoring Committee (DSMC): 
In accordance with the Trial Terms of Reference for the DMC, periodically reviewing 
overall safety data to determine patterns and trends of events, or to identify safety issues, 
which would not be apparent on an individual case basis.  
9.5 
Notification of deaths  
All deaths will be reported to the Sponsor in accordance with the SAE reporting timeline 
described previously and within 24hours of the investigator becoming aware of it. 
9.6  
Reporting of Adverse Events to Genentech 
For all Safety Reporting information please refer to the authorised Safety Data Exchange 
Agreement (referred to as "SDEA”) which describes the procedures and time frames and 
defines the responsibilities between the University of Leicester and Genentech to ensure 
compliance with the applicable laws and regulations pertaining to safety reporting and its 
related activities, as well as related activities for the trial. The Funder (Genentech) who is 
remaining blinded, and an Independent Data Monitoring Committee (IDMC), who is unblinded, 
share the responsibility for regularly monitoring the overall safety of patients in the trial.   
Adverse events related to the Genentech drug MSTT1041A (Anti-ST2) might potentially 
disclose important safety information. The investigator should copy Genentech into all 
communications when expediting SARs or SUSARs to the Sponsor, health and regulatory 
authorities in accordance with Sponsor Safety Reporting SOPs and should report all SARs 
related to Genentech’s product to the local affiliate safety department within the time-frame as 
agreed upon in the SDEA.  
 
• Serious AE reports that are related to the product or where the causality is assessed as 
unknown or not provided shall be transmitted to Genentech within fifteen (15) calendar 
days of the awareness date, except for life-threatening or fatal SADRs which shall be 
transmitted to Genentech within seven (7) calendar days of the awareness date. 
• All deaths in which causality is unrelated to product shall be transmitted to Genentech 
within (15) calendar days of the awareness date. 
• Serious AE reports that are unrelated to the product shall be transmitted to Genentech 
within thirty (30) calendar days of the awareness date. This would include pregnancy 
reports where the foetus may have been exposed to the trial drug, and follow up until 
the outcome of the pregnancy is known, whenever possible based upon due diligence 
taken to obtain the follow-up information. 
 


 
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• Adverse Events of Special Interest (AESI) (serious or non-serious) are a subset of 
Events to Monitor (EtMs) of scientific and medical concern specific to the Funder’s 
product or program, for which ongoing monitoring and expedited reporting to Genentech 
are required. Separate reporting forms have been provided by Genentech to capture 
these which will also be captured on the trial database. AESIs for this trial, which will 
include Major Adverse Cardiac Events (MACE) and Anaphylaxis (related or possibly 
related to Genentech product), shall be forwarded to Genentech within fifteen (15) 
calendar days of the awareness date. Others (non-related to Genentech product) shall 
be sent within thirty (30) calendar days. For further information please refer to the SDEA 
agreement. 
 
• In addition, the following Special Situations Reports should be collected (using the 
Sponsor SAE reporting from) even in the absence of an AE: 
o Data related to the product usage during pregnancy or breastfeeding, data related 
to overdose, abuse, misuse or medication error 
o Data related to a suspected transmission of an infectious agent via a medicinal 
product (STIAMP). 
Safety Reporting to Genentech will be done according to the current SDEA. 
9.7 
Pregnancy and pregnancy reporting  
The effects of Anti-ST2 on embryo-foetal development have not yet been studied.  Based 
on current scientific knowledge, embryo-foetal exposure to mAbs (Anti-ST2 type) during 
organogenesis is understood to be low in humans. It is not known whether Anti-ST2 can 
cross the placenta or cause harm to the foetus when administered to pregnant women or 
whether it affects reproductive capacity. As such participants will not be eligible to continue 
in this trial if they are pregnant, breastfeeding or intent to become pregnant. Two separate 
contraceptive methods must be declared. 
• A woman is considered of childbearing potential (WOCBP), i.e. fertile, following 
menarche and until becoming post-menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and 
bilateral oophorectomy. 
 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a post-menopausal state in women not using hormonal 
contraception or hormonal replacement therapy. However in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient. 
 
• A man is considered fertile after puberty unless permanently sterile by bilateral 
orchidectomy. 
Women of child-bearing potential must have a negative blood serum pregnancy test 
performed at the screening visit and must agree to use two methods of birth control, (one of 
which must be a barrier method. However given this disease population and the average 


 
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age range, this will not be a significant proportion. Additional testing will also occur at any 
time during the trial if a menstrual period is missed or as required by local law. 
Participants of child bearing potential both male and female will be given clear instructions 
regarding contraception throughout the trial which will be captured in the CRF. Adequate 
contraceptive measures have been defined as sterilisation, intra-uterine device, oral 
contraceptives, consistent use of barrier methods, male sterilisation or true abstinence 
(when this is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence 
(such as calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are 
not acceptable methods of contraception]. 
All pregnancies within the trial (either the trial participant or the participant’s partner, with 
participants consent) should be reported to the Chief Investigator, the LCTU and the 
Sponsor using the relevant Pregnancy Reporting Form within 24 hours of notification 
Pregnancy is not considered an AE unless a negative or consequential outcome is recorded 
for the mother or child/foetus. If the outcome meets the serious criteria, this would be 
considered an SAE. 
The pregnancy must be followed up to determine outcome (including premature termination) 
and status of mother and child in accordance with Sponsor and local reporting requirements 
and timelines. 
Any SAE occurring in association with a pregnancy, brought to the investigator’s attention 
after the participant has completed the trial and considered by the investigator as possibly 
related to the trial treatment, must be promptly reported to sponsor in accordance with 
Sponsor and local reporting requirements and timelines. 
Genentech reporting requirements are such that whilst pregnancy reports are not serious 
AEs or Adverse Drug Reactions (ADRs) per se, any reports of pregnancy (including 
pregnancy occurring in the partner of a male trial subject), where the foetus may have been 
exposed to the Product, shall be transmitted to Genentech within thirty (30) calendar days 
of the awareness date. Pregnancies will be followed-up until the outcome of the pregnancy 
is known, whenever possible, based upon due diligence taken to obtain the follow-up 
information. 
9.7 
Overdose  
The dose of anti-ST2 considered to be an overdose has not been defined. There are no known 
antidotes. The investigator should use clinical judgement in treating the symptoms of a 
suspected overdose. 
9.8 
Urgent safety measures  
The Sponsor and Investigator may take appropriate urgent safety measures to protect clinical 
trial participants from any immediate hazard to their health and safety. The measures must be 
taken immediately; Sponsor, MHRA, REC, HRA and R&D approval is not required before 
implementation. 


 
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Reporting of Urgent Safety Measures should adhere to Sponsor SOPs. Sponsor and the 
regulatory authorities, Genentech and the LCTU must be informed in writing of the measures 
taken and the circumstances giving rise to those measures, in the form of a substantial 
amendment within three days. The process for submitting amendments as a result of Urgent 
Safety Measures is covered in the Sponsor SOPs. 
9.9 
The type and duration of the follow-up of participants after adverse reactions. 
Following an adverse drug reaction (ADR) the participants will be followed-up for an appropriate 
length of time as dictated by the nature of ADR and their clinical needs.  ADR will continue to 
be recorded and reported for up to 3 months after the last dose of IMP has been administered.  
Any SUSAR will need to be reported to the Sponsor irrespective of how long after IMP 
administration the reaction has occurred until resolved. 
9.10 Development safety update reports 
Within 90 days following the anniversary of the authorisation date for the trial, a Development 
Safety Update Reports (DSURs) will be sent by the Chief Investigator to the MHRA and the 
Main Research Ethics Committee. A copy of the report will also be sent to Genentech (as the 
trial funder/drug supplier), the University of Leicester (as the trial Sponsor), and all host 
organisations. The LCTU will prepare the DSUR report on behalf of the CI and submit to the 
Sponsor who is responsible for reporting to the Competent Authority (MHRA) within the 
specified time frame.  
The LCTU on behalf of the Trial Sponsor (University of Leicester) will also forward quarterly 
listings of non-serious AEs originating from the Trial to Genentech. 
10 
STATISTICS AND DATA ANALYSIS 
See full statistical analysis plan for further details.  
 
10.1 Sample size calculation 
Recruitment of 80 participants with a drop-out rate of 10% will be sufficient to give 80% power 
at the 5% level assuming either an annualised exacerbation frequency 2 or 2.5 per year in the 
placebo group to observe a 50% or 40% reduction in exacerbation frequency in those receiving 
anti-ST2 respectively.  
This sample size estimate is based upon a negative binomial model. The estimation of the over-
dispersion was derived from the BEAT-COPD (Biomarkers to Target Antibiotic and Systemic 
Corticosteroid Therapy in COPD Exacerbations) [ISRCTN92422949] data and was 1.3 with a 
mean exacerbation frequency of 2.85.  
 
10.2 Planned recruitment rate 
Based on our experience of recruitment, we anticipate a recruitment rate of approximately 3 
participants per week.  We expect a screen failure rate of 30%. 


 
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10.3 Statistical analysis plan 
A separate Statistical Analysis Plan (SAP) will contain full details of all statistical analyses and 
will be prepared early in the trial and finalised prior to database lock.  
Reporting of results will be based on the CONSORT statement. A Trial Steering Committee 
and Data Monitoring Committee will be established, with appropriate charters which will specify 
their remit.  
A total of 80 participants will be randomised in a 1:1 ratio to receive anti-ST2 or placebo.  For 
safety and tolerability, AEs, SAEs, vital signs, physical examinations, ECGs, and clinical 
laboratory assessments at specific time points will be evaluated. All safety data will be 
summarised descriptively.  Number and percentage of AEs will be presented for each treatment 
by Preferred Term and System Organ Class of the current Medical Dictionary for Regulatory 
Authorities (MedDRA) dictionary. Individual listings of all SAEs and AEs leading to 
investigational product (IP) discontinuation will be summarised using the current MedDRA 
dictionary. Similar analyses will be performed for potentially significant and clinically important 
AEs. Number of COPD exacerbations will be summarised using frequency count and 
percentage. 
Summaries and listings of vital signs, physical examination, ECG, and laboratory test results 
will be presented. 
 
10.4 Summary of baseline data and flow of participants 
A diagram of participants flow through the trial has been produced (Appendix 3).  
Baseline demographics and measurements will be summarised using number and percentage 
for categorical data; while continuous variables will be summarised using mean and standard 
deviation where data follows normality assumptions or median and interquartile range where 
normality assumptions are not meet. No statistical tests are planned to assess the difference in 
baseline variables between arms. 
The baseline variables that will be summarised include the following: 
• Age 
• Gender 
• Ethnicity 
• Frequency of moderate-to-severe exacerbations in the last 12 months 
• GOLD COPD stage 
• Smoking pack years 
• Diagnosed with diabetes mellitus 
• History of hypertension 
• Previous heart failure (HF) 
 


 
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10.5 Primary outcome analysis 
The primary outcome will fit a negative binomial model for the outcome of number of COPD 
exacerbations in 48 week treatment period* with explanatory variables of treatment arm and 
number of exacerbation in the 12 months prior to the trial (stratification factor). The primary 
analysis will be based on an intention-to-treat population.  
*Where a COPD exacerbation is defined by symptomatic worsening of COPD requiring: 
• Use of systemic corticosteroids for at least 3 days; a single depot injectable dose of 
corticosteroids will be considered equivalent to a 3-day course of systemic 
corticosteroids; 
and/or 
• Use of antibiotics;  
and/or 
• An inpatient hospitalisation or death due to COPD 
 
10.6 Secondary outcome analysis 
Secondary outcomes will be analysed using estimates with confidence intervals and not have 
hypothesis tests carried out unless otherwise stated in the statistical analysis plan. 
10.7 Exploratory outcomes analysis 
The accumulation of the exploratory outcome data will take several months following 
completion of the week 60 follow-up period. Therefore the exploratory outcome analysis will not 
form part of initial data lock and analysis of this data will occur after the primary and secondary 
outcomes have been completed and reported. 
10.8 Subgroup analyses 
The Statistical analysis plan will include a planned sub-group analysis based on baseline blood 
eosinophil count as described in section 3.4. 
10.9 Adjusted analysis 
The analysis of the primary outcome measure (frequency of exacerbations) will take account 
of the frequency of exacerbation in the previous 12 months, which is used as a stratification 
factor at randomisation. Analyses for other outcomes will be unadjusted in the main analyses 
and will only be adjusted in sensitivity analyses if specified by the statistical analysis plan. 
10.10 Interim analysis and criteria for the premature termination of the trial 
There will be no interim analysis or formal criteria for the premature termination of the trial. 
The DSMC will receive reports on the safety and other outcomes every 3-6 months (as defined 
in the charter), with their main focus being to ensure the safety of the trial. DSMC report will 


 
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report AEs, SAEs, demographics and efficacy outcomes. The open session of the DSMC will 
only report data overall, not split by arm.  Outcome data will be restricted to the closed report. 
There will not be any formal test or criteria for early stopping of the trial. The DSMC will advise 
on stopping the trial only if the acquired data provides proof that would alter current clinical 
management, in the light of the observed data and any other published literature. 
10.11 Participant population 
The primary analysis for each efficacy outcome will be by ‘intention to treat’ analysis; all the 
participants randomised in to the trial (regardless of whether they received trial drug) will be 
analysed in their allocated group, outcome data obtained from all participants will be included 
in the data analysis. The analysis of safety outcomes will be analysed using the safety 
population. The safety population will be compromised of the all individuals that received at 
least one injection of either the active dose or the placebo, with individuals that received any 
injections of the active dose being in the Anti-ST2 arm. Secondary analysis will be carried out 
on important outcomes using a per protocol population. 
10.12 Procedure(s) to account for missing or spurious data  
The primary analyses will consider any missing data to be missing at random (MAR). However, 
if comparison of patterns of missingness and descriptive differences between treatment arms 
indicate this assumption is not valid additionally sensitivity analyses may be carried out and will 
be specified in the statistical analysis plan.  
10.13 Other statistical considerations 
Any changes to the original statistical analysis plan will be detailed along with the reason(s) for 
their change in subsequent statistical analysis plans. 
10.14 Economic evaluation 
N/A 
11 
DATA MANAGEMENT  
LCTU will be responsible for data management within the trial and will include validation as part 
of the database specification, undertake database queries and data reviews throughout the trial 
in line with SOPs. 
11.1 Data collection tools and source document identification 
Source Data is defined as the first place data is recorded, this will include: 
• Medical Records 
• Paper CRFs 
• Laboratory Reports 


 
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• Printouts from equipment (i.e. ECG, Scales) 
• Participant reported outcome questionnaires/diaries 
Data collection tools will comprise of: 
• Macro Database (transcribed from CRFs) and direct source data entry 
• Participant reported outcome questionnaires/diaries 
The research team will seek consent from participants to re-contact them based on their results, 
phenotype, genotype, and response to treatment following the completion of the trial. This will 
incur further analysis and/or additional tests on those who have responded to the treatment. In 
future, we may use the same cohort of patients and their data from the trial to investigate the 
link between their disease progression and the environmental pollution in the area in which they 
live. The research team will seek permission to use participants’ postcodes for future studies 
that will link the outcomes with environmental pollution. 
The research team will also request the ability to extract primary and secondary care patient 
data. The reason for this data linkage is many-fold; without it we cannot corroborate previous 
exacerbation history, often having a sporadic medical and drug history. If people are admitted 
during the study we can then explore the severity of the event e.g. respiratory failure. The 
primary care records will also have serial spirometry and in the very rare event of pregnancy 
we could then look at the obstetric care. We will only look at data that will be linked to 
understanding outcomes and mechanisms of the intervention and the people looking at these 
data will only be the study team. 
11.2 CRF/Data Collection Sheet Management 
Paper Case Report Forms (CRF) and trial questionnaires are the primary data collection 
instruments and treated as source data. All data requested in the CRF will be recorded. All 
missing data will be followed up and resolved where possible. If the item is not applicable to 
the individual case, N/A will be written. All entries will be printed legibly in black ink, following 
ICH guidelines for Good Clinical Practice. 
The research team may contact the participants’ GP to obtain additional information/clarification 
related to medical history, COPD exacerbations and medications if required. 
Data captured in the paper CRFs will then be entered into a validated database under the 
management of the LCTU. A copy of the patient consent form and information sheet will be 
placed in the hospital notes of all participants and in the Investigator Site File. A sticker will be 
placed on the cover of the notes (or inside cover) detailing the trial title, contact details of the 
PI and the fact that the notes should not be destroyed for 25 years from the end of the trial. All 
trial visits summaries and AEs will be recorded in the hospital notes.  
All CRFs will be stored in a secure area. Each enrolled participant will be allocated a unique 
trial ID so that the CRFs and electronic database remains anonymous. 


 
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According to the ICH guidelines for Good Clinical Practice, the monitoring team must check the 
CRF entries against the source documents, except for the pre-identified source data directly 
recorded in the CRF. The informed consent form will include a statement by which the patient 
allows the Sponsor and LCTU’s duly authorised personnel, the Ethics Committee, and the 
regulatory authorities to have direct access to original medical records which support the data 
on the CRFs (e.g., subject’s medical file, appointment books, original laboratory records, etc.). 
These personnel, bound by professional secrecy, must maintain the confidentiality of all 
personal identity or personal medical information (according to confidentiality and personal data 
protection rules). 
11.3 Documentation storage, access, security 
All study documentation containing identifiable patient data will be managed in accordance with 
ICH GCP, the UK Policy Framework for Health and Social Care, the Data Protection Act and 
the EU General Data Protection Regulation (GDPR).  
Information will only be obtained from the patient if necessary for the trial. The trial team will 
use the participants name, NHS number and contact details, to contact them about participating 
in the study and to make sure that relevant information about the study is recorded, to ensure 
patient care and for quality assurance purposes. Individuals from the Sponsor, the LCTU and 
regulatory organisations may look at participants medical and research records to check the 
accuracy of the research study. The trial team will pass these details to the Sponsor and the 
LCTU, along with the information collected from the participant and their medical records. The 
only people in the Sponsor organisation who will have access to identifiable information will be 
those requiring it for trial purposes or for audit of the data collection process. Those trial team 
members only involved in analysis will not have access to identifiable information.  
The trial team will keep identifiable information for 6-12 months after the study has finished. 
Consent forms and details of record linkage (i.e., participant ID numbers/pseudonyms) will be 
kept for 25 years as part of the research data so that in the event of the data being challenged, 
this will allow for verification of the quality of the data. 
Explicit consent will be obtained to store or share identifiable patient data, which will clearly 
outline how individual data will be used. 
All electronic data will be stored on secure network drives, to which only the relevant trial staff 
have access, which is granted by the IT services or the research team.  This drive is backed up 
daily by the University of Leicester Information Management & Technology (IM&T). 
Direct access will be granted to authorised representatives from the Sponsor, host institution, 
the Leicester Clinical Trials unit, the Funder and the regulatory authorities to permit trial-related 
monitoring, audits and inspections, where applicable and in line with participant consent. 
For the purposes of this clinical trial the Data Controller will be the Chief Investigator.  
 
 


 
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11.4 Database management 
Paper CRF data will be entered by trained member(s) of the research team at site into a 
commercially available web based CDMS provided by the LCTU. On-entry validation checks 
will be applied where required and data entered will be checked for completeness, accuracy 
and timeliness by the trial team/trial manager/data manager, with queries managed using the 
data clarification functionality within the CDMS system. 
The contacts database (which contains participant contact details) will be held separately from 
the trial database. This will be password protected and managed at site by the research team 
following their usual clinical practice. 
A Data Management Plan will be created with specific details on data handing and record 
keeping.  
11.5 Archiving 
Personal identifiable data generated by the trial will be retained for the minimum time 
determined by the regulatory authorities following the notification of the end of the trial before 
being destroyed in a confidential manner. 
Following completion of the trial data analysis, data and essential trial records, including the final 
trial report, will be archived in a secure location, for at least 25 years after the completion of the 
trial, in accordance with EU regulations. No trial-related records, including hospital medical 
notes, will be destroyed unless or until the Sponsor gives authorisation to do so. 
 
 
12 
MONITORING, AUDIT & INSPECTION 
The University of Leicester, as Sponsor, operates a risk-based monitoring and audit 
programme, to which this trial will be subject. The LCTU operates a risk-based Quality 
Management System which will apply to this trial with Quality Checks and Quality Assurance 
Audits performed as required.  
Regular monitoring will be performed according to ICH GCP. Data will be evaluated for 
compliance with the protocol and accuracy in relation to source documents. Following written 
standard operating procedures, the monitors will verify that the clinical trial is conducted and 
data are generated, documented and reported in compliance with the protocol, GCP and the 
applicable regulatory requirements.  
As part of the quality management process, the trial will be subject to a risk assessment and a 
monitoring plan will be developed by the Sponsor in accordance with the level of risk identified 
to participant safety, integrity of the trial and trial data validity. All trial monitoring will be 
conducted in accordance with the monitoring plan and will be undertaken by the trial Sponsor. 
All monitoring will be performed by staff who are ICH/GCP trained and are competent in 
monitoring to all applicable regulatory guidelines. A documented monitoring log and audit trail 
will be maintained throughout the lifetime of the trial. The trial may also be subject to audit by 
the Sponsor delegate.  


 
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The trial manager will also undertake quality checks and assurance audits to ensure 
compliance with protocol, ICH GCP and regulatory requirements.  
All source data, trial documents, and participant notes will be made available for monitoring, 
audits and inspections by the Sponsor (or their delegate), NHS Host Organisation and the 
regulatory authorities. 
 
13  
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1  Research Ethics Committee (REC) review & reports 
Before the start of the trial, approval will be sought from a REC for the trial protocol, informed 
consent forms and other relevant documents e.g. advertisements.  Any substantial 
amendments that require review by REC will not be implemented until the REC grants a 
favourable opinion for the trial. 
All correspondence with the REC will be retained in the Trial Master File/Investigator Site File 
and an annual progress report (APR) will be submitted to the REC by CI within 30 days of the 
anniversary date on which the favourable opinion was given, and annually until the trial is 
declared ended.  The CI will also be responsible for informing the REC of the end of trial.  After 
completion of the trial, CI will submit a final report with the results to the REC.   
13.2  Peer review 
The trial has been reviewed by the Genentech Respiratory Group including clinicians and senior 
scientists. This review team have had the protocol reviewed by their internal senior 
management and approved for support. 
13.3  Public and Patient Involvement 
Through the NIHR BRC the trial design has been discussed by our patient involvement team within 
the BRC Respiratory Theme and across the wider BRC PPI group. This group will also be sent 
copies of the participant documentation for review. We will also invite several members of this 
group to act as lay committee members on the Trial Steering Committee, for which we will provide 
expense payments. 
 
13.4  Regulatory Compliance  
The trial will not commence until Clinical Trial Authorisation (CTA) is obtained from MHRA and 
REC and Sponsor Green Light has been issued.  The protocol and trial conduct will comply with 
the Medicines for Human Use (Clinical Trials) Regulations 2004 and any relevant amendments.  
As the participants may have a non-contrast CT scan and Chest X-Ray at the start and end of 
trial, the procedures are compliant with the Ionising Radiation (Medical Exposure) Regulations. 
The trial will be conducted in accordance with the UK Policy Framework for Health and Social 
Care Research (2017) and the Medicines for Human Use (Clinical Trials) Regulations, 2004. The 


 
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Sponsor responsible for checking research governance arrangements will be the University of 
Leicester. 
13.5 Known and Potential Benefits to Participants 
For those participants that will be randomised to receive Anti-ST2 they may experience a 
reduction in exacerbations and an overall improvement in COPD. Those participants receiving 
the placebo may also experience the placebo effect in which the expectation of receiving 
treatment can result in health improvements. 
For all participants participation in this trial will help by making a significant contribution to 
research into COPD and will improve management of patients in the future. During the trial all 
participants will receive close monitoring of their COPD and attention to ensure that they are 
receiving the optimal medical treatment. Any exacerbations would also be investigated and 
followed up by the trial team. Any abnormal findings arising from the trial procedures that are 
considered clinically significant by the trial team will be reported to the GP for further 
investigation.  
Participants will be reimbursed for the inconvenience and burden of the trial visit schedule and 
due to the moderately higher than standard care risk of participation (see section 7.1.3) 
 
13.6 Known and Potential Risk to Participants 
The trial is as low risk as the Investigators can make it. Although some of the appointments with 
the full testing maybe fairly long (~half day), therefore participants will be offered a break and 
refreshments provided. 
There is a possibility that a temporary halt or change to medications may cause worsening of 
symptoms. These will be adjusted at clinical review and revised where necessary.  
Both the placebo and trial drug can potentially cause local reactions (e.g. rash, inflammation). 
Anti-ST2 may reduce exacerbation risk and symptoms and therefore might offer beneficial 
effects. The safety profile for this drug is considered good with a slightly higher risk than the 
patient would receive from standard care, based on the previous asthma studies that have been 
conducted at this time. 
The effects and discomforts of each individual test are detailed in the Patient Information Leaflet 
(PIL) and described briefly below: 
• Non Contrast CT Scan (Chest) – This is a painless procedure. The CT scan exposes 
patients to ionising radiation, which has theoretical risks to health. However the dose 
received (~7 mSv) is comparable to natural background radiation for 2 years, and 
therefore the risks are not considered clinically relevant. 
• Chest X-Ray (CXR) - This is a painless procedure. The Chest X-ray exposes patients 
to ionising radiation, which has theoretical risks to health. However the dose received 
(~0.1 mSv) is comparable to natural background radiation for 10 days, and therefore 
the risks are not considered clinically relevant. 


 
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• Echocardiogram (Echo) - This is a safe test utilising ultrasound that some 
participants will have had before. Patients may notice some mild discomfort when the 
probe is pressed on their chest but there are no known long term side effects known 
(takes ~20min). 
• Electrocardiogram (ECG) - The ECG is a simple painless test, with 10 electrodes 
used to record 12 different views of the heart’s electrical activity. An electrode is 
attached to each ankle and wrist with sticky pads and six more are attached to the 
chest. The patient lies almost flat with the head and chest raised a little. Relaxing for a 
few minutes before the recording is made. Very rarely someone may have a slight skin 
reaction to the electrodes, but normally there are no after effects. 
• Blood sample - Blood testing may cause some mild discomfort and occasionally some 
bruising. All samples will be taken by a doctor or fully trained health professional. Each 
donation of blood will be a 100ml (about 7 tablespoons) maximum per visit. 
• Sputum Collection – involves inhaling a salty solution for three 5-minute periods. This 
can cause some chest tightness, wheezing and/or cough. These can all readily be 
reversed by inhaling a bronchodilator (ventolin). In order to monitor this, lung function 
testing will be performed before and during this test 
Breathing tests – Spirometry, PEX (Particle Exhaled) Machine and other breathing 
tests may cause some temporary light headedness, and coughing.  The blowing tests 
during this procedure may cause airway irritation which will be reversed with 
Salbutamol if required. 
• Nasal Epithelial Sampling - A small brush or scoop is inserted and gently rubbed 
inside the nostril (a few seconds) or a small volume of sterile salt solution will be 
inserted into each nostril, then allowed to run out into a collection pot (several 
minutes).  There may be a little discomfort that induces sneezing, coughing and, rarely, 
minor bleeding for a short period of time. This sample will be optional. 
• Nasosorption: A small piece of paper will be inserted into the nostril to collect nasal 
fluid.  
13.6.1 Possible Side Effects of the Trial Medication and the Placebo 
Anti-ST2 (MSTT1041A) is being developed by Genentech for the treatment of uncontrolled 
severe asthma and COPD. Due to its mechanism of action, Anti-ST2 has the ability to block 
inflammation, prevent exacerbations, and improve lung function and quality of life in both patient 
populations. 
Anti-ST2 is in early clinical development, and the safety profile in humans is not fully known. 
Anti-ST2 is contraindicated in subjects with known hypersensitivity to the active substance or 
any of the excipients.  Other exclusion criteria are listed in Section 6.2.  
Three Phase I studies of Anti-ST2 to provide PK, PD, and safety information over a broad dose 
range have completed dosing and safety follow-up in all subjects.  These include a SAD study 
(AMG Study 20110235), a MAD study (AMG Study 20110236), and a single-dose PK study in 
subjects of Japanese heritage (AMG Study 20130177). In the three completed AMG Phase I 


 
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studies there were no serious adverse events (SAEs) or adverse events (AEs) that led to 
treatment discontinuation in healthy subjects from the three completed AMG Phase I studies, 
who received single SC doses of Anti-ST2 ranging from 2.1-560 mg and IV doses ranging from 
210-700 mg.  
 
In the Phase I studies there were no clinically relevant trends in any of the following safety 
parameters: 
• Laboratory abnormalities 
• Percent change in vital signs measurements: systolic and diastolic blood pressure, 
pulse rate, temperature, or respiratory rate 
• QTcF interval 
Based on preliminary data from these studies, a Phase IIb study was initiated to study patients 
with uncontrolled severe asthma who are receiving standard asthma therapy. This study is 
currently ongoing (EudraCT 2016-001549-13, NCT 02918019).  
Our trial will be the first looking at Anti-ST2 in COPD. As Anti-ST2 is in early clinical 
development the full safety profile in humans is not yet known. Please refer to the associated 
current Investigator’s Brochure (IB) which lists the potential known risks and side effects for 
both the IMP and the placebo. 
13.7  Protocol compliance  
The trial team will monitor and review protocol compliance, deviations from the protocol will be 
captured both within the source data and the LCTU Quality Management System. Drug 
accountability will be monitored throughout the trial period. Where deviations frequently reoccur 
this may meet the criteria for a Serious Breach of GCP and will be reported in line with Section 
13.6.  
13.8  Notification of Serious Breaches to GCP and/or the protocol  
Any serious breach (a breach which is likely to effect to a significant degree the safety or 
physical or mental integrity of the participants of the trial; or the scientific value of the trial) will 
be reported to Sponsor immediately.  
13.9  Data protection and patient confidentiality  
All investigators and trial site staff will comply with the requirements of relevant legislation with 
regards to the collection, storage, processing and disclosure of personal information for the 
University of Leicester, the Leicester Clinical Trials Unit and the local NHS Trusts. 
The personal information that is collected will be kept secure and maintained by: 
• The creation of a unique participant ID number, depersonalised data where the 
participant’s identifying information is replaced by an unrelated sequence of characters 


 
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• Secure maintenance of the data, in both electronic and paper forms and the linking code 
in separate locations  
• limiting access to the minimum number of individuals necessary for quality control, audit, 
and analysis 
• Paper based anonymised trial records will be stored in locked filing cabinets within a 
locked office. Electronic records will be stored on secure University of Leicester IM&T 
server systems. 
• The database will be password protected and only researchers collecting data will have 
access. All data collected during the trial will be stored anonymously. 
• Participant’s contact details will be held separate to the trial visit data and used to arrange 
data collection visits by the research team or direct care team. 
• Any data transmitted will be done securely in approved University of Leicester methods 
(i.e. encrypted file transfer, internal email system) in accordance with LCTU SOPs. 
•  
13.10  Financial and other competing interests for the chief investigator, PIs at each site 
and committee members for the overall trial management  
All real and perceived conflicts will be recorded and reported to the TSC. Members of the TSC 
and DSMC Committees will be required to sign a declaration of conflicts of interest forms which 
will be retained in the TMF. 
 
13.11  Indemnity 
Sponsorship and insurance for the trial will be provided by the University of Leicester. 
If a participant is harmed due to negligence, this would be covered by the local NHS Trust(s) 
indemnity arrangements for all participants in clinical trials. If a trial participant wishes to make 
a complaint about any aspects of the way they have been treated or approached during the 
research project, the standard National Health Service complaint system will be available to 
them, the contact details for which are in the participant information sheet. 
 
13.12  Amendments  
Amendments will be submitted by the PI after approval by the Sponsor and will be implemented 
following all required ethical, competent authority and Sponsor approvals.  
13.13  Post trial care 
After the completion of trial participants will be discharged back to the care of their GP and 
won’t be followed up, unless they have had an adverse reaction to IMP.   
13.14  Access to the final trial dataset 
CI and his appointed deputies will have access to trial dataset.   
 


 
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14  
DISSEMINIATION POLICY 
14.1  Dissemination policy 
A publication plan will be written by the TMG during the trial with the sponsor and funder 
approvals. It is envisaged that the results of the trial will be published in the relevant peer-
reviewed journals. Acknowledgement of any supporting organisations, including funders, 
University of Leicester and the LCTU, will be included. 
14.2 Authorship eligibility guidelines and any intended use of professional writers 
Authorship will be determined in line with the International Committee of Medical Journal 
Editors. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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15.      REFERENCES 
 
1.       Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for 
Chronic Obstructive Lung Disease (GOLD). 2017  [cited 2017 02/10/2017]; Available from: 
http://goldcopd.org. 
 
2. 
The global burden of disease. [Report]  [cited 2017 12/12/2017]; Available from: 
http://www.who.int/respiratory/copd/en/. 
 
3. 
Ford, E.S., et al., COPD surveillance--United States, 1999-2011. Chest, 2013. 144(1): p. 284-
305. 
 
4. 
Kaur, D., et al., IL-33 drives airway hyper-responsiveness through IL-13-mediated mast cell: 
airway smooth muscle crosstalk. Allergy, 2015. 70(5): p. 556-67. 
 
5. 
Cayrol, C. and J.P. Girard, Interleukin-33 (IL-33): A nuclear cytokine from the IL-1 family. 
Immunol Rev, 2018. 281(1): p. 154-168. 
 
6. 
Cayrol, C. and J.P. Girard, IL-33: an alarmin cytokine with crucial roles in innate immunity, 
inflammation and allergy. Curr Opin Immunol, 2014. 31: p. 31-7. 
 
7. 
Jackson, D.J., et al., IL-33-dependent type 2 inflammation during rhinovirus-induced asthma 
exacerbations in vivo. Am J Respir Crit Care Med, 2014. 190(12): p. 1373-82. 
 
 
 
16.  
APPENDICES 
Appendix 1: Schedule of Procedures 
Appendix 2: Amendment History 
Appendix 3: Participant Trial Flow Chart 
 


 
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   EudraCT: 2018-000919-24 
 
 
 
 
 
 
 
 
16.1  Appendix 1 – Schedule of Procedures 
 
 
Trial 
assessment 
 
 
Screen 
Randomised treatment (visit window +/- 7 days) 
Efficacy 
end 
point 
3 month 
post-trial 
follow-up 
Withdrawal 
Unscheduled 
visit 
(e.g. 
exacerbation) 
V0 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V 10 
V 11 
V 12 
V13 
+/-7 
days 
V14 
+/-14 
days 
Wk 
0 
Wk
4 
Wk
8 
Wk
12 
Wk
16 
Wk
20 
Wk
24 
Wk
28 
Wk
32 
Wk36 
Wk40 
Wk44 
Wk 48 
Wk 60 
Consent 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review 
Inclusion & 
Exclusion 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x♦ 
x♦ 
Randomisation 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dosing 
 
 
x 
x 
 x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
Demographics 
(age, gender, 
BMI, ethnicity, 
smoking status) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
(pulse, BP, 
temp, O2 sats) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x^ 
x^ 
x♦ 
x♦ 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Med 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x♦ 
x♦ 
Physical 
examination 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x^ 
 
x♦ 
Safety AE/SAE 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x♦ 
x♦ 
COPD ++ 
Exacerbation 
frequency  
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x♦ 
SGRQ-c 
 
x 
x 
 
x 
 
 
x 
 
 
x 
 
 
x^ 
x^ 
x♦ 
x♦ 
mMRC 
x 
x 
x 
 
x 
 
 
x 
 
 
x 
 
 
x^ 
x^ 
x♦ 
x♦ 
CAT 
 
x 
x 
 
x 
 
 
x 
 
 
x 
 
 
x^ 
x^ 
x♦ 
x♦ 
VAS (dyspnoea, 
cough, sputum) 
 
x 
x 
 
x 
 
 
x 
 
 
x 
 
 
x^ 
x^ 
x♦ 
x♦ 
Sputum Purulence 
Colour Card 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x^ 
x^ 
x♦ 
x♦ 


 
 
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EudraCT: 2018-000919-24 
 
 
 
 
 
 
 
 
 
 
Trial 
assessment 
 
Screen 
Randomised treatment (visit window +/- 7 days) 
Efficacy 
end 
point 
3 month 
post-trial 
follow-up  
Withdrawal 
Unscheduled 
visit 
(e.g. 
exacerbation) 
V0 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V 10 
V 11 
V 12 
V13 
+/-7 
days 
V14 
+/-14 
days 
Wk 
0 
Wk
4 
Wk
8 
Wk
12 
Wk
16 
Wk
20 
Wk
24 
Wk
28 
Wk
32 
Wk36 
Wk40 
Wk44 
Wk 48 
Wk 60 
VOC (PTRMS & 
ADVION) 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x^ 
x^ 
 
x♦ 
Post- BD 
spirometry 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
x^ 
x^ 
x♦ 
x♦ 
Pre and post BD 
spirometry 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x^ 
 
 
 
‘Body box’ 
x+ 
 
 
 
 
 
 
 
 
 
 
 
 
x^ 
 
 
 
HbA1c 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
x^ 
x^ 
 
x♦ 
FBC 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
x^ 
x^ 
x♦ 
x♦ 
U&Es 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
x^ 
x^ 
x♦ 
x♦ 
LFTs 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
x^ 
x^ 
x♦ 
x♦ 
CRP 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
x^ 
x^ 
x♦ 
x♦ 
RNA (PAXgene) 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
x^ 
x^ 
x♦ 
x♦ 
DNA (PAXgene)   
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total IgE & 
RAST (HDM, 
pollen, cat, dog) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum/plasma 
inflam 
biomarkers  
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
x^ 
x^ 
x♦ 
x♦ 
Lipid profile 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x^ 
 
 
 
Pharmacokinetic
s PK$  
 
x 
x 
 
 
 
 
x 
 
 
 
 
 
x^ 
 
 
x♦ 
ADA 
 
x 
x 
 
 
 
 
x 
 
 
 
 
 
x^ 
 
 
x♦ 
Pharmacogeneti
cs SNPs 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x^ 
 
 
 
NTproBNP 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
x^ 
x^ 
x♦ 
x♦ 
Participant Diary 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x♦ 
x♦ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
       Page 50 of 60 
Anti-ST2 in COPD Protocol     
 Version 7.0, 07/07/2020   
     IRAS No: 244758 
   
  
EudraCT: 2018-000919-24 
 
 
 
 
 
 
 
 
 
 
Trial 
assessment 
Screen 
Randomised treatment (visit window +/- 7 days) 
Efficacy 
end 
point 
3 month 
post-trial 
follow-up  
Withdrawal 
Unscheduled 
visit 
V0 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V 10 
V 11 
V 12 
V13 
+/-7 
days 
V14 
+/-14 
days 
(e.g. 
exacerbation) 
Wk 
0 
Wk
4 
Wk
8 
Wk
12 
Wk
16 
Wk
20 
Wk
24 
Wk
28 
Wk
32 
Wk36 
Wk40 
Wk44 
Wk 48 
Wk 60 
Urine sample  
(10-20ml) for 
Inflam 
Biomarker 
x 
x 
x 
 
x 
 
 
x 
 
 
x 
 
 
x^ 
x^ 
x♦ 
x♦ 
Sputum for 
Biomarkers 
Differential cell 
count, qPCR 
and Microbiome 
 
x 
x 
 
x 
 
 
x 
 
 
x 
 
 
x^ 
x^ 
 
x♦ 
Nasal epithelial 
sampling & 
nasosorption 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x^ 
x^ 
 
x♦ 
Pregnancy 
Testing ** 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x^ 
x^ 
x♦ 
x♦ 
ECG£ 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x^ 
 
 
x♦ 
ECHO* 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x♦ 
CXR 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x♦ 
Non-contrast CT 
chest$$ 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x^ 
 
 
 
 
* For clinically meaningful increase in NTproBNP OR new symptoms/signs concerning for HF or cardiac dysfunction OR clinically significant ECG changes 
from baseline 
+ Body plethysmography (‘body box’) will be done anytime between screening and week 12, unless patient has had the test within 12 months prior to 
screening  
$ Pk samples should be taken pre-dose 
£ 12 lead ECG. If, in the opinion of investigator, the ECG is grossly abnormal (e.g. LBBB, prolonged QTc), it will be compared to old ECGs.  If there are no 
old ECGs for comparison, the investigator will make a clinical judgement about the suitability of the patients to take part in trial. 
$$ CT scan.  Patients who are claustrophobic or unable to lie flat won’t be offered CT scan.  
++ COPD Exacerbation frequency where a COPD exacerbation is defined by symptomatic worsening of COPD requiring use of systemic corticosteroids for 
at least 3 days, a single depot injectable dose of corticosteroids will be considered equivalent to a 3-day course of systemic corticosteroids; and/or Use of 
antibiotics; and/or An inpatient hospitalisation or death due to COPD. 


 
 
       Page 51 of 60 
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     IRAS No: 244758 
   
  
EudraCT: 2018-000919-24 
 
 
 
 
 
 
 
 
** Pregnancy testing (blood and urine) can be at any trial visit for WOCBP (i.e.fertile, following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy) or if they have missed a 
menstrual cycle. 
 
^ During the COVID-19 restriction period, these assessments will not be completed at Visit 13 (week 48) and Visit 14 (week 60). All remaining assessments 
will be competed as per the protocol remotely via a telephone consultation (i.e. participants will not be required to attend the research clinic). Should the 
restrictions be lifted, participants can attend the research clinic and complete all procedures. 
 
♦ During the COVID-19 restriction period, participants will not be seen at the research clinic for unscheduled and withdrawal visits. Should the restrictions be 
lifted, participants can attend the research clinic and complete all procedures. 
 
 
 
 
 
 


      Page 52 of 60 
Anti-ST2 in COPD Protocol    
 Version 7.0, 07/07/2020  
     IRAS No: 244758 
EudraCT: 2018-000919-24 
16.2 
Appendix 2 – Amendment History 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
SA05 
7.0 
Niamh 
Quann 
Prof Chris 
Brightling 
Seid 
Mohammed 
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.
11/09/2020


      Page 53 of 60 
Anti-ST2 in COPD Protocol    
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     IRAS No: 244758 
EudraCT: 2018-000919-24 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
SA04 
6.0 
08/07/2020 
Niamh 
Quann 
Prof Chris 
Brightling 
Dr Ahmed 
Yousuf 
Seid 
Mohammed 
Cassey 
Brookes 
•
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.
•
Update to Sponsor’s email address.
•
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.
•
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.
•
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.
•
Addition of full BEAT-COPD study name for clarification purposes.
•
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.


 
 
       Page 54 of 60 
Anti-ST2 in COPD Protocol     
 Version 7.0, 07/07/2020   
     IRAS No: 244758 
   
  
EudraCT: 2018-000919-24 
 
 
 
 
 
 
 
 
 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
SA03 
5.0 
27/05/2020 
Niamh 
Quann 
Prof Chris 
Brightling 
Dr Ahmed 
Yousuf 
 
• 
Week 60 washout (visit 14) reinstated following MHRA non-acceptance of its 
removal on medical grounds (Notice of Non-Acceptance dated 01/05/2020). 
• 
Original schematic of trial design and participant trial flow chart reinstated in 
accordance with the above.  
• 
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). 
• 
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.  
 
 
Note: As this amendment was to cover an Urgent Safety Measure and was COVID-
related, all other changes proposed but not implemented as part of SA02 will be 
submitted as a separate substantial amendment (SA04) at a later date. 
 
 


 
 
       Page 55 of 60 
Anti-ST2 in COPD Protocol     
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     IRAS No: 244758 
   
  
EudraCT: 2018-000919-24 
 
 
 
 
 
 
 
 
 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
SA02 
4.0 
Not issued 
due to 
MHRA non-
acceptance 
of 
amendment. 
Niamh 
Quann 
Prof Chris 
Brightling 
Dr Ahmed 
Yousuf 
Seid 
Mohammed 
Cassey 
Brookes 
• 
Update to Sponsor’s email address. 
• 
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.  
• 
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). 
• 
Update to Schematic of Trial Design for anti-ST2, schedule of procedures and 
participant trial flow chart to reflect removal of week 60.  
• 
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).  
• 
Clarification of subgroup objectives and analyses. 
• 
Addition of full BEAT-COPD study name for clarification purposes. 
• 
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. 
 
 


 
 
       Page 56 of 60 
Anti-ST2 in COPD Protocol     
 Version 7.0, 07/07/2020   
     IRAS No: 244758 
   
  
EudraCT: 2018-000919-24 
 
 
 
 
 
 
 
 
 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
NSA02 
3.2 
10/12/2019 
Niamh 
Quann 
1. Administrative corrections to appendix 1- schedule of procedures: 
• 
Visit 13 (end of efficacy endpoint): addition of visit window +/- 7 days. 
• 
Visit 14 (3 month post trial follow-up): addition of visit window +/- 14 days.  
 
2. Administrative correction to appendix 3- participant trial flow chart: 
• 
Re-arrangement of wording to ensure clear visit window for visit 13. 
• 
Change in visit 14 window from +/- 7 days to +/- 14 days. 
 
The visit windows were omitted in error from the schedule of procedures and 
ambiguous in the flow chart. As a result, this incurred a large number of protocol 
deviations due to staffing and participant availability. Therefore it has been amended 
to avoid unnecessary deviations, as well as to allow flexibility for participants. 
 
The text has been amended under section 8.10 to reflect +/-14 day window for visit 
14.   
 


 
 
       Page 57 of 60 
Anti-ST2 in COPD Protocol     
 Version 7.0, 07/07/2020   
     IRAS No: 244758 
   
  
EudraCT: 2018-000919-24 
 
 
 
 
 
 
 
 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
NSA01 
3.1 
01/10/2019 
Niamh 
Quann 
Administrative corrections to Appendix 1- Schedule of Procedures: 
1. Heading of visit 13 and visit 14 updated for clarification purposes. 
2. Pre and post BD spirometry moved from visit 14 to visit 13. 
3. Body box added to visit 13- originally only included at baseline and omitted 
from visit 13 in error.  
4. Lipid profile moved from visit 14 to visit 13. 
5. ECG moved from visit 14 to visit 13. 
6. Non-contrast CT chest moved from visit 14 to visit 13. 
These all form part of the secondary outcomes and thus must be completed at visit 
13 (i.e. the efficacy endpoint). 
NB: As agreed with East Midlands Leicester South REC via email communication on 
11/09/2019, the PIS will not be updated as all participants have been recruited and 
have consented to undergo the trial procedures which are documented accurately 
within the main text. Instead a file note will be completed to explain the discrepancy.  
 
 
 
 
 
 


 
 
       Page 58 of 60 
Anti-ST2 in COPD Protocol     
 Version 7.0, 07/07/2020   
     IRAS No: 244758 
   
  
EudraCT: 2018-000919-24 
 
 
 
 
 
 
 
 
 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
SA01 
3.0 
28/05/2019 
Niamh 
Quann 
Cassey 
Brookes 
Seid 
Mohammed 
Dr Ahmed 
Yousuf 
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 a 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. 
 
 
 


 
 
       Page 59 of 60 
Anti-ST2 in COPD Protocol     
 Version 7.0, 07/07/2020   
     IRAS No: 244758 
   
  
EudraCT: 2018-000919-24 
 
 
 
 
 
 
 
 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
N/A- part of 
initial 
submission 
2.0 
09/07/2018 
Prof Chris 
Brightling 
Dr Ahmed 
Yousuf 
Niamh Quann 
1. Rationale included to support both the dose and the duration of treatment. 
2. Clarification that both the IMP and placebo will be ready for use and will not need to 
be diluted prior to administration. 
3. Duration of follow-up, including recording and reporting of AEs/SAEs changed to 
100 days after last IMP administration. 
4. Clarification that the IMP will be discontinued in case of an adverse event which the 
investigator considers sufficient to jeopardise the safety of the trial participant. 
5. Clarification that COPD exacerbation, progression, signs and symptoms do not meet 
the definition of an adverse event unless they are considered related to the study 
drug by the investigator and then they constitute a reaction. 
6. Section 7.4- Emergency Unblinding: To test the validity of the blinding both the 
patients and anaesthetists will be asked if they were aware of treatment allocation. 
Anaesthetists has been changed to researchers as this was a typo. 
7. Section 11.1- Data collection: The CI would like to re-call patients based on 
response to treatment, phenotype and genotype, extract primary and secondary 
care patient data, and link participants’ postcodes with environmental pollution. This 
was raised at the REC meeting. This has been included in the protocol, consent 
form and PIS. 
8. Appendix 1- Schedule of procedures: The mMRC was omitted from visit 0 
(screening) in error. It is part of the eligibility criteria and the schedule of procedures 
has been updated to reflect this. LFT blood test is to be done at visit 0 (screening) 
so that we have baseline result. The schedule of procedures has been updated to 
reflect this. 


 
 
 Page 60 of 60 
Anti-ST2 in COPD Protocol   Version 7.0, 07/07/2020   IRAS No: 244758   EudraCT: 2018-000919-24 
 
 
 
 
 
 
 
 
16.3  APPENDIX 3 – Participant Trial Flow Chart 
 
 
 
Begin Study treatment and measures visits  
at Respiratory BRC (Glenfield Hospital) 
 
Visits 1 -12 for 44 weeks  
[Last dosing at 44 weeks] 
FINAL Data Collection (Visit 14) 
End of Wash out period  
 
12 weeks from efficacy endpoint (week 48) 
Week 60 (±14 days)  
Treatment (Dosing) Visits  
Anti-St2 dosing every 4 weeks 
(safety and retention)  
 
(V1-12) +/-7days 
Weeks 0, 4, 8, 12, 16, 20, 24,  
28, 32, 36, 40, 44
Clinical Follow-up Visits 
Repeat Measures  
(safety and retention)  
 
(V1, 2, 4, 7, 10, 13) ± 7 days     
Weeks 0, 4, 12, 24, 36,   
Screening Visit (Visit 0) 
Screened for eligibility and informed consent (-2 weeks) 
Data Collection Visit 1 - Baseline Visit (Visit 1) 
Eligibility confirmed, Baseline measurements,  
RANDOMISATION and INITIAL DOSING  
Excluded 
Declined to 
participate 
Participants Invited to study  
Randomised (double blind) 
Anti-ST2 (n= 40) 
Placebo (n= 40) 
Exacerbation 
Visit(s) 
(Unscheduled) 
FOLLOW-UP PERIOD (duration 12 weeks) 
(VISIT 13)– Follow up repeat measures 
Week 48 (±7 days)  

SAP_001.pdf: 
 
A randomised placebo-
controlled trial of anti-ST2 
in COPD (COPD-ST2OP)  
 
 
 
 
 
 
 
 
NCT 03615040 
 
 
Statistical analysis plan 
V3.0, 11th January 2021 


Trial: 
COPD-ST2OP 
SAP Version: 
3.0 
Version Date: 11-Jan-2021 
ST-QRD-1 v2 
Author: Seid Mohammed 
Page 1 of 36 
PRINTED COPY MAY NOT BE THE MOST UP TO DATE VERSION 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
A randomised placebo-controlled trial of 
anti-ST2 in COPD 
(COPD-ST2OP) 
 
 
SAP Version: 
V3.0 
Date: 
11-Jan-2021 
 
Based on protocol: Anti-ST2 in COPD Protocol V7.0 07-July-2020 
Trial registration: ClinicalTrials.gov Identifier: NCT03615040 


Trial: 
COPD-ST2OP 
SAP Version: 
3.0 
Version Date: 11-Jan-2021 
ST-QRD-1 v2 
Author: Seid Mohammed 
Page 2 of 36 
PRINTED COPY MAY NOT BE THE MOST UP TO DATE VERSION 
 
 
Key contacts 
Sponsor: 
University of Leicester 
Research Governance Office 
Research & Enterprise Division 
Academic Departments 
Leicester General Hospital 
Leicester, LE5 4PW 
Email: rgosponsor@leicester.ac.uk 
Trial Statistician: 
Seid Mohammed 
Leicester Clinical Trials Unit 
University of Leicester, College of Life Sciences 
Maurice Shock Building 
University Road 
Leicester, LE1 7RH 
Email: seid.mohammed@leicester.ac.uk 
Principal Statistician: 
Cassey Brookes 
Leicester Clinical Trials Unit 
University of Leicester, College of Life Sciences 
Maurice Shock Building 
University Road 
Leicester, LE1 7RH 
Email: cassey.brookes@leicester.ac.uk 
Chief Investigator: 
Prof Chris Brightling 
Department of Respiratory Sciences 
NIHR Leicester Biomedical Research Centre - Respiratory 
Glenfield Hospital 
Groby Road 
Leicester, LE3 9QP 
Email: ceb17@leicester.ac.uk 
Sub-Investigator 
Dr Ahmed J Yousuf 
Department of Respiratory Sciences 
NIHR Leicester Biomedical Research Centre - Respiratory 
Glenfield Hospital 
Groby Road 
Leicester, LE3 9QP 
Email: ajy7@leicester.ac.uk 
Trial Manager: 
Niamh Quann 
Leicester Clinical Trials Unit 
University of Leicester, College of Life Sciences 
Maurice Shock Building 
University Road 
Leicester, LE1 7RH 
Email: niamh.quann@leicester.ac.uk / COPD- 
ST2OP@leicester.ac.uk 


Trial: 
COPD-ST2OP 
SAP Version: 
3.0 
Version Date: 11-Jan-2021 
ST-QRD-1 v2 
Author: Seid Mohammed 
Page 3 of 36 
PRINTED COPY MAY NOT BE THE MOST UP TO DATE VERSION 
 
 
 
Revision History 
 
Version 
Date 
Author(s) and Role 
Summary of Changes/Comments 
0.1 
15-Oct-2018 
Seid Mohammed 
Initial version 
0.2 
14-Mar-2019 
Seid Mohammed 
After the whole document was 
reviewed by CLB 
0.3 
29-Mar-2019 
Seid Mohammed 
• 
After the whole document was 
reviewed by CEB 
• 
Detailed information added on the 
subgroup analysis based on the 
COPD-ST2OP Biomarker Research 
Proposal 
0.4 
06-Nov-2019 
Seid Mohammed 
• 
After the whole document was 
updated using the COPD-ST2OP 
mock paper and also updated 
based on the amended protocol 3.1 
dated 11-Sep-2019 
1.0 
28-May-2020 
Seid Mohammed 
• 
After the whole document was 
updated based on the substantial 
amendment 02. This includes 
removal of reference to interim 
analysis, removal of week 60 
washout period, updates to 
schematic of trial design and 
clarification of secondary 
endpoints. 
• 
COPD-ST2OP Protocol version 5.0; 
11 May 2020 
1.1 
09-July-2020 
Seid Mohammed 
• 
After the whole document was 
reviewed by NQ, AY, and CLB. 
• 
After the whole document was 
updated based on NQ, AY and CLB 
comments and suggestions 
1.2 
27-July-2020 
Seid Mohammed 
• 
After the whole document was 
reviewed by CLB. 
• 
Clarification of the sub group 
analysis 
1.3 
10-Aug-2020 
Seid Mohammed 
• 
After the whole document was 
updated based on Protocol version 
7.0, 07 July 2020 
• 
After the whole document was 
reviewed by AY, CEB and NQ. 
• 
Schedule visit table was updated 
based on the current protocol 
2.0 
18-Aug-2020 
Seid Mohammed 
• 
Sign off version 
2.1 
02-Dec-2020 
Seid Mohammed 
• 
Following database lock and review 
of the draft statistical analysis 
report post hoc, i) in addition to the 


Trial: 
COPD-ST2OP 
SAP Version: 
3.0 
Version Date: 11-Jan-2021 
ST-QRD-1 v2 
Author: Seid Mohammed 
Page 4 of 36 
PRINTED COPY MAY NOT BE THE MOST UP TO DATE VERSION 
 
 
 
median eosinophil count the 
clinically important cut-off 300 
cells/µL was added to the subgroup 
analyses and ii) SGRQ-c domain 
scores (Symptoms, Activity and 
Impacts) were added and provided 
by the study team as an excel file 
rather than entered in the MACRO 
database. 
3.0 
11-Jan-2021 
Seid Mohammed 
• 
Sign off version 


Trial: 
COPD-ST2OP 
SAP Version: 
3.0 
Version Date: 11-Jan-2021 
ST-QRD-1 v2 
Author: Seid Mohammed 
Page 5 of 36 
PRINTED COPY MAY NOT BE THE MOST UP TO DATE VERSION 
 
 
 
SAP approval for finalised version: 
 
 
 
Trial Statistician 
 Seid Mohammed 
 
 
11-01-2021 
Signature 
Date 
 
 
 
Chief Investigator 
  Prof Chris Brightling 
 
11-01-2021 
Date 
Signature 
 
 
Principal 
Statistician 
Cassey Brookes 
11.01.2021 
Signature 
Date 


Trial: 
COPD-ST2OP 
SAP Version: 
3.0 
Version Date: 11-Jan-2021 
ST-QRD-1 v2 
Author: Seid Mohammed 
Page 6 of 36 
PRINTED COPY MAY NOT BE THE MOST UP TO DATE VERSION 
 
 
LIST OF ABBREVIATIONS 
 
AE 
ANCOVA 
BMI 
CAT 
CI 
CONSORT 
COPD 
CRF 
CSR 
CTIMP 
CTU 
DSMC 
EudraCT 
FEV1 
FVC 
ICH 
IL-33 
ITT 
LFT 
MAR 
MI 
mMRC 
OR 
QoL 
RR 
RV 
SAE 
SAP 
SD 
SGRQ-C 
SUSAR 
TLC 
VAS 
Adverse Event 
Analysis of covariance 
Body Mass Index 
COPD Assessment Test 
Confidence Interval 
Consolidated Standard of Reporting Trials 
Chronic Obstructive Pulmonary Disease 
Case Report Form 
Clinical Study Report 
Clinical Trial of Investigational Medicinal Product 
Clinical Trials Unit 
Data Safety Monitoring Committee 
European Clinical Trials Database 
Forced expiratory volume in 1 second 
Forced vital capacity 
International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
Interleukin-33 
Intention-to-treat 
Lung Function Test 
Missing at Random 
Multiple imputation 
Modified Medical Research Council 
Odds Ratio 
Quality of life 
Rate Ratio 
Residual volume 
Serious Adverse Event 
Statistical Analysis Plan 
Standard deviation 
St. George’s Respiratory Questionnaire for COPD patients 
Suspected unexpected serious adverse reaction 
Total lung capacity 
Visual Analogue Scale 


Trial: 
COPD-ST2OP 
SAP Version: 
3.0 
Version Date: 11-Jan-2021 
ST-QRD-1 v2 
Author: Seid Mohammed 
Page 7 of 36 
PRINTED COPY MAY NOT BE THE MOST UP TO DATE VERSION 
 
 
 
Contents 
1 
Introduction..................................................................................................................... 9 
1.1 
Study Objectives ................................................................................................ 9 
1.1.1 
Primary Objectives ...................................................................................... 9 
1.1.2 
Secondary Objectives ................................................................................. 9 
1.1.3 
Exploratory Objectives................................................................................ 9 
1.1.4 
Subgroup Objectives ................................................................................. 10 
1.2 
Trial Design ....................................................................................................... 10 
1.2.1 
Overview ................................................................................................... 10 
1.2.2 
Participants ............................................................................................... 11 
1.2.3 
Treatment groups ..................................................................................... 11 
1.2.4 
Sample size ............................................................................................... 11 
1.2.5 
Randomisation and blinding ..................................................................... 11 
1.2.6 
Emergency unblinding .............................................................................. 12 
1.3 
Visit schedule ................................................................................................... 13 
2 
Outcomes and other variables ............................................................................... 16 
2.1 
Primary Outcome ............................................................................................. 16 
2.1.1 
Definition and Derivation of Primary Outcome ....................................... 16 
2.1.2 
Hypothesis to be investigated .................................................................. 16 
2.2 
Secondary Outcomes ....................................................................................... 16 
2.2.1 
Definition and Derivation of Secondary Outcomes .................................. 16 
2.2.2 
Hypotheses to be investigated ................................................................. 18 
2.3 
Exploratory Outcomes ..................................................................................... 18 
2.3.1 
Definition and Derivation of Exploratory Outcomes ................................ 18 
2.4 
Subgroups and/or interactions ........................................................................ 18 
2.5 
Treatment Compliance .................................................................................... 18 
3 
Analysis Sets/Populations ....................................................................................... 20 
3.1 
Protocol deviations .......................................................................................... 20 
3.1.1 
Major deviations ....................................................................................... 20 
3.1.2 
Minor deviations ....................................................................................... 20 
3.2 
Intention-to-treat Population .......................................................................... 20 
3.3 
Modified intention-to-treat population .......................................................... 20 
3.4 
Per-protocol Population .................................................................................. 20 
3.5 
Safety Population ............................................................................................. 20 
3.6 
Other Analysis Populations .............................................................................. 20 
4 
General Issues for Statistical Analysis ................................................................. 21 
4.1 
Derived/ Computed Variables ......................................................................... 21 
4.2 
Multiple Testing ............................................................................................... 22 
4.3 
Interim Analysis and Data Review ................................................................... 22 
4.4 
Analysis Software ............................................................................................. 22 
5 
Statistical Methodology ............................................................................................ 22 
5.1 
Disposition of Patients ..................................................................................... 22 
5.2 
Demographic and Baseline Characteristics ..................................................... 24 


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5.3 
Comparison of losses to follow-up .................................................................. 24 
5.4 
Primary Outcome Analysis ............................................................................... 25 
5.4.1 
Primary Analysis of Primary Outcome ...................................................... 25 
5.4.2 
Secondary Analyses of Primary Outcome ................................................ 25 
5.4.3 
Sensitivity Analyses ................................................................................... 25 
5.5 
Secondary Outcome Analyses.......................................................................... 26 
5.5.1 
Primary Analysis of Secondary Outcomes ................................................ 26 
5.5.2 
Secondary analysis of the Secondary outcome ........................................ 26 
5.5.3 
Sensitivity Analyses ................................................................................... 27 
6 
Exploratory Outcome Analyses .............................................................................. 27 
6.1 
Subgroup Analyses ........................................................................................... 27 
6.2 
Changes to the Planned Analysis ..................................................................... 27 
7 
Safety and Adverse Events ....................................................................................... 28 
8 
References ..................................................................................................................... 30 
9 
Appendices .................................................................................................................... 31 
9.1 
Appendix 1: Templates for Tables, Listings and Figures .................................. 31 
9.2 
Appendix 2: Line listing of the adverse events ................................................ 36 
 


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1 Introduction 
This Statistical Analysis Plan (SAP) describes the planned analyses and reporting for a 
randomised placebo-controlled trial of anti-ST2 in COPD (COPD-ST2OP). The structure 
and content of this SAP provides sufficient detail to meet the requirements identified by 
the FDA and International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH): Guidance on Statistical Principles 
in Clinical Trials. All work planned and reported for this SAP follows internationally 
accepted guidelines, published by the American Statistical Association and the Royal 
Statistical Society for statistical practice. 
This SAP should be read in conjunction with the most recent version of the clinical trial 
protocol. 
The purpose of this SAP is to outline the planned analyses that are to be performed on 
the data to support the completion of the Clinical Study Report (CSR). The SAP will be 
amended if there are substantial changes to the planned analyses, and in any case will 
be finalised before the database lock for this study. Exploratory post-hoc or unplanned 
analyses not necessarily identified in this SAP may be performed on these data as 
required. These analyses will be clearly identified in the CSR. 
 
1.1 Study Objectives 
1.1.1 Primary Objectives 
 
The primary objective of the trial is 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 add-on to 
standard of care. 
1.1.2 Secondary Objectives 
 
The secondary objectives are to assess: 
 
1. Safety and tolerability 
2. Health status and respiratory symptoms 
3. Lung function 
4. Inflammatory cell differentials 
i. 
Sputum cell count 
ii. 
Blood cell count 
1.1.3 Exploratory Objectives 
 
The exploratory objectives are to assess: 
 
1. Systemic inflammation 
2. Upper airway inflammation 
3. Airway infection and ecology 


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4. Breath volatile organic compound profiling 
5. Quantitative airway geometry and densitometry 
6. Pharmacogenomics 
7. Pharmacokinetics and ADA level 
8. Pharmacogenomics response analysis in subgroups determined by SNPs for 
alleles associated with the IL33/ST2 axis. 
1.1.4 Subgroup Objectives 
 
To evaluate the efficacy of anti-ST2 versus placebo on the outcome rate of protocol 
defined COPD exacerbations, change in St George’s Respiratory Questionnaire for COPD 
patients (SGRQ-C), and FEV1 through 48 weeks treatment period, in subgroups defined 
by baseline blood eosinophil count (dichotomised about median value). 
 
1.2 Trial Design 
1.2.1 Overview 
 
This is a single-centre, double-blind, placebo-controlled, parallel group, randomised 
trial to assess the efficacy and safety of anti-ST2 compared to placebo, in patients with 
moderate to very severe COPD (GOLD II-IV). Anti-ST2/placebo will be administered via 
subcutaneous injection once every 4 weeks (Week 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 
and 44) during the 48-week treatment period. The treatment period will followed by a 
12-week follow-up period (i.e washout period). An overview of the trial design is 
presented in 
. 
 
Figure 1: Schematic of Trial Design for COPD-ST2OP 


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1.2.2 Participants 
 
Participants will have a diagnosis of moderate to very severe COPD (GOLD II to IV). For 
further details please refer to the complete inclusion/exclusion criteria in section 6 of 
the trial protocol. 
1.2.3 Treatment groups 
 
1.2.3.1 Intervention group 
The intervention is MSTT1041A (anti-ST2). It is a first-in-class, fully human, IgG2 
monoclonal antibody (mAb) being developed for use in the treatment of asthma and 
COPD. Anti-ST2 binds with high affinity to the human receptor for IL-33/ST2, and blocks 
IL-33 binding, thus inhibiting association with the IL-1R accessory protein (AcP) co- 
receptor and formation of an activated receptor complex. 
 
Anti-ST2 is presented as sterile, clear, and colourless to slightly yellow liquid. Each sterile 
vial is filled with a 1 mL deliverable volume of 70 mg/mL. It is formulated with 15 mM 
sodium acetate, 9.0% (w/v) sucrose, 0.01% (w/v) polysorbate 20, pH 5.2. 
1.2.3.2 Placebo 
Placebo for Anti-ST2 (MSTT1041A) is formulated with 10 mM sodium acetate, 9.0% 
(w/v) sucrose, 0.004% (w/v) polysorbate 20, pH 5.2, and is supplied in an identical vial 
configuration. 
1.2.4 Sample size 
 
Recruitment of 80 participants with a drop-out rate of 10% will be sufficient to give 80% 
power at the 5% level assuming either a 48 week exacerbation frequency 2 or 2.5 per 
year in the placebo group to observe a 50% or 40% reduction in exacerbation frequency 
in those receiving anti-ST2 respectively. 
 
This sample size estimate is based upon a negative binomial model. The estimation of 
the over-dispersion was derived from the BEAT-COPD (Biomarkers to Target Antibiotic 
and Systemic Corticosteroid Therapy in COPD Exacerbations) [ISRCTN92422949] data 
and was 1.3 with a mean exacerbation frequency of 2.85. 
1.2.5 Randomisation and blinding 
 
Participants, investigators, the trial management team and everyone involved in trial 
conduct will remain blinded with regard to the allocation sequence and randomised 
treatment assignments until after database lock. 
 
Unblinded personnel will include: 
• The trial statistician, in order for the unblinded DSMC to make safety decisions 
• The Pharmacy team, to take receipt of and dispense the IMP/placebo 
• The designated individuals from the Respiratory BRC responsible for 
reconstituting the IMP/placebo. 


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• The trial monitor, in order to perform drug accountability and reconciliation. The 
Sponsor and the trial monitor are one entity; therefore it will not be possible to 
maintain the blind of the Sponsor. 
 
Leicester Clinical Trials Unit (LCTU) will supply a web-based randomisation system from 
a third party (Sealed Envelope Ltd). Participants will be randomised in a 1:1 ratio to anti- 
ST2 or placebo. This will be set up as a blinded randomisation process, whereby a 
blinded randomisation code is allocated to a participant which corresponds to either the 
anti-ST2 or placebo. Decoding lists are held by unblinded personnel and available via 
Sealed Envelope for emergency unblinding. Randomisation will be stratified by 
frequency of moderate to severe exacerbation in the previous 12 months (i.e Low [2 or 
3] and High [4 or more]). 
 
1.2.6 Emergency unblinding 
 
If it is deemed necessary by the clinical or research team to unblind the patient to the 
allocated treatment the Chief Investigator must be contacted. Only the Chief 
Investigator or delegated individual on the delegation log can decide to unblind. 
Emergency unblinding will be available to the investigator / pharmacist / Sponsor via the 
web-based Sealed Envelope system. The Sealed Envelope system will be fully audit 
traceable until the end of the trial to ensure that blinding has not been compromised. 
Unblinding will only occur in the case of a medical emergency or if a patient experiences 
an unexpected serious reaction such as a suspected unexpected serious adverse 
reaction (SUSAR). 
 
Unblinding of all subjects will take place when the last patient has completed their final 
visit assessments and data collection and validation is complete. 
 
To test the validity of the blinding both the participants and researchers will be asked if 
they were aware of treatment allocation; this will be recorded on the visit 14 CRF. 


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1.3 Visit schedule 
Table 1: Schedule of Procedures 
 
Trial assessment 
Screen 
Randomised treatment (visit window +/- 7 days) 
Efficacy end 
point 
(visit window 
+/- 7 days) 
3 month post- 
trial follow-up 
Withdrawal 
Unscheduled 
visit 
(e.g. 
exacerbation) 
V0 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
+/- 14 days 
Wk 
0 
Wk 
4 
Wk 
8 
Wk 
12 
Wk 
16 
Wk 
20 
Wk 
24 
Wk 
28 
Wk 
32 
Wk 
36 
Wk 
40 
Wk 
44 
Wk 48 
Wk 60 
Consent 
x 
Review Inclusion & Exclusion 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x♦ 
x♦ 
Randomisation 
x 
Dosing 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
Demographics (age, gender, 
BMI, ethnicity, smoking status) 
x 
Vital signs (pulse, BP, temp, O2 
sats) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
x^ 
x^ 
x♦ 
x♦ 
Medical history 
x 
Concomitant Med 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x♦ 
x♦ 
Physical examination 
x 
x 
x^ 
x♦ 
Safety AE/SAE 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x♦ 
x♦ 
COPD ++ Exacerbation 
frequency 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x♦ 
SGRQ-c 
x 
x 
x 
x 
x 
x^ 
x^ 
x♦ 
x♦ 
mMRC 
x 
x 
x 
x 
x 
x 
x^ 
x^ 
x♦ 
x♦ 
CAT 
x 
x 
x 
x 
x 
x^ 
x^ 
x♦ 
x♦ 
VAS (dyspnoea, cough, sputum) 
x 
x 
x 
x 
x 
x^ 
x^ 
x♦ 
x♦ 
Sputum Purulence Colour Card 
x 
x 
x 
x 
x^ 
x^ 
x♦ 
x♦ 


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Trial assessment 
Screen 
Randomised treatment (visit window +/- 7 days) 
Efficacy end 
point 
(visit window 
+/- 7 days) 
3 month post- 
trial follow-up 
Withdrawal 
Unscheduled 
visit 
(e.g. 
exacerbation) 
V0 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
+/- 14 days 
Wk 
0 
Wk 
4 
Wk 
8 
Wk 
12 
Wk 
16 
Wk 
20 
Wk 
24 
Wk 
28 
Wk 
32 
Wk 
36 
Wk 
40 
Wk 
44 
Wk 48 
Wk 60 
VOC (PTRMS & ADVION) 
x 
x 
x 
x 
x^ 
x^ 
x♦ 
Post- BD spirometry 
x 
x 
x 
x 
x 
x^ 
x^ 
x♦ 
x♦ 
Pre and post BD spirometry 
x 
x^ 
‘Body box’ 
x+ 
x^ 
HbA1c 
x 
x 
x 
x 
x 
x^ 
x^ 
x♦ 
FBC 
x 
x 
x 
x 
x 
x^ 
x^ 
x♦ 
x♦ 
U&Es 
x 
x 
x 
x 
x 
x^ 
x^ 
x♦ 
x♦ 
LFTs 
x 
x 
x 
x 
x 
x^ 
x^ 
x♦ 
x♦ 
CRP 
x 
x 
x 
x 
x 
x^ 
x^ 
x♦ 
x♦ 
RNA (PAXgene) 
x 
x 
x 
x 
x 
x^ 
x^ 
x♦ 
x♦ 
DNA (PAXgene) 
x 
Total IgE & RAST (HDM, pollen, 
cat, dog) 
x 
Serum/plasma inflam 
biomarkers 
x 
x 
x 
x 
x 
x^ 
x^ 
x♦ 
x♦ 
Lipid profile 
x 
x^ 
Pharmacokinetics PK$ 
x 
x 
x 
x^ 
x♦ 
ADA 
x 
x 
x 
x^ 
x♦ 
Pharmacogenetics SNPs 
x 
x^ 
NTproBNP 
x 
x 
x 
x 
x 
x^ 
x^ 
x♦ 
x♦ 
Participant Diary 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x♦ 
x♦ 


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Trial assessment 
Screen 
Randomised treatment (visit window +/- 7 days) 
Efficacy end 
point 
(visit window 
+/- 7 days) 
3 month post- 
trial follow-up 
Withdrawal 
Unscheduled 
visit 
(e.g. 
exacerbation) 
V0 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
+/- 14 days 
Wk 
0 
Wk 
4 
Wk 
8 
Wk 
12 
Wk 
16 
Wk 
20 
Wk 
24 
Wk 
28 
Wk 
32 
Wk 
36 
Wk 
40 
Wk 
44 
Wk 48 
Wk 60 
Urine sample (10-20ml) for 
Inflam Biomarker 
x 
x 
x 
x 
x 
x 
x^ 
x^ 
x♦ 
x♦ 
Sputum for Biomarkers 
Differential cell count, qPCR 
and Microbiome 
x 
x 
x 
x 
x 
x^ 
x^ 
x♦ 
Nasal epithelial sampling & 
nasosorption 
x 
x 
x 
x 
x^ 
x^ 
x♦ 
Pregnancy Testing ** 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
x^ 
x^ 
x♦ 
x♦ 
ECG£ 
x 
x^ 
x♦ 
ECHO* 
x 
x♦ 
CXR 
x♦ 
Non-contrast CT chest$$ 
x 
x^ 
* For clinically meaningful increase in NTproBNP OR new symptoms/signs concerning for HF or cardiac dysfunction OR clinically significant ECG changes from baseline 
+ Body plethysmography (‘body box’) will be done anytime between screening and week 12, unless patient has had the test within 12 months prior to screening 
$ Pk samples should be taken pre-dose 
£ 12 lead ECG. If, in the opinion of investigator, the ECG is grossly abnormal (e.g. LBBB, prolonged QTc), it will be compared to old ECGs. If there are no old ECGs for comparison, the investigator will make a 
clinical judgement about the suitability of the patients to take part in trial. 
$$ CT scan. Patients who are claustrophobic or unable to lie flat won’t be offered CT scan. 
++ COPD Exacerbation frequency where a COPD exacerbation is defined by symptomatic worsening of COPD requiring use of systemic corticosteroids for at least 3 days, a single depot injectable dose of 
corticosteroids will be considered equivalent to a 3-day course of systemic corticosteroids; and/or Use of antibiotics; and/or An inpatient hospitalisation or death due to COPD. 
** Pregnancy testing (blood and urine) can be at any trial visit for WOCBP (i.e.fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods 
include hysterectomy, bilateral salpingectomy and bilateral oophorectomy) or if they have missed a menstrual cycle. 
^ During the COVID-19 restriction period, these assessments will not be completed at Visit 13 (week 48) and Visit 14 (week 60). All remaining assessments will be competed as per the protocol remotely via a 
telephone consultation (i.e. participants will not be required to attend the research clinic). Should the restrictions be lifted, participants can attend the research clinic and complete all procedures. 
♦ During the COVID-19 restriction period, participants will not be seen at the research clinic for unscheduled and withdrawal visits. Should the restrictions be lifted, participants can attend the research clinic 
and complete all procedures. 


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2 Outcomes and other variables 
2.1 Primary Outcome 
2.1.1 Definition and Derivation of Primary Outcome 
 
The primary outcome is the frequency of moderate to severe exacerbation (defined as 
requiring treatment with systemic corticosteroids and/or antibiotics in the community 
of hospital or hospitalisation) in the 48 weeks. COPD exacerbations is defined by 
symptomatic worsening of COPD requiring: 
• Use of systemic corticosteroids for at least 3 days; a single depot injectable 
dose of corticosteroids will be considered equivalent to a 3-day course of 
systemic corticosteroids; 
and/or 
• Use of antibiotics; 
and/or 
• An inpatient hospitalisation or death due to COPD 
 
The total number of moderate to severe exacerbation over 48 weeks is defined as a 
count outcome. This will be derived using the number of moderate to severe 
exacerbations each participant had over the course of 48 weeks. The outcome will have 
a minimum value of zero. 
 
Maximum study time for a patient is approximately 49 weeks (48 weeks + 7 days); 
defined as the time from randomisation to the date of visit 13 (week 48). This will be 
calculated; (visit-13 date – randomisation date + 1). 
 
2.1.2 Hypothesis to be investigated 
 
COPD patients treated with anti-ST2 therapy will have reduced COPD exacerbation 
frequency after 48 weeks treatment compared to placebo treated patients. 
 
2.2 Secondary Outcomes 
2.2.1 Definition and Derivation of Secondary Outcomes 
 
Note: * indicates this data is held on Macro database; ^ indicates this data is held 
externally to the Macro database and will be provided by the team at NIHR Leicester 
Biomedical Research Centre – Respiratory. 
 
The secondary endpoints/outcomes are: 
 
1. Safety and tolerability (All visits) 
• AE event rate in the 48 weeks of the trial from first dose* 
• SAE event rate in the 48 weeks of the trial from first dose* 


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2. Patient related outcomes (PROs) (Weeks 0, 4, 12, 24, 36 and 48)* 
• St George’s Respiratory Questionnaire for COPD patients (SGRQ-c) 
o Total score* 
o Domains (post hoc): 
i. Symptoms score^ 
ii. Activity score^ 
iii. Impacts score^ 
• COPD Assessment Test (CAT) 
• mMRC Dyspnoea Scale 
• Visual analogue score (VAS) 
o Total 
o Dyspnoea 
o Cough 
o Sputum production 
• Sputum purulence colour card 
 
3. Lung function (Weeks 0 and 48) 
 
• Pre and post BD Spirometry* 
o FEV1 
o FEV1 % predicted 
o FVC 
o FEV1/FVC % 
o BD reversibility % 
• Whole body plethysmography (body box)* 
o TLC 
o RV 
o RV/TLC % 
 
4. Inflammation (Weeks 0, 4, 12, 24, 36, 48) 
• Cell count 
o Blood inflammatory cell differentials* 
- WBC 
- Eosinophils 
- Neutrophils 
o Sputum inflammatory cell differentials 
- Eosinophils 
- Neutrophils 
- Macrophages 
- Lymphocytes 
- Epilthelial cells 
- Total 


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2.2.2 Hypotheses to be investigated 
 
All secondary outcomes measures are hypothesised to benefit from the anti-ST2 
intervention. 
 
2.3 Exploratory Outcomes 
2.3.1 Definition and Derivation of Exploratory Outcomes 
 
• Quantitative measures of airway geometry and densitometry – Contrast thoracic 
CT-derived outcomes ( Weeks 0 and 48) 
o MLD E/I (small airway) 
o % WA 
o LA (Larger airways) 
• Mediators 
o Sputum mediator profiling (biomarkers) 
o Blood biomarkers 
• Cell subset analysis including but not restricted to exploration of ILC2 cells 
• Urine biomarkers of inflammation 
• Mediator profiling (biomarkers) 
• Upper airway inflammation: 
o nasosorption 
o nasal epithelial sampling (optional) 
• Airway infection and ecology: 
o targeted qPCR (bacteria and viruses) for common airway pathogens 
o microbiomics 
• Breath volatile organic compound (VOC) profiling (PTRMS and ADVION) – 
breathomics 
• Pharmacogenomics response analysis in subgroups determined by SNPs for 
alleles associated with the IL33/ST2 axis 
 
2.4 Subgroups and/or interactions 
There will be a subgroup analysis of the primary outcome, rate of protocol-defined 
moderate to severe COPD exacerbations through 48 weeks treatment period and 
secondary outcomes SGRQ-C and FEV1 by baseline blood eosinophil count 
(dichotomised about median value). 
 
2.5 Treatment Compliance 
All doses of the trial treatment will be administered subcutaneously (SC) at the research 
site by blinded research staff. The prescribed dosage, and mode of administration 
should not be changed. If a participant misses a dose, the missed dose can be given 
within 1 week. Any changes from the intended regimen will be recorded in the CRF. 
 
A summary of the treatment received will be provided by treatment arms. This will 
 include information in terms of dosing, administration, changes and delays from Visit 1 


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(week 0) to Visit 13 (week 48). Any treatment compliance will be presented by treatment 
arm and deviations from protocol including loss to follow-up, withdrawal by clinician 
and withdrawal of consent will be included. 


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3 Analysis Sets/Populations 
3.1 Protocol deviations 
3.1.1 Major deviations 
 
Protocol deviations that will affect inclusion in trial populations are: 
• Participants found to be ineligible after randomisation 
• Participants who receive the wrong study treatment 
• Participants who miss greater than one dose of study treatment 
• Participants who delay a scheduled study visit greater than 4 weeks 
3.1.2 Minor deviations 
 
All other (non-major) protocol deviations will be reported but will not affect analysis 
populations. e.g. Missing one dose of study treatment, visit assessments delays less than 
4 weeks, visit assessments earlier than scheduled (refer to Table 2 in Appendix 1). 
 
3.2 Intention-to-treat Population 
The intention-to-treat population will be comprised all the participants randomised in 
to the trial (regardless of whether they received trial drug) analysed in their allocated 
group, outcome data obtained from all participants will be included in the data analysis 
(i.e regardless of study completion or data completeness). All data up to the time of 
study discontinuation will be included for participants who withdrew prematurely. 
 
3.3 Modified intention-to-treat population 
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. 
 
3.4 Per-protocol Population 
The per-protocol population will comprise all participants recruited in to the trial who 
had their intervention administered and who do not have major protocol deviations. 
 
3.5 Safety Population 
The safety population will be comprised of the all individuals that received at least one 
injection of either the anti-ST2 or placebo, with individuals that received any injections 
of the active dose being analysed in the Anti-ST2 arm, regardless of randomised 
allocation. 
 
3.6 Other Analysis Populations 
None 


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4 General Issues for Statistical Analysis 
4.1 Derived/ Computed Variables 
Body mass index (BMI): This will be derived as per WHO Guidelines, BMI measures 
as Kg/m2. 
 
Age: Age will be measured in years and will be derived from the date of birth at the 
randomisation date. 
 
COPD Assessment Tool (CAT) score: The CAT consists of 8 items with scores ranging 
from 0 to 5 (0= no impairment). An overall score will be calculated by adding the 
score from each item with total scores ranging from 0 to 40, higher scores indicating 
a more severe health status impairment or a poorer control of COPD. 
 
St George’s Respiratory Questionnaire for COPD patients (SGRQ-C): The SGRQ-C is 
in two parts. Part I produces the Symptoms score, and Part 2 the Activity and 
Impacts scores. A Total score is then produced. Each questionnaire response has a 
unique empirically derived `weight’. The lowest possible weight is zero and the 
highest is 100. A Total and three component scores are calculated: Symptoms; 
Activity; Impacts. 
 
The Symptoms component consists of all the questions in Part 1. The weights for 
Questions 1-7 are summed. A single response is required to each item. If multiple 
responses are given to an item, then average weight should be calculated. 
The Activity component is calculated from the summed weights for the positive 
responses to items Questions 9 and 12 in Part 2 of the questionnaire. 
The Impacts component is calculated from Questions 8, 10, 11, 13, 14 in Part 2 of 
the questionnaire. 
Then the Total score is calculated by summing the weights to all the positive 
responses in each component. 
 
FEV1/FVC ratio: FEV1 is the volume of air exhaled in 1 second, FVC is FVC is the full 
amount of air that can be exhaled with effort in a complete breath. FEV1/FVC ratio 
is a measure of airflow obstruction, with values <0.7 (70%) indicating airflow 
obstruction. 
 
BD Reversibility percentage: this will be computed as % Reversibility = (post-BD 
FEV1- pre-BD FEV1) × 100/pre-BD FEV1 
 
RV/TLC ratio: this is the residual volume (RV) to total lung capacity (TLC). It is 
𝑅𝑅𝑅𝑅 
calculated using 
 
 
𝑇𝑇𝑇𝑇𝑇𝑇 𝑥𝑥 100% 


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4.2 Multiple Testing 
There will be no adjustment for multiple comparisons as there will be only one primary 
analysis. 
 
4.3 Interim Analysis and Data Review 
There is no interim analysis planned. The DSMC will receive report three monthly during 
recruitment period, then six monthly thereafter during 12 month follow-up period. The 
report will contain tables on recruitment, disposition of participants, trial and data 
quality, adverse events, and protocol deviations. There will be open and closed sessions. 
The open sessions will involve presentation of data relating to recruitment and retention 
based on pooled data and data quality (e.g data return dates, treatment compliance) 
blind to treatment allocation. The closed session will involve presentation of efficacy 
and safety data unblinded by treatment group. 
 
Recruitment and disposition will also be presented in a Consolidated Standards of 
Reporting Trials (CONSORT) diagram. 
 
4.4 Analysis Software 
It is anticipated that the analysis will be done in STATA, R or SAS statistical software 
(versions will be recorded in the statistical report). The University of Leicester holds the 
relevant licences for this software. 
 
5 Statistical Methodology 
The statistical analysis will be based on relevant guidelines (e.g. ICH E3 and E9 statistical 
principles for clinical trials). The date of data extraction from the database will be 
included in each report. 
 
5.1 Disposition of Patients 
Patient disposition will be presented with respect to trial completion status, reason for 
non-completion, protocol deviations, primary outcome data completeness and length 
of stay in the trial (Figure 3). Results will be tabulated and summarised over time by 
intervention arm. 
 
A CONSORT [1] diagram will display the flow of patients through the trial. A graph of 
cumulative recruitment will be presented in addition to summaries of recruitment (e.g. 
start and end date). 


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Lost to follow-up (n= ) 
• 
Reasons 
Discontinued intervention (n= ) 
• 
Reasons 
Lost to follow-up (n= ) 
• 
Reasons 
Discontinued intervention (n= ) 
• 
Reasons 
Allocated to Placebo (n= ) 
• 
Received allocated intervention (n= ) 
• 
Did not receive allocated intervention (n= ) 
• 
Reasons 
Allocation 
Allocated to Anti-ST2 (n= ) 
• 
Received allocated intervention (n= ) 
• 
Did not receive allocated intervention (n= ) 
• 
Reasons 
Randomised (n= ) 
Excluded (n= ) 
 
Not meeting inclusion criteria (n=  ) 
 
Declined to participate (n= ) 
 
Other reasons (n= ) 
Enrolment 
Assessed for eligibility (n= ) 
Analysed (n= ) 
• 
Excluded from analysis (n= ) 
o Reasons 
Analysis 
Analysed (n= ) 
• 
Excluded from analysis (n= ) 
o Reasons 
 
Figure 2: CONSORT Diagram 
 
 
 
 
 
 
 
For detailed information on the reasons for exclusion criteria please refer to Table 3 in 
Appendix-1. 
Follow-Up 


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5.2 Demographic and Baseline Characteristics 
Numbers (with percentages) for binary and categorical variables and means (and 
standard deviations), and medians (with lower and upper quartiles) for continuous 
variables will be presented. There will be no tests of statistical significance nor 
confidence intervals for differences between randomised groups on any baseline 
variable. 
 
The stratification variable will be summarised by treatment arm in order to check the 
balance of the low and high frequency of moderate to severe exacerbation in the 
previous 12 months prior to the study between the two randomised arms. 
 
The baseline variables that will be summarised are included in Table 4 in Appendix-1. 
 
5.3 Comparison of losses to follow-up 
The numbers (with percentages) of losses to follow-up, withdrawals and discontinuation 
of study treatment will be reported descriptively between the intervention and placebo 
arms. Any deaths (and their causes) will be reported separately. 


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5.4 Primary Outcome Analysis 
5.4.1 Primary Analysis of Primary Outcome 
 
The main approach to primary analyses will be an intention-to-treat (ITT), where the ITT 
population consist of all randomised participants into the trial (regardless of whether 
they received trial drug). Descriptive statistics of the estimated exacerbations rates in 
the 48 week treatment period will be presented by treatment arm and overall (Table 5 
in Appendix-1). Histogram of the number of exacerbations in the 48 week period by 
patient will be drawn to check the distribution of the number of exacerbations during 
treatment (Figure 5). Cumulative number of exacerbations will be plotted by treatment 
arm (Figure 6). 
 
A generalised linear model (assuming a negative binomial distribution, which accounts 
for variability among patients in the number of and frequency of exacerbation) will be 
fitted for the primary outcome of COPD exacerbations during the 48 week treatment 
period as an outcome with explanatory variables of treatment arm and number of 
exacerbation in the 12 months prior to the trial (stratification factor), and log-time on 
study as an offset. The offset (log-time), allows for different lengths of time on treatment 
for each participant [2]. This assumes that missing data is missing at random (MAR), and 
will be applied where all of the available observed data are analysed without deletion 
nor imputation. 
 
The primary outcome data is assumed to follow a negative binomial distribution with 
the over dispersion estimated to be 1.3. The primary analysis of the primary outcome 
will give an estimate of the significance of the dispersion parameter. If the dispersion is 
found to be non-significant (i.e no evidence of over-dispersion) we will consider the 
simpler Poisson model where the dispersion parameter equals to zero. The ratio of the 
exacerbation rates (RR) on the anti-ST2 relative to the placebo, associated two-sided 
95% confidence interval (CI) and p-value will be reported (Table 5 in Appendix-1). A value 
of 1.0 would indicate the same rate as placebo; the lower the ratio the greater reduction 
in exacerbations compared with placebo. A two-sided p-value ≤ 0.05 will be considered 
as a significant difference in the number of COPD exacerbations in 48 weeks between 
the two treatment arms. 
5.4.2 Secondary Analyses of Primary Outcome 
 
The secondary analysis of the primary outcome will be carried out on the per-protocol 
population. In this analysis participants with major protocol deviations (as defined in 
section 3.1.1) will be excluded from the analysis. All other methods regarding the model 
construction and presentation will remain the same. 
5.4.3 Sensitivity Analyses 
 
To examine the sensitivity of the result of the primary analysis to departures from the 
underlying assumptions (i.e MAR), additional analysis will be performed using the 
controlled multiple imputation method [3]. 


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5.5 Secondary Outcome Analyses 
5.5.1 Primary Analysis of Secondary Outcomes 
 
All secondary end-points will be analysed using the modified intention-to-treat 
population, with the exception of adverse events, for which we will analyse the safety 
population, consisting of all participants who received at least one dose of trial 
medication. 
 
Descriptive statistics of all the secondary outcomes listed in section 2.2 will be presented 
by treatment arms and overall by assessment time points (i.e by visit). Numbers (with 
percentages) for binary and categorical variables and means (and standard deviations), 
and medians (with lower and upper quartiles) for continuous variables will be presented. 
 
All binary secondary outcomes will be compared between treatment groups using 
logistic regression. Odd ratio (OR) with two-side 95% CI and P-value will be reported for 
those outcomes. 
 
All continuous longitudinal outcomes (repeated measurements i.e week 0, 4, 12, 24, 36 
and 48) will be compared using mixed effects model with explanatory variables of 
treatment arm, number of exacerbations in the 12 months prior to the trial 
(stratification factor), visit number in weeks (categorical) and patient identification as a 
random effect to account for repeated measures over time. This method will able to 
handle missing data happening during the follow-up measurements. Adjusted mean 
differences alongside two sided 95% CI and P-value will be reported for these outcomes. 
If the distribution of the variable found to be far from normal distribution, a log 
transformation will be used to modify the non-normality. Adjusted geometric mean 
difference alongside two sided 95% CI and P-value will be reported. 
 
To compare change from baseline to 48 weeks (pre and post treatment measurements), 
analysis of covariance (ANCOVA) model with baseline value as a covariate will be used. 
Adjusted mean differences with 95% confidence interval will be reported if the data are 
normally distributed. If there is severe departure from normality the first approach will 
be data transformation with the above technique applied to the transformed data. 
Adjusted geometric mean difference with 95% CI and P-value will be reported. If the 
data cannot be transformed to normality then the Mann-Whitney U test will be used 
and in this case no baseline adjustment will be made. 
 
All safety data will be analysed as described in section 7 of this SAP. 
 
5.5.2 Secondary analysis of the Secondary outcome 
 
Per-protocol population analysis will be carried out for key secondary outcomes. These 
are FEV1 post-bronchodilator, SGRQ-C and CAT. All other methods regarding the model 
construction and presentation will remain the same. 


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5.5.3 Sensitivity Analyses 
 
There will be no sensitivity analyses carried out for any secondary outcome measures. 
 
6 Exploratory Outcome Analyses 
The accumulation of the exploratory outcome data will take several months following 
completion of the week 60 follow-up period. Therefore the exploratory outcome 
analyses will not form part of initial data lock and analysis of this data will occur after 
the primary and secondary outcomes have been completed and reported. All 
exploratory end-points will be analysed at a later stage outside the remit of Leicester 
CTU. Therefore those analyses may not bound by this SAP, though they are expected to 
follow the broad principles laid out within this document. 
 
6.1 Subgroup Analyses 
A subgroup analysis of the primary outcome will be carried out based on baseline blood 
eosinophil, dichotomised by the median value. The primary outcome of COPD 
exacerbations in 48 weeks will be summarised by low or high eosinophil count and 
analysed as described in section 5.4.1. An indicator variable to specify the eosinophil 
group (low or high) will be added to the analysis model. The additional of an interaction 
term between eosinophil indicator variable and treatment group will assess the 
difference in treatment efficacy between low and high eosinophil groups. Post hoc the 
clinically important eosinophil cut-off (>300 eosinophils/µL) was included as an 
additional subgroup analysis. 
 
Additional subgroup analyses of the SGRQ-C and FEV1 will also be carried out based on 
the baseline blood eosinophil, dichotomised by the median value. The SGRQ-C sore and 
FEV1 will be summarised by low or high eosinophil count and analysed as described in 
section 5.4.1. An indicator variable to specify the eosinophil group (low or high) will be 
added to the analysis model. The addition of an interaction term between eosinophil 
indicator variable and treatment group will assess the difference in SGRQ-C score and 
FEV1 between the low and high eosinophil groups. 
 
 
6.2 Changes to the Planned Analysis 
All changes to the original planned analysis will be noted in the statistical report 
alongside the reasons and justifications. 


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7 Safety and Adverse Events 
All safety data will be presented according to the safety population. Any adverse events 
and serious adverse events occurring from the first dose throughout the trial period will 
be recorded on the AE CRF, Sponsor’s SAE form and SAE tracking log. 
 
An Adverse Event (AE) is any untoward medical occurrence in a patient, associated with the use 
of a medicinal product, whether or not considered related to the medicinal product. 
 
Events meeting the definition of an AE include: 
 
• 
Exacerbation of a chronic condition (except COPD) 
• 
New conditions detected or diagnosed after trial treatment administration even though 
it may have been present prior to the start of the trial 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of trial treatment 
• 
Any unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
Adverse events that are related to a protocol mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive procedures 
such as biopsies) 
 
Events that do not meet the definition of an AE include: 
 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE 
• 
Situations where an untoward medical occurrence did not occur (social admission to a 
hospital) 
• 
COPD exacerbation, progression, signs and symptoms (unless they are considered to be 
related to the trial drug by the investigator; then they would constitute a reaction) 
 
An adverse reaction (AR) is an untoward and unintended response(s) related to the study 
treatment. All cases judged by either the reporting medically qualified professional or the 
sponsor as having a reasonable suspected causal relationship to the study treatment qualify as 
adverse reactions. 
 
A Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) is defined as any adverse event 
or adverse reaction in a trial participant that: 
 
• 
Results in death 
• 
Is life threatening (the subject was at risk of death at the time of event) 


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• 
Requires hospitalisation or prolongation of an existing hospitalisation 
• 
Results in persistent or significant disability or incapacity 
• 
Consists of a congenital anomaly or birth defect 
• 
Other serious Important Medical Event - an event that may not be immediately life 
threatening or result in death or hospitalisation but may jeopardise the subject or may 
require intervention to prevent one of the outcomes listed above should be considered. 
 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is defined as an adverse reaction 
that is both unexpected (not consistent with the Reference Safety Information) and also meets 
the definitions of a Serious Adverse Reaction. 
 
All adverse events will be listed including, seriousness, duration, relatedness, severity, 
action taken, outcome, and treatment arm and overall. 
 
For detailed information on the ways of reporting AEs and SAEs please refer to Table 7 
and Table 8 in Appendix-1. 


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8 References 
1, Schulz KF, Altman DG, Moher D, for the CONSORT Group. CONSORT 2010 Statement: 
updated guidelines for reporting parallel group randomised trials. Ann Int Med 
2010;152. Epub 24 March. 
 
2, Keene ON, Calverley PM, Jones PW, Vestbo J, Anderson JA. Statistical analysis of 
exacerbation rates in COPD: TRISTAN and ISOLDE revisited. Eur Respir J 2008; 32: 17–24. 
 
3, Keene ON, Roger JH, Hartley BF, Kenward MG. Missing data sensitivity analysis for 
recurrent event data using controlled imputation. Pharmaceutical Statistics 
2014;13:258-64. 


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9 Appendices 
9.1 Appendix 1: Templates for Tables, Listings and Figures 
 
Table 2: Protocol deviations by treatment arm and overall 
 
Deviation Type 
Anti-ST2 ( n = ) 
n (%) 
Placebo ( n = ) 
n (%) 
Total ( n= ) 
n (%) 
Major deviations 
ineligible after randomisation 
received the incorrect trial treatment 
missed greater than one dose of trial treatment 
delayed a scheduled trial visit > 4 weeks 
Minor 
Total 
 
 
Table 3: Expansion of reasons for exclusion from the COPD-ST2OP trial 
 
N 
%1 
Patients assessed for eligibility and consent 
Eligible and recruited to the trial 
Excluded from the trial 
Did not meet inclusion criteria 
Reason 1 
Reason 2 
Reason 3 
Refused to participate 
Reason 1 
Reason 2 
Reason 3 
Other reasons 
1Percentage calculated over the total of assessed patients (n= ) 
 
 
Figure 3: Time to study drug discontinuation or withdrawal 


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Table 4: Demographic and Baseline Clinical Characteristics 
 
Characteristics 
Anti-ST2 
(n = ) 
Placebo 
(n = ) 
Total 
(n = ) 
Age (years), Mean (SD) 
Male sex, n (%) 
Ethnicity, n (%) 
White 
Asian 
BMI (kg/m2), Mean (SD) 
Smoking status, n (%) 
Current 
Former 
Pack- years, mean (SD) 
Number of exacerbations in the previous 12 months, Mean (SD) 
Number of exacerbations in the previous 12 months, n (%) 
1 
2 
3 
≥4 
Number of exacerbations in the previous 12 months, n (%) 
Low [2 or 3] 
High [4 or more] 
Baseline eosinophil count, cells/µL, Mean (SD) 
Sputum eosinophils (%) 
Post-BD FEV1, % predicted normal, mean (SD) 
Post-BD FVC, % predicted normal, mean (SD) 
Post-BD FEV1/FVC, % mean (SD) 
GOLD status 
II 
III 
IV 
Previous diagnosis of asthma, n (%) 
Participants questionnaires, mean (SD) 
VAS dyspnoea score 
VAS sputum score 
VAS cough score 
mMRC dyspnoea score 
SGRQ-C total score 
CAT score 
Data are n (%), mean (SD), or median (IQR), unless otherwise stated. 


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Table 5: Summary of estimated exacerbation rates 
 
Anti-ST2 
Placebo 
Total 
Number of exacerbations 
N 
Exacerbation rate in 48 weeks 
Mean (SD) 
Median (IQR) 
Min, Max 
Patients experienced an exacerbation 
n (%) 
Patients did not experience any 
exacerbations 
n (%) 
Abbreviations: SD= Standard deviation; IQR= Inter-quartile range, Min=Minimum; Max=Maximum; N= 
number of observations 
Data are n (%), mean (SD), or median (IQR), unless otherwise stated. 
 
 
Figure 4: Distribution of the number of moderate to severe exacerbation among 
subjects (overall) 
 
Figure 5: Distribution of the number of moderate to severe exacerbation among 
subjects (by treatment arm) 
 
Figure 6: Cumulative number of moderate to severe exacerbations occurred in each 
trial arm over the course of 48 weeks plotted over time by treatment arm 
 
 
Table 6: Summary of treatment comparisons 
 
Anti-ST2 versus placebo 
RR* 
95% CI 
p-value^ 
Frequency of   Exacerbations   in   Anti-ST2 
relative to Placebo 
*Adjusted for the number of exacerbation in the 12 months prior to the trial 
^A two-sided p-value ≤ 0.05 will be considered as a significant difference in the number of COPD 
exacerbations in 48 weeks between the two treatment arms. 
Abbreviations: RR= Rate Ratio; CI=Confidence interval 


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Table 7: Adverse events 
 
Anti-ST2 
(n = ) 
Placebo 
(n = ) 
Total 
(n = ) 
Number of treatment-emergent adverse events 
Adverse events leading to deaths 
Patient reporting one or more treatment-emergent 
adverse event 
Number of treatment-emergent serious adverse events 
Patients reporting   one   or   more   treatment-emergent 
serious adverse event 
Patient with treatment-emergent adverse events leading 
to discontinuation 
Treatment-emergent adverse events by system organ 
Respiratory, thoracic and mediastinal disorders 
Upper respiratory tract infection 
Lower respiratory tract infection 
Musculoskeletal and connective tissue disorders 
General disorders and administration-site disorders 
Nervous system disorders 
Gastrointestinal disorders 
Skin and subcutaneous-tissue disorders 
Injury, and procedural complications 
Cardiac disorders 
Vascular disorders 
Metabolic disorders 
Renal and urinary tract disorders 
Reproductive system and breast disorders 
 
Figure 7: Frequency of AE term by treatment arm 
 
Figure 8: Number of adverse events per patient by treatment arm 
Table 8: Prevalence of AEs and SAEs by relatedness and severity 
Anti-ST2 (n = ) 
n (%) 
Placebo (n = ) 
n (%) 
Overall (n = ) 
n (%) 
Total AEs 
By severity 
Mild 
Moderate 
Severe 
By relatedness to IMP 
Unrelated 
Unlikely 
Possibly 
Probably 
Definitely 
Unknown 
Total SAEs 
By Severity 


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Anti-ST2 (n = ) 
n (%) 
Placebo (n = ) 
n (%) 
Overall (n = ) 
n (%) 
Mild 
Moderate 
Severe 
By relatedness to IMP 
Unrelated 
Unlikely 
Possibly 
Probably 
Definitely 
Unknown 


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9.2 Appendix 2: Line listing of the adverse events 
 
 
Preferred AE term 
AE system 
Seriousness 
Start date 
End date 
Relatedness 
Severity 
Outcome 
Treatment arm