A Phase II, Two-Part, Randomised, Multi-Centre, Multinational, Double-Blind, Placebo-Controlled, Parallel Group Study to Compare the Efficacy and Safety of BCT197 When Added on to Standard of Care for the Treatment of Acute Respiratory Exacerbations of Chronic Obstructive Pulmonary Disease Requiring Hospitalisation in Adults
Phase: PHASE2
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Mereo BioPharma

Mereo BioPharma 1 Ltd 
 
CONFIDENTIAL 
Protocol No. MBCT206 
 
 
 
Protocol Version Final 5.0, 08 November 2016 
Page 1 of 95 
 
1 
TITLE PAGE 
CLINICAL STUDY PROTOCOL 
A Phase IIa, two-part, randomised, multi-centre, multinational, double-blind, 
placebo-controlled, parallel group study to compare the efficacy and safety of BCT197 
when added on to standard of care for the treatment of acute respiratory exacerbations 
of chronic obstructive pulmonary disease (COPD) requiring hospitalisation in adults 
 
 
Protocol No.: MBCT206 
EUDRACT No.: 2015-004631-13 
Test Product: 
BCT197 
Indication: 
Acute exacerbations of chronic obstructive 
 
pulmonary disease 
Sponsor: 
Mereo BioPharma 1 Ltd 
 
 
Development Phase: 
Phase IIa 
Sponsor Signatory: 
Dr Alastair Mackinnon 
Sponsor Medical Expert: 
Dr Jackie Parkin 
Date of the Protocol: 
08 November 2016 
Version of the Protocol: 
Final 5.0 
 
 
The confidential information in this document is provided to you as an investigator, potential 
investigator or consultant for review by you, your staff and applicable Independent Ethics 
Committee and/or Institutional Review Board. It is understood that the information will not 
be disclosed to others without written authorisation from Mereo BioPharma 1 Ltd except to 
the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. 
 

Mereo BioPharma 1 Ltd 
 
CONFIDENTIAL 
Protocol No. MBCT206 
 
 
 
Protocol Version Final 5.0, 08 November 2016 
Page 3 of 95 
 
3 
GENERAL INFORMATION 
A Phase IIa, two-part, randomised, multi-centre, multinational, double-blind, 
placebo-controlled, parallel group study to compare the efficacy and safety of BCT197 
when added on to standard of care for the treatment of acute respiratory exacerbations 
of chronic obstructive pulmonary disease (COPD) requiring hospitalisation in adults 
Protocol No.: 
MBCT206 
Date of the Protocol: 
26 May 2016 
Date and Number of Amendment(s): 
23 December 2015, Amendment 1 
 
10 March 2016, Amendment 2 
 
26 May 2016, Amendment 3 
Sponsor: 
Mereo BioPharma 1 Ltd 
 
4th Floor 
 
1 Cavendish Place 
 
London W1G 0QF 
 
UK 
Clinical Research Organisation: 
ICON Clinical Research Ltd 
 
South County Business Park 
 
Leopardstown 
 
Dublin 18 
 
Ireland 
Sponsor Signatory: 
 
 
4th Floor 
 
1 Cavendish Place 
 
London W1G 0QF 
 
UK 
 
Tel No.: +44 (0)3330 237314 
 
Fax No.: +44 (0)3330 237301 
Sponsor Medical Expert: 
 
Mereo BioPharma 1 Ltd 
 
4th Floor 
 
1 Cavendish Place 
 
London W1G 0QF 
 
UK 
 
Tel No.: +44 (0)3330 237320 
 
Fax No.: +44 (0)3330 237301 
Principal Investigator: 
Prof Wisia Wedzicha 
 
Professor of Respiratory Medicine 
 
National Heart and Lung Institute 
 
Imperial College 
 
London 
 
Biostatistics: 
 
rch UK Ltd 
 
2 Globeside Business Park 
 
Marlow 
 
Buckinghamshire 
 
UK 
 
Tel No.: +44 (0)1628 493520 

Mereo BioPharma 1 Ltd 
 
CONFIDENTIAL 
Protocol No. MBCT206 
 
 
 
Protocol Version Final 5.0, 08 November 2016 
Page 4 of 95 
 
4 
STUDY SYNOPSIS 
Name of Sponsor/Company: 
Mereo BioPharma 1 Ltd 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
BCT197 
Name of Active Ingredient: 
3-[5-Amino-4-(3-cyano-benzoyl)-
pyrazol-1-yl]-Ncyclopropyl-4-
methyl-benzamid 
Title of Study: 
A Phase IIa, two-part, randomised, multi-centre, multinational, double-blind, placebo-controlled, parallel group 
study to compare the efficacy and safety of BCT197 when added on to standard of care for the treatment of 
acute respiratory exacerbations of chronic obstructive pulmonary disease (COPD) requiring hospitalisation in 
adults 
Study Centres: 
It is planned that approximately 90 centres will be initiated for this study in approximately 12 countries 
worldwide. 
Publications: 
None. 
Development Phase: 
Phase IIa 
Objectives: 
Primary Objective: 
1. To evaluate the efficacy of two different dosing regimens of BCT197 added to standard of care (SoC) 
versus placebo added to SoC in the treatment of acute respiratory exacerbations of COPD that required 
hospitalisation by comparison of change in forced expiratory volume in 1 second (FEV1) from Baseline 
(pre-dose) to Day 7. 
 
Secondary Objectives: 
The secondary objectives are to evaluate the efficacy and tolerability of two different dosing regimens of 
BCT197 added to SoC versus placebo added to SoC in treatment of an acute exacerbation of COPD requiring 
hospitalisation by measuring the following: 
1. Comparison of FEV1 on Days 3, 10, and 14 
2. Normalisation evaluation of spirometry parameter (FEV1, forced vital capacity [FVC], and FEV1/FVC) 
response over time (performed daily from Days 1 to 7, 10, and 14, and Weeks 8, 12 and 26) compared with 
the most recent test performed within the last 12 months outside an exacerbation (pre-study FEV1, FVC, 
and FEV1/FVC value) 
3. Time taken to improvement of 100 mL in FEV1 compared to Baseline versus placebo 
4. Assessment of AUC of FEV1 over time among groups 
5. Respiratory rate (RR) normalisation over time (performed daily from Days 1 to 7, 10, and 14) among 
groups 
6. RR at Days 3, 7, 10, and 14 among groups 
7. Time to improvement based on EXACT-PRO total score 
8. Assessment of AUC of EXACT-PRO over time among groups 
9. Evaluate the number of COPD-related deaths among groups 
10. Evaluate the number of moderate/severe COPD exacerbations (classified according to European Medicines 
Agency (EMA)/Committee for Medicinal Products for Human Use (CHMP) guidelines, refer to 
Section 11.2.3) over time among groups 
11. Evaluate time to next moderate/severe COPD exacerbation 
12. Change from Baseline at each inter-visit period and over the entire period of the study in the average 
EXACT-PRO total score and domain scores 

Mereo BioPharma 1 Ltd 
 
CONFIDENTIAL 
Protocol No. MBCT206 
 
 
 
Protocol Version Final 5.0, 08 November 2016 
Page 5 of 95 
 
Name of Sponsor/Company: 
Mereo BioPharma 1 Ltd 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
BCT197 
Name of Active Ingredient: 
3-[5-Amino-4-(3-cyano-benzoyl)-
pyrazol-1-yl]-Ncyclopropyl-4-
methyl-benzamid 
13. Evaluate the use of rescue therapy during the study 
14. Evaluate time from hospitalisation until subject is medically ready (COPD-related) for discharge 
15. To characterise the pharmacokinetics (PK) of BCT197 in adults with COPD. 
 
Safety and tolerability of BCT197 
1. Evaluation of each treatment emergent adverse event (TEAE)/serious adverse event (SAE) (from first dose 
of study drug until study completion) 
2. Evaluation of the incidence of pneumonia from first dose of study drug until completion 
3. TEAEs of special interest: rash, acneiform dermatitis, cervical/vaginal inflammation, headache, pruritus and 
liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], bilirubin) 
4. Evaluation of vital signs and laboratory parameters 
5. Evaluation of QTc intervals overtime at Baseline, Day 1 to Day 7 (daily), Days 10 and 14 
6. Quantitative sputum culture over Days 1 to 14 whenever sputum is collected for clinical purposes. 
 
Exploratory Objectives 
Exploratory assessments will evaluate: 
1. Exploratory composite scale endpoints comparing among the three groups at Weeks 8, 12 and 26: 
o 
Number of events of worsening of symptoms warranting the addition of antibiotics 
o 
Number of events of worsening of symptoms warranting an increase of oral dose of corticosteroids or 
initiation of new oral corticosteroids 
o 
Number of events of worsening of symptoms requiring additional treatment with oral corticosteroids 
and/or antibiotics after completion of the initial regimen 
o 
Number of events of COPD exacerbations that required re-hospitalisation 
o 
Number of COPD-related deaths. 
2. Chronic respiratory questionnaire (CRQ) at Baseline, Day 14 and at Weeks 8, 12 and 26 to evaluate 
recovery comparing among the three groups over time 
3. Cumulative oral /intravenous (IV) steroid dose on Days 1 to 14, and from Day 14 to Week 26 
4. Change in inflammatory blood biomarkers (IL-6, TNF-α, fibrinogen, high-sensitivity C-reactive protein 
[hs-CRP], and myeloperoxidase [MPO]) daily during Part 1 of the study, and at Weeks 8, 12 and 26 
5. Explore the relationship between BCT197 exposure and efficacy/safety endpoints 
6. Change from Baseline in modified Medical Research Council (mMRC) dyspnoea scale over time 
7. Body mass index, airflow Obstruction, Dyspnoea and Exercise (BODE) index among the three groups at 
Day 14. 
Methodology: 
This is a two-part, randomised, multi-centre, multinational, double-blind, placebo-controlled, three arm study of 
BCT197 added to SoC (which includes at least steroids and/or antibiotics) in subjects with an acute respiratory 
exacerbation of COPD, which require hospitalisation (per the GOLD 2015 definition of exacerbation). As well 
as SoC, subjects will receive one of two oral dosing regimens of BCT197 or matching oral placebo administered 
according to the schedule in the following table: 

Mereo BioPharma 1 Ltd 
 
CONFIDENTIAL 
Protocol No. MBCT206 
 
 
 
Protocol Version Final 5.0, 08 November 2016 
Page 6 of 95 
 
Name of Sponsor/Company: 
Mereo BioPharma 1 Ltd 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
BCT197 
Name of Active Ingredient: 
3-[5-Amino-4-(3-cyano-benzoyl)-
pyrazol-1-yl]-Ncyclopropyl-4-
methyl-benzamid 
Subjects will only be eligible for Randomisation and study treatment if they present with an acute respiratory 
exacerbation of COPD requiring hospitalisation and meet all inclusionary criteria and none of the exclusionary 
criteria. 
The study will consist of a Screening/Baseline visit starting the Acute Exacerbation Phase, followed by a 
Stabilisation Phase. After signing of informed consent, all subjects will be assessed for eligibility by confirming 
inclusion/exclusion criteria, randomised and receive their first dose of study treatment within 24 hours of 
presentation with acute exacerbation (Day 1). Subjects will be eligible only if their treatment (SoC) has been 
initiated less than 24 hours before Randomisation and dosing. 
Subjects will be randomised to treatment on Day 1 and enter into Part 1 (Acute Exacerbation Phase) of the 
study. The Acute Exacerbation Phase includes efficacy and safety assessments for up to 14 days. Part 2 
(Stabilisation Phase) begins after completion of the Acute Exacerbation Phase and includes visits at Weeks 8, 12 
and 26. The subject’s medical condition will be monitored at each visit and SoC medication adjusted as needed. 
Assessments during Part 1 and Part 2 include: 
1. Part 1 (Acute Exacerbation Phase): Inpatient hospitalisation and Randomisation which will include daily 
assessments of pulmonary function (FEV1 and RR) for the first 7 days of hospitalisation and treatment. If 
the subject is discharged before Day 7 then daily visits to the hospital should be performed up to Day 7. 
Further evaluations will be performed on Days 10 and 14. 
2. Part 2 (Stabilisation Phase): Outpatient phase at which FEV1 will be collected at all visits up to Week 26 
and/or early termination of the study. 
A number of exploratory assessments will be performed throughout the study and will include an exploratory 
composite scale. The BODE index will be calculated on Day 14, using the standard criteria of body mass index 
(BMI), FEV1 (percentage of predicted), mMRC dyspnoea scale and exercise tolerance using the 6-minute walk 
test.  
The exploratory composite scale evaluates treatment failure as defined by: 
1. Worsening of symptoms warranting the addition of antibiotics 
2. Worsening of symptoms warranting an increase in dose of oral corticosteroids or initiation of new oral 
corticosteroids 
3. Worsening of symptoms requiring additional treatment of oral corticosteroids and/or antibiotics after 
completion of the initial regimen 
4. Re-hospitalisation due to worsening of COPD and requiring additional treatment during the duration of the 
study due to exacerbations of respiratory symptoms 
5. COPD-related death. 
A total of 12 visits are planned for the two parts of the study. 
All subjects will have routine safety monitoring throughout the study, including TEAEs, 12-lead 
electrocardiograms (ECGs), vital signs, quantitative sputum culture (if collected as part of routine clinical care), 
haematology (including eosinophil percentages), blood chemistry, and urinalysis laboratory assessments. 
Subjects will also be followed up for time to next moderate/severe COPD exacerbation and number of 
moderate/severe COPD exacerbations as secondary objectives. 
Accumulating safety data will be reviewed periodically by an independent, external data monitoring committee 
(DMC). Once subjects have completed study treatment, all new reports of exacerbation of COPD and events of 
hospitalisations due to new exacerbations of COPD will be evaluated by an external Independent Adjudication 
Committee (IAC). 
Number of Subjects: 
It is planned that approximately 320 subjects will be screened to randomise approximately 270 subjects. It is 
expected that approximately 255 subjects will complete the study and follow-up. 
 

Mereo BioPharma 1 Ltd 
 
CONFIDENTIAL 
Protocol No. MBCT206 
 
 
 
Protocol Version Final 5.0, 08 November 2016 
Page 7 of 95 
 
Name of Sponsor/Company: 
Mereo BioPharma 1 Ltd 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
BCT197 
Name of Active Ingredient: 
3-[5-Amino-4-(3-cyano-benzoyl)-
pyrazol-1-yl]-Ncyclopropyl-4-
methyl-benzamid 
Diagnosis and Main Criteria for Inclusion: 
Inclusion: 
1. Male and female adults aged ≥ 40 years 
2. Written informed consent obtained prior to any study-related procedure 
3. Presence of an active exacerbation of the ongoing COPD requiring hospitalisation for treatment: 
“A sustained worsening of the patient’s condition (dyspnoea, cough and/or sputum production/purulence), 
from the stable state and beyond normal day-to-day variations, that is acute in onset and necessitates a 
change in regular medication in a patient with underlying COPD that includes prescriptions of systemic 
corticosteroids and/or antibiotics and need for hospitalisation” 
4. Subjects with a diagnosis of COPD with spirometry performed outside an exacerbation within the last 
12 months prior to the Screening Visit 
5. Current smokers or ex-smokers with a smoking history of at least 10 pack-years (pack-years = [number of 
cigarettes per day x number of years/20]) 
6. A FEV1 < 65% of the predicted normal value 
7. A documented history of at least one moderate or severe COPD exacerbation in the 12 months preceding 
the Screening Visit that required antibiotics and/or systemic corticosteroid (addition or increment on subject 
current use) as defined below: 
o 
 “A 
sustained 
worsening 
of 
the 
patient’s 
condition 
(dyspnoea, 
cough 
and/or 
sputum 
production/purulence), from the stable state and beyond normal day-to-day variations, that is acute in 
onset and necessitates a change in regular medication in a patient with underlying COPD that includes 
prescriptions of systemic corticosteroids and/or antibiotics or need for hospitalisation” 
o 
Also, documented visits to an emergency department due to COPD exacerbation are considered 
acceptable to fulfil this criterion. 
8. Current regular treatment for COPD (categories C and D according to GOLD guidelines, updated 2015) for 
at least 2 months prior to the Screening Visit with either: 
o 
Inhaled corticosteroids/long-acting β2-agonist combination, long-acting muscarinic antagonist without 
regular use of any short-acting bronchodilator (any short-acting bronchodilator allowed if used as 
needed [PRN]) or 
o 
Inhaled corticosteroids/long-acting β2-agonist combination, without regular use of any short-acting 
bronchodilator (any short-acting bronchodilator allowed if used PRN) or 
o 
Inhaled corticosteroids/long-acting muscarinic antagonist combination, without regular use of any 
short-acting bronchodilator (any short-acting bronchodilator allowed if PRN) or 
o 
Inhaled long-acting β2-agonist and inhaled long-acting muscarinic antagonist (with any PRN short 
acting bronchodilator)  or 
o 
Subjects under monotherapy with long-acting muscarinic antagonist (with any PRN short acting 
bronchodilator) 
9. Ideally subjects should be screened, randomised and dosed on the same day. Where information is not 
available, the Screening period can be extended to a maximum of 24 hours before Randomisation and 
dosing. 
Exclusion: 
1. Current diagnosis of asthma 
2. Subjects who have already completed treatment for the current exacerbation of COPD 
o 
Subjects whose treatment for the current exacerbation (systemic corticosteroids or antibiotics) was 
initiated longer than 24 hours before Randomisation 
3. Subjects who have been treated with or require use of the following medications: 
o 
A course of systemic steroids longer than 3 days for COPD exacerbation in the 4 weeks prior to the 

Mereo BioPharma 1 Ltd 
 
CONFIDENTIAL 
Protocol No. MBCT206 
 
 
 
Protocol Version Final 5.0, 08 November 2016 
Page 8 of 95 
 
Name of Sponsor/Company: 
Mereo BioPharma 1 Ltd 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
BCT197 
Name of Active Ingredient: 
3-[5-Amino-4-(3-cyano-benzoyl)-
pyrazol-1-yl]-Ncyclopropyl-4-
methyl-benzamid 
current exacerbation 
o 
A course of antibiotics for COPD exacerbation longer than 7 days in the 4 weeks prior to the current 
exacerbation 
o 
Phosphodiesterase type 3/4 (PDE3/PDE4) inhibitors 
o 
Any p38 mitogen-activated protein kinase (p38) inhibitor treatment 
o 
Use of antibiotics for a lower respiratory tract infection (e.g. pneumonia) in the 4 weeks prior to the 
current exacerbation (except for treatment of the current exacerbation, but not longer than 2 days) 
4. Subjects currently requiring intensive care unit (ICU) and/or mechanical ventilation 
5. Subjects treated with non-cardioselective β-blockers in the 10 days preceding the Screening Visit. Those 
subjects may enter the study after non-selective β-blockers withdrawal and/or cardioselective β-blockers 
intake for at least 10 days before Randomisation 
6. Subjects treated with long-acting anti-histamines unless taken at stable regimen at least 2 months prior to 
Screening and to be maintained constant during the study, or if taken as PRN 
7. Known respiratory disorders other than COPD which may impact the efficacy of the study drug according 
to the investigator’s judgement. This can include but is not limited to α-1 antitrypsin deficiency, active 
tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension and interstitial 
lung disease 
8. Subjects who have had pulmonary lobectomy or lung volume reduction surgery or lung transplantation 
9. Subjects who have had a live vaccination in the last 30 days prior to study start 
10. Subjects who have a clinically significant cardiovascular condition (including, but not limited to, unstable 
ischemic heart disease, New York Heart Association (NYHA) Class III/IV, left ventricular failure, acute 
myocardial infarction); or the current exacerbation is due to a cardiovascular condition 
11. An abnormal and clinically significant 12-lead ECG which may impact the safety of the subject according 
to the investigator’s judgement at Screening or Baseline 
12. Subjects whose 12-lead ECG shows QTcF > 450 msec at Screening and at Randomisation visits; ECG does 
not need to be repeated if Screening and Randomisation visit are on the same day 
13. Current diagnosis of pneumonia (clinical or radiographic), pulmonary embolus or pneumothorax 
14. History of hypersensitivity to anti-cholinergics, β2-agonist, corticosteroids or any of the excipients 
contained in any of the formulations used in the study which may raise contra-indications or impact the 
efficacy of the study drug according to the investigator’s clinical judgement 
15. Clinically significant laboratory abnormalities indicating a significant or unstable concomitant disease 
which may impact the efficacy or the safety of the study drug according to the investigator’s clinical 
judgement 
16. Subjects with liver enzyme alterations (serum alanine aminotransferase and/or aspartate aminotransferase 
> 2 x upper limit of normal [ULN], bilirubin > 1.5 ULN) 
17. Impairment of renal function (defined as creatinine clearance (CrCL) < 60 mL/min (estimated by 
Cockcroft-Gault) 
18. Concomitant/recent use of the CYP3A inhibitors or P-gp inhibitors including, but not limited to macrolide 
antibiotics, troleandomycin, erythromycin, clarithromycin, roxithromycin and chloramphenicol (with the 
exception of azithromycin, which is not prohibited), and the calcium channel blockers verapamil and 
diltiazem; consumption of grapefruit will also be excluded (Refer to Table 10-1) 
19. Unstable concurrent disease: e.g. uncontrolled hyperthyroidism, uncontrolled diabetes mellitus or other 
endocrine disease; significant hepatic impairment; significant renal impairment; uncontrolled 
gastrointestinal disease (e.g. active peptic ulcer); uncontrolled neurological disease; uncontrolled 
haematological disease; uncontrolled auto-immune disorders or other which may impact the efficacy or the 
safety of the study drug according to the investigator’s judgement 

Mereo BioPharma 1 Ltd 
 
CONFIDENTIAL 
Protocol No. MBCT206 
 
 
 
Protocol Version Final 5.0, 08 November 2016 
Page 9 of 95 
 
Name of Sponsor/Company: 
Mereo BioPharma 1 Ltd 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
BCT197 
Name of Active Ingredient: 
3-[5-Amino-4-(3-cyano-benzoyl)-
pyrazol-1-yl]-Ncyclopropyl-4-
methyl-benzamid 
20. History of alcohol abuse and/or substance/drug abuse within 12 months prior to the Screening Visit 
21. Participation in another interventional clinical study where the investigational drug was received within 
< 5 x half-lives of the drug or 8 weeks (whichever is longer) (6 months in the case of a monoclonal 
antibody) prior to the Screening Visit. Participation in observational/non-interventional studies is allowed 
22. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception 
and until the termination of gestation, confirmed by a positive urine test at Screening 
23. Sexually active men unless they are using double barrier method for the period of dosing and for the 
5 half-lives (8 days) afterwards 
24. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, 
unless they are using highly effective methods of contraception during the study and for 8 days after 
treatment with investigational medication. Highly effective contraception methods include: 
o 
Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic 
abstinence (calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception 
o 
Female sterilisation (surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at 
least six weeks before taking study treatment. In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow-up hormone level assessment 
o 
Male sterilisation (at least 6 months prior to Screening). For female subjects on the study, the 
vasectomised male partner must be the sole partner for that subject 
o 
Combination of the following: 
a) Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or 
transdermal hormone contraception. In case of use of oral contraception women should have been 
stable on the same pill for 3 months before taking study treatment 
b) Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
o 
Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of 
natural (spontaneous) amenorrhoea with an appropriate clinical profile (e.g. age appropriate, history of 
vasomotor symptoms) or have had a surgical bilateral oophorectomy (with or without hysterectomy) or 
tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow-up hormone level assessment is she considered not of 
child-bearing potential. Sexually active men must use double barrier method while taking drug and for 
5 half-lives (8 days) after completing investigational medication and should not father a child in this period. 
A condom is required to be used also by vasectomised men in order to prevent delivery of the drug via 
seminal fluid. 
 
Permitted concomitant medications 
1. Long-acting anti-histamines if taken at stable regimen at least 2 months prior to Screening or if taken PRN. 
For subjects not on stable, long-acting anti-histamines, short courses are allowed during the study period 
(≤ 7 days). Other anti-histamines are allowed during the study period for a short course (≤ 10 days) or if 
taken PRN 
2. If required for respiratory symptoms or a COPD exacerbation: 
o 
Systemic corticosteroid (oral/IV/intramuscular) 
o 
Inhaled short acting β2-agonists and/or short acting muscarinic antagonists or combination of both 
o 
Nebulised β2-agonists, anti-cholinergics and/or steroids 
o 
Antibiotics 
o 
Oxygen. 

Mereo BioPharma 1 Ltd 
 
CONFIDENTIAL 
Protocol No. MBCT206 
 
 
 
Protocol Version Final 5.0, 08 November 2016 
Page 10 of 95 
 
Name of Sponsor/Company: 
Mereo BioPharma 1 Ltd 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
BCT197 
Name of Active Ingredient: 
3-[5-Amino-4-(3-cyano-benzoyl)-
pyrazol-1-yl]-Ncyclopropyl-4-
methyl-benzamid 
3. Mechanical ventilation at the investigator’s discretion 
o 
Mechanical ventilation is exclusionary at Screening. However, if the subject requires mechanical 
ventilation during the course of the study, they should remain on the study until Week 26, even if 
further study drug cannot be administered or assessment carried out. 
4. Short courses (≤10 days) of nasal corticosteroids (maximum two courses) are allowed 
5. Current regular therapy for COPD as stated in inclusion criterion 8 
6. Current regular theophylline. 
Test Product, Dose and Mode of Administration: 
 
 
 
 
 
 
Placebo, Dose and Duration of Administration: 
 
 
Duration of Treatment: 
 
Variables: 
Efficacy: 
1. FEV1, FVC and FEV1/FVC on Day 1 to Day 7 (daily), 10, 14, and at Weeks 8,12 and 26 
2. FEV1, FVC and FEV1/FVC from the most recent test performed within the last 12 months outside an 
exacerbation 
3. Time to improvement of 100 mL in FEV1 
4. AUC of FEV1 
5. Respiratory rate on Days 1 to 7 (daily), Days 10, 14, and at Weeks 8,12 and 26 
6. EXACT-PRO score daily from Baseline up to the end of subject participation 
7. AUC of EXACT-PRO 
8. Number of COPD-related deaths from first dose intake up to the end of study participation (Week 26) 
9. Number of moderate/severe COPD exacerbations over time among groups 
10. Time to next moderate/severe COPD exacerbation (in days) 
11. Number of uses of rescue therapy during the study 
12. Time from hospitalisation until the subject is medically ready for discharge 
13. Exploratory composite endpoints: 
o 
Number of events of worsening of symptoms warranting the addition of antibiotics 
o 
Number of events of worsening of symptoms warranting an increase of oral dose of corticosteroids or 
initiation of new oral corticosteroids 
o 
Number of events of worsening symptoms requiring additional treatment with oral corticosteroids 

Mereo BioPharma 1 Ltd 
 
CONFIDENTIAL 
Protocol No. MBCT206 
 
 
 
Protocol Version Final 5.0, 08 November 2016 
Page 11 of 95 
 
Name of Sponsor/Company: 
Mereo BioPharma 1 Ltd 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
BCT197 
Name of Active Ingredient: 
3-[5-Amino-4-(3-cyano-benzoyl)-
pyrazol-1-yl]-Ncyclopropyl-4-
methyl-benzamid 
and/or antibiotics after completion of the initial regimen 
o 
Number of events of COPD exacerbations that required re-hospitalisation 
o 
Number of COPD-related deaths. 
14. CRQ scores at Baseline, Day 14 and at Weeks 8, 12 and 26 
15. Cumulative oral/IV steroid dose Days 1 to 14, and from Day 14 to Week 26 
16. Blood biomarkers (IL-6, TNF-α, fibrinogen, hs-CRP, and MPO) 
17. BCT197 exposure on Days 1, 3, and 5 
18. Body Mass Index at Baseline, Days 7, 14, and Weeks 8, 12 and 26 
19. Dyspnoea (mMRC dyspnoea scale) at Baseline, Days 7, 14, and Weeks 8, 12 and 26 
20. Six minute walk test and BMI at day 14 (for BODE index calculation). 
 
Pharmacokinetics: 
1. Sparse PK sampling in all subjects on any two of the 3 dosing occasions will be undertaken: one sample to 
be taken pre-dose, one sample taken 0-2 h post-dose, one sample taken 4-8 hours post-dose and one sample 
no earlier than 12 hours post-dose. 
 
Pharmacodynamics: N/A 
 
Pharmacogenetics: N/A 
 
Safety: 
1. TEAEs/SAEs (from first dose of study drug until study completion) 
2. TEAEs of special interest (pneumonia) 
3. TEAEs of special interest (liver enzymes [ALT, AST, bilirubin total and fractions], rash, acneiform 
dermatitis, cervical/vaginal inflammation, headache and pruritus) 
4. Vital signs (body temperature, RR, pulse rate, blood oxygen [measured using a pulse oximeter], systolic and 
diastolic blood pressure) 
5. QTc intervals at Baseline, from Day 1 to Day 7 (daily), Days 10 and 14 
6. Laboratory data including sputum cultures and blood eosinophil percentages. 
 
Study Endpoints: 
Primary: 
Change in FEV1 from Baseline (pre-dose) at Day 7. 
 
Secondary: 
1. Comparison of forced expiratory volume in 1 second (FEV1) on Days 3, 10, and 14 
2. Normalisation evaluation of spirometry parameter (FEV1, FVC, and FEV1/FVC) response over time 
(performed daily from Days 1 to 7, 10, and 14, and Weeks 8, 12 and 26) compared with the most recent test 
performed within the last 12 months outside an exacerbation (pre-study FEV1 , FVC and FEV1/FVC value) 
3. Time taken to improvement of 100 mL in FEV1 compared to Baseline versus placebo 
4. Comparison of AUC of FEV1 over time among groups 
5. Change in RR over time (performed daily from Days 1 to 7, 10 and 14) among groups 
6. Change in RR on Days 3, 7, 10 and 14 among groups 

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Name of Sponsor/Company: 
Mereo BioPharma 1 Ltd 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
BCT197 
Name of Active Ingredient: 
3-[5-Amino-4-(3-cyano-benzoyl)-
pyrazol-1-yl]-Ncyclopropyl-4-
methyl-benzamid 
7. Time to improvement based on EXACT-PRO total score 
8. Comparison of AUC of EXACT-PRO over time among groups 
9. Number of COPD-related deaths during the study 
10. Number of moderate/severe COPD-related exacerbations during the study 
11. Time to next moderate/severe COPD exacerbation 
12. Change from Baseline at each inter-visit period and over the entire period of the study in the average 
EXACT-PRO total score and domain scores 
13. Number of times each subject required rescue therapy during the study 
14. Time from hospitalisation until the subject is medically ready (COPD-related) for discharge 
15. Nonlinear mixed effects pharmacokinetic/pharmacodynamics (PK/PD) models evaluating the relationship 
between BCT197 exposure and efficacy/safety endpoints. 
 
Safety: 
1. TEAEs/SAEs (from first dose of study drug until study completion) 
2. Evaluation of the incidence of pneumonia from first dose of study drug until completion 
3. TEAEs of special interest (liver enzymes [ALT, AST, bilirubin total and fractions], rash, acneiform 
dermatitis, cervical/vaginal inflammation, headache and pruritus) 
4. Vital signs (body temperature, RR, pulse rate, blood oxygen [measured using a pulse oximeter], systolic and 
diastolic blood pressure) and laboratory parameters 
5. QTc intervals and ECG findings (arrhythmias, conduction blocks, changes in ST segment) at Baseline, from 
Day 1 to Day 7, Days 10 and 14 
6. Laboratory data including sputum cultures and blood eosinophil percentages. 
 
Exploratory: 
1. Exploratory composite scale comparing the following among the three groups at Weeks 8, 12 and 26: 
o 
Number of events of worsening symptoms warranting the addition of antibiotics 
o 
Number of events of worsening of symptoms warranting an increase of oral dose corticosteroids or 
initiation of new oral corticosteroids 
o 
Number of events of worsening of symptoms requiring additional treatment with oral corticosteroids 
and/or antibiotics after completion of the initial regimen 
o 
Number of events of COPD exacerbations that required re-hospitalisation 
o 
Number of COPD-related deaths. 
2. Change in CRQ from Baseline at Day 14 and Weeks 8, 12 and 26 to evaluate recovery, comparing among 
the three groups over time 
3. Cumulative oral/IV steroid dose from Day 1 to Day 14, and from Day 14 to Week 26 
4. Change in inflammatory blood biomarkers (IL-6, TNF-α, fibrinogen, hs-CRP, and MPO) daily during 
Part 1 of the study, and at Weeks 8, 12 and 26 
5. Relationship between BCT197 exposure and efficacy/safety endpoints 
6. Change from Baseline in mMRC dyspnoea scale over time 
7. BODE index among the three groups at Day 14. 
 
Statistical Methods: 
Sample Size and Power: 

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Name of Sponsor/Company: 
Mereo BioPharma 1 Ltd 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
BCT197 
Name of Active Ingredient: 
3-[5-Amino-4-(3-cyano-benzoyl)-
pyrazol-1-yl]-Ncyclopropyl-4-
methyl-benzamid 
 
 
 
 
 
Change of FEV1 from Baseline up to and including Day 7 will be assessed with a mixed-model repeated 
measures (MMRM) analysis, with treatment regimen as a factor and Baseline FEV1 as a covariate. The adjusted 
mean difference between regimens will be presented along with 95% confidence intervals for the Day 7 time-
point. 
Exploratory exposure-response (E-R): 
Nonlinear mixed effects modelling will be undertaken to evaluate the relationship between BCT197 exposure 
and selected safety/efficacy endpoints. 
 
Version and Date of the Protocol: Final 5.0, 08 November 2016 

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5 
TABLE OF CONTENTS 
1 
TITLE PAGE ................................................................................................................. 1 
2 
SIGNATURE PAGES ................................................................................................... 2 
3 
GENERAL INFORMATION ........................................................................................ 3 
4 
STUDY SYNOPSIS ...................................................................................................... 4 
5 
TABLE OF CONTENTS ............................................................................................ 14 
5.1 
List of Tables .................................................................................................. 18 
5.2 
List of Figures................................................................................................. 18 
5.3 
List of Appendices and Supplements ............................................................. 18 
6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................ 19 
7 
INTRODUCTION ....................................................................................................... 22 
7.1 
Background..................................................................................................... 22 
7.2 
Rationale ......................................................................................................... 26 
8 
STUDY OBJECTIVES ............................................................................................... 27 
8.1 
Primary Objectives ......................................................................................... 27 
8.2 
Secondary Objectives ..................................................................................... 27 
8.3 
Exploratory Objectives ................................................................................... 28 
9 
INVESTIGATIONAL PLAN ...................................................................................... 29 
9.1 
Overall Study Design and Plan....................................................................... 29 
9.1.1 
Description ................................................................................................. 29 
9.1.2 
Schedule of Assessments ........................................................................... 30 
9.1.3 
Study Assessments ..................................................................................... 34 
9.1.3.1 
Screening (Visit 1)...................................................................... 34 
9.1.3.2 
Day 1 to Day 14 – Acute Exacerbation Phase ............................ 35 
9.1.3.3 
Weeks 8, 12 and 26 – Stabilisation Phase .................................. 40 
9.2 
Discussion of Study Design............................................................................ 40 
9.2.1 
Risk/Benefit and Ethical Assessment ........................................................ 41 
9.3 
Selection of Study Population ........................................................................ 42 
9.3.1 
Inclusion criteria ........................................................................................ 42 
9.3.2 
Exclusion Criteria ...................................................................................... 43 
9.3.3 
Withdrawal of Subjects from the Study ..................................................... 46 
9.3.4 
Study Drug Discontinuation ...................................................................... 46 
9.3.5 
Continued study participation .................................................................... 47 
9.3.6 
Discontinuation of Study Sites .................................................................. 48 
9.3.7 
Discontinuation of Study ........................................................................... 48 
9.3.8 
Lost to Follow-up ...................................................................................... 48 
10 
TREATMENT OF SUBJECTS ................................................................................... 48 
10.1 
Identity of Study Treatment(s) ....................................................................... 48 

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10.1.1 
Administration of Study Treatment(s) ....................................................... 48 
10.2 
Study Treatment Packaging and Labelling..................................................... 49 
10.2.1 
Packaging ................................................................................................... 49 
10.2.2 
Labelling .................................................................................................... 49 
10.2.3 
Storage ....................................................................................................... 49 
10.2.4 
Blinding and Randomisation of Study Treatments .................................... 49 
10.3 
Procedure for Breaking the Randomisation Code .......................................... 50 
10.4 
Subject Compliance ........................................................................................ 50 
10.5 
Study Treatment Accountability ..................................................................... 50 
10.6 
Concomitant Therapy ..................................................................................... 51 
10.6.1 
Permitted Concomitant Medication for COPD .......................................... 51 
10.6.2 
Prohibited Therapy .................................................................................... 51 
11 
ASSESSMENT OF EFFICACY ................................................................................. 53 
11.1 
Efficacy Variables .......................................................................................... 53 
11.2 
Efficacy Assessments ..................................................................................... 54 
11.2.1 
Spirometry ................................................................................................. 55 
11.2.2 
Body mass index, airflow obstruction, dyspnoea, and exercise 
(BODE) index ............................................................................................ 56 
11.2.3 
COPD exacerbations .................................................................................. 57 
11.2.4 
Number of COPD-related deaths ............................................................... 57 
11.2.5 
Exploratory composite endpoints .............................................................. 57 
11.2.6 
Chronic Respiratory Questionnaire ........................................................... 58 
11.2.7 
Blood Biomarkers ...................................................................................... 58 
11.2.8 
EXACT-PRO ............................................................................................. 58 
11.3 
Pharmacokinetics ............................................................................................ 59 
12 
ASSESSMENT OF SAFETY...................................................................................... 60 
12.1 
Adverse Events ............................................................................................... 60 
12.1.1 
Definitions ................................................................................................. 60 
12.1.2 
Recording of Adverse Events .................................................................... 61 
12.1.3 
Causal Assessment ..................................................................................... 62 
12.1.4 
Abnormal Laboratory Values/Vital Signs/Electrocardiograms ................. 63 
12.1.5 
Overdose .................................................................................................... 64 
12.1.6 
Pregnancy .................................................................................................. 64 
12.1.7 
Adverse Event of Special Interest .............................................................. 64 
12.1.8 
Reporting of Serious Adverse Events and Adverse Events of Special 
Interest ....................................................................................................... 65 
12.2 
Safety Endpoints ............................................................................................. 67 
12.3 
Laboratory Assessments ................................................................................. 67 
12.4 
Medical Evaluation/Physical Examination ..................................................... 68 
12.5 
Vital Signs ...................................................................................................... 68 

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12.6 
12-lead ECG ................................................................................................... 68 
12.7 
24/7 Medical Emergency Coverage ............................................................... 68 
12.8 
Data Monitoring Committee (DMC) .............................................................. 69 
12.9 
Independent Adjudication Committee (IAC) ................................................. 69 
13 
STATISTICAL EVALUATION ................................................................................. 70 
13.1 
Sample Size and Power .................................................................................. 70 
13.2 
Randomisation ................................................................................................ 70 
13.3 
Analysis Sets .................................................................................................. 70 
13.3.1 
Intention to treat (ITT) (Full Analysis Set) ................................................ 70 
13.3.2 
Per protocol (PP) ........................................................................................ 71 
13.3.3 
Safety population ....................................................................................... 71 
13.3.4 
PK population ............................................................................................ 71 
13.4 
Endpoints ........................................................................................................ 71 
13.4.1 
Primary Efficacy Endpoint(s) .................................................................... 71 
13.4.2 
Secondary Efficacy Endpoint(s) ................................................................ 71 
13.4.3 
Exploratory Endpoints(s) ........................................................................... 72 
13.4.4 
Safety Endpoint(s) ..................................................................................... 72 
13.5 
Description of Statistical Analyses ................................................................. 73 
13.5.1 
General Considerations .............................................................................. 73 
13.5.2 
Analysis of Primary Endpoint.................................................................... 74 
13.5.3 
Analysis of Secondary Endpoints .............................................................. 74 
13.5.4 
Analysis of Exploratory Endpoints ............................................................ 74 
13.5.4.1 Population PK/PD modelling ..................................................... 74 
13.5.5 
Safety Analyses ......................................................................................... 74 
13.5.6 
Analysis of Further Endpoints ................................................................... 76 
13.6 
Interim Analysis ............................................................................................. 76 
14 
DIRECT ACCESS TO SOURCE DATA/NOTES ..................................................... 77 
15 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 77 
15.1 
Conduct of the Study ...................................................................................... 77 
15.2 
Study Monitoring............................................................................................ 77 
16 
ETHICS ....................................................................................................................... 78 
16.1 
Independent Ethics Committee/Institutional Review Board .......................... 78 
16.2 
Written Informed Consent .............................................................................. 78 
17 
DATA HANDLING AND RECORD KEEPING ....................................................... 79 
17.1 
Case Report Forms/Source Data Handling..................................................... 79 
17.2 
Retention of Essential Documents .................................................................. 79 

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18 
FINANCING AND INSURANCE .............................................................................. 80 
19 
PUBLICATION POLICY ........................................................................................... 81 
20 
SIGNATURE OF INVESTIGATOR .......................................................................... 82 
21 
REFERENCE LIST ..................................................................................................... 83 
22 
APPENDICES ............................................................................................................. 85 
 

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5.1 
List of Tables 
Table 7-1 
Study Dosing Schedules ..................................................................................... 25 
Table 9-1 
Schedule of Assessments ................................................................................... 31 
Table 10-1 
Prohibited Medication ........................................................................................ 52 
 
5.2 
List of Figures 
Figure 9-1: Schematic of Study Design .................................................................................... 30 
 
 
5.3 
List of Appendices and Supplements 
Appendix I 
World Medical Association Declaration of Helsinki, 2013 
Appendix II 
BODE index 
Appendix III Modified Medical Research Council 

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6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADME 
absorption, distribution, metabolism and excretion 
AE 
adverse event 
AESI 
adverse event of special interest 
AKI 
acute kidney injury 
ATF-2 
activating transcription factor-2 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATS 
American Thoracic Society 
AUC 
area under the curve 
β-HCG 
beta-human chorionic gonadotropin 
BMI 
body mass index 
BODE 
Body mass index, airflow Obstruction, Dyspnoea and Exercise index 
BUN 
blood urea nitrogen 
C/EBP 
CCAAT/enhancer binding protein 
CHMP 
Committee for Medicinal Products for Human Use 
Cmax 
maximal concentration of analyte in blood/plasma 
COPD 
chronic obstructive pulmonary disease 
CPB 
cardiopulmonary bypass 
CrCL 
creatinine clearance 
CRQ 
chronic respiratory questionnaire 
CYP3A 
cytochrome P450 subtype 3A 
DMC 
Data monitoring committee 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
EDC 
electronic data capture 
ERS 
European Respiratory Society 
eGFR 
estimated glomerular filtration rate 
EMA 
European Medicines Agency 
ER 
emergency room 
E-R 
exposure-response 
EUDRACT 
European Union Drug Regulatory Agency Clinical Trial 
EXACT-PRO 
The EXAcerbations of Chronic pulmonary disease Tool-Patient 
Reported Outcome 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in one second 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 

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GOLD 
Global initiative for chronic obstructive lung disease 
HR 
heart rate 
hs-CRP 
high-sensitivity C-reactive protein 
IAC 
Independent adjudication committee 
IBD 
inflammatory bowel disease 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICU 
Intensive care unit 
IEC 
Independent ethics committee 
IL-6 
interleukin-6 
IL-8 
interleukin-8 
INR 
international normalised ratio 
IRB 
Institutional review board 
IRT 
Interactive response technology 
ITT 
intention to treat 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
intravenous 
Ki 
inhibitory constant 
KIM-1 
kidney injury molecule-1 
LPS 
lipopolysaccharides 
MAPK 
mitogen activated protein kinase 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mL 
millilitre 
MMRM 
mixed model repeated measures 
mMRC 
modified Medical Research Council 
MPO 
myeloperoxidase 
MSAP 
modelling and simulation plan 
MSS 
medical and safety services 
NNT 
number needed to treat 
NYHA 
New York Heart Association 
p38 
p38 mitogen-activated protein kinase 
p53 
p53 tumour suppressor protein 
PoC 
proof of concept 
PD 
pharmacodynamics 
PDE4 
phosphodiesterase type 4 
PK 
pharmacokinetics 

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PFT 
pulmonary function test 
PP 
per protocol 
PRN 
as needed 
PRO 
patient reported outcome 
QTc 
corrected QT interval of the electrocardiogram 
RA 
rheumatoid arthritis 
RR 
respiratory rate 
RUQ 
right upper quadrant 
SABA 
short-acting β2 agonist 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SoC 
standard of care 
SOP 
standard operating procedure 
STAT-1 
Signal Transducers and Activators of Transcription 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment emergent adverse event 
TNF-α 
tumour necrosis factor-alpha 
ULN 
upper limit of normal 
6MWT 
6-minute walk test 
 

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7 
INTRODUCTION 
7.1 
Background 
Chronic obstructive pulmonary disease (COPD) is a progressive condition that is a major 
cause of poor health and death worldwide (GOLD Guidelines 2015) and contributes 
significantly to health care costs and comorbidity (Lopez et al 2006), (Chapman et al 2006). 
COPD is a chronic disease for which worldwide prevalence (currently estimated at 
210 million) and mortality rate (2.74 million died in 2000) are still increasing. COPD is 
currently ranked as the fourth cause of death (GOLD Guidelines 2015) and is anticipated to 
become the third by 2020. 
COPD exacerbations account for 50-75% of the cost of healthcare services in COPD 
(Mittmann et al 2008, Toy et al 2010). The impact of the exacerbations on patient’s overall 
well-being is significant, and the symptoms and deterioration in lung function may persist for 
several weeks before recovering to Baseline values (Seemungal et al 2000). On average, 
COPD patients experience approximately 1-3 exacerbations per year, although this varies 
with the severity of underlying COPD (Seemungal et al 2009; Langsetmo et al 2008). A 
median duration of exacerbation of 13 (6 to 24) days has been reported in patients receiving 
SoC, and 9 (6 to 14) days in patients receiving long-term therapy with macrolide antibiotics 
in addition to SoC. Of these exacerbations, 37% (patients treated with long-term macrolides 
in addition to SoC) and 60% (patients treated with SoC) had not resolved within 10 days 
(Seemungal et al 2008). A recent retrospective observational database study showed a median 
duration of hospital stay due to moderate to severe COPD exacerbation of 9 to 10 days 
(Molinari et al 2015). Based on published literature, approximately 32% of exacerbations 
occur within 8 weeks of a preceding exacerbation event (Hurst 2009), and approximately 
60% of patients are readmitted to the hospital within 12 months because of an exacerbation 
(Almagro et al 2006; Garcia-Aymerich et al 2003; Lau 2001), highlighting the need for more 
effective treatments. 
Since frequent COPD exacerbations are known to promote disease progression 
(Donaldson 2002 et al; Rennard and Farmer 2004), there is a high unmet need for more 
effective treatment to reduce the number and severity of exacerbations as well as the length 
and number of hospitalisations. 
There is an increasingly pressing need for the effective treatment of exacerbations with 
limited options available, i.e., bronchodilators, oxygen, antibiotics and oral steroids. Since the 
seminal trials performed around 15 years ago (Davies et al 1999) oral corticosteroid use has 
become widespread for this indication. Following oral corticosteroid treatment, hospital stay 
is shortened by only 1.22 days (mean stay around 9 days) with a number needed to treat 
(NNT) of 10 to prevent one treatment failure (i.e. a change in the original treatment) at 
30 days. However, there is no improvement in overall mortality when using oral 
corticosteroids and a significant risk of an adverse event occurring (one per 5 people treated). 
In particular, patients who frequently exacerbate have worse long term outcomes compared 
with those who do not and any therapy which can modulate the natural history of an 

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exacerbation with particular reference to the complete recovery of baseline lung function 
could potentially provide a significant therapeutic advance. 
New treatments are needed that reduce the severity of exacerbations and provide a more 
effective treatment compared to current rescue therapies, particularly intravenous (IV) and 
oral steroids. 
Therefore, there is an unmet need for an appropriate compound targeting the treatment of 
acute exacerbations, with anti-inflammatory activity, low systemic side effects, and with the 
potential to significantly change the way COPD patients and their exacerbations are 
managed. 
The Mereo BioPharma 1 Ltd compound, BCT197, is an inhibitor of the p38 mitogen-
activated protein kinase (MAPK). BCT197 is a 5-amino-pyrazole representing one series in 
the chemically diverse class of p38 MAPK inhibitors. The p38 MAPK pathway is activated 
in a variety of inflammatory conditions and p38 MAPK inhibitors have been studied in a 
number of different diseases, including severe asthma, COPD, acute coronary syndrome and 
auto-immune diseases such as rheumatoid arthritis (RA), psoriasis and inflammatory bowel 
disease (IBD) (Kumar et al 2003, Lee and Dominguez 2005) but with limited success. 
Inhibition of p38 MAPK has been shown to block release of inflammatory mediators both in 
vitro and in vivo. p38 MAPK regulates transcription through the phosphorylation of 
transcription factors involved in the inflammatory process such as ATF-2, p53, C/EBP- 
homologous protein, muscle-specific transcription factor-2 and STAT-1. Inhibition of p38 
MAPK blocks TNF-α and IL-8 release by LPS-stimulated monocyte/macrophages, IL-6 
release by bronchial epithelial cells in response to cigarette smoke and regulates a range of 
different neutrophil functions including adhesion, activation, chemotaxis and apoptosis. 
Moreover, increased phosphorylation of p38 has been demonstrated in the lungs of COPD 
patients (Renda et al 2008, Chin et al 2005). Therefore, a putative blockade of this pathway 
should result in attenuation of airway inflammation seen in acute exacerbations of COPD. 
Thus far, 
BCT197 
has 
been 
investigated 
in 
three healthy 
volunteer 
studies 
[CBCT197A2205], [CBCT197A2101] and [CBCT197A1101] and in a proof of concept 
study in COPD [CBCT197A2201] and another study of acute kidney injury in subjects 
undergoing elective cardiac surgery with cardiopulmonary bypass (CPB) [CBCT197A2202]. 
Two healthy volunteer studies were single ascending dose studies, with doses from 
 
 were conducted in Caucasians [CBCT197A2101] and in Japanese volunteers 
[CBCT197A1101]. One healthy volunteer study was a single oral dose study to investigate 
the pharmacokinetics (PK) of 75 mg of 14C-labelled BCT197 [CBCT197A2205]. 
Single administration of BCT197 at doses up to 
[CBCT197A2101] was well tolerated 
and provided nearly complete suppression of blood TNF-α levels after in vivo LPS challenge, 
showing that BCT197 might have an inhibitory effect on p38 MAPK signalling. However, 
acneiform rash occurred in 21 of 32 subjects treated with BCT197 once daily over 14 days at 
doses of 
 and in 5 of 16 placebo-treated subjects. Two of 16 subjects receiving single 
administration of BCT197 also exhibited acneiform rash after LPS challenge, although no 

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acneiform rash occurred in healthy subjects receiving single administration of BCT197 alone. 
The time of onset of acneiform rash varied widely among subjects ranging from the 8th day of 
repeated administration of BCT197, to about 1 week after completion of the 14-day treatment 
with BCT197. 
In the human ADME study A2205, metabolism was found to be the principal method of 
clearance. The human metabolite was the acid compound M14 (BHA784). Based on plasma 
Cmax and AUC, the systemic exposure to M14 was about 40% of that of BCT197. The 
concentration-time curves of radioactivity for BCT197 and M14 were parallel, showing 
similar half-lives. Low levels of M14 were also found in skin biopsies. M14 was excreted 
mainly in urine (28% of dose). M14 is not pharmacologically active, i.e. it does not inhibit 
p38 MAP kinase to a relevant extent. 
The proof of concept (PoC) study [CBCT197A2201] was conducted in subjects with acute 
exacerbations of COPD. The effects of BCT197 on COPD subjects presenting with an acute 
exacerbation were evaluated in this double-blind, placebo-controlled proof of concept study. 
 
reater improvements in lung function (forced expiratory 
volume in 1 second [FEV1]) compared with placebo and prednisone, 2 days after single and 
repeat doses were consistently observed in all 4 study parts. However, in three of the 
treatment regimens these effects were only sustained for 2 days after dosing. No noticeable 
differences in FEV1 changes from Baseline compared to control arms were seen 4 days after 
dosing, with the exception of the 75 mg repeat dose on Day 6 which led to a greater 
improvement in lung function than placebo, sustained until study Day 14. In the PoC 
[CBCT197A2201] study, no acneiform rashes were observed. 
CBCT197A2202 was a two-part study of BCT197 in the treatment of acute kidney injury 
(AKI) following cardiopulmonary bypass surgery for either coronary artery bypass grafting 
or cardiac valve repair/replacement. This was a PoC study to determine if a single, pre-
operative dose of BCT197 ameliorated the decrease in estimated glomerular filtration rate 
(eGFR) associated with cardiac surgery with CPB, measured at 48 hours after dosing. The 
two parts, A and B, conducted in parallel. Part A was an open label design in subjects with 
eGFR in the 30 to 60 mL/min/1.73 m2 range, inclusive, who were scheduled for elective 
cardiac surgery with CPB. Subjects received a single oral dose of 
 of BCT197 2 hours 
± 30 minutes prior to the estimated time of initial sternal incision while in the pre-operative 
holding area. The subject had serial PK blood draws up to Day 5. The end of study 
procedures were conducted when the subject was discharged or at Day 8 after dosing. Part B 
was a double-blind, randomised, placebo-controlled study in subjects with eGFR 
> 60 mL/min/1.73 m2 who were scheduled for elective cardiac surgery with CPB. Subjects 
received a single oral dose of 
 of BCT197 or placebo 2 hours ± 30 minutes prior to the 
estimated time of initial sternal incision while in the pre-operative holding area. Biomarker 
assessments, including KIM-1 and eGFR, were used to assess efficacy. 
A total of approximately 140 subjects were planned to be enrolled to participate in the study 
and randomised. A total of eight subjects were assessed in Part A, and approximately 

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132 subjects were expected to be assessed in Part B. As of 31 October 2013, 83 Part B 
subjects had been enrolled (42 on active treatment). Serious adverse events (SAEs) have been 
reported in 23 subjects up to 31 October 2013. None of the SAEs was suspected to be related 
to study medication by the investigator. There have been no suspected unexpected serious 
adverse reactions (SUSARs). There was one death due to respiratory failure, sepsis, and 
multi-organ failure. 
A preplanned interim analysis of Part B was conducted in October 2013 which included 
66 subjects who had completed Day 5. At that time the AKI rate was higher on BCT197 
[6/31 (19%)] than on placebo [2/33 (6%)], whereby AKI was defined as 25% or more 
reduction in eGFR at 48 hours. The reported (expected) control rate of AKI is in the 10 to 
20% range. None of the subjects required dialysis. Furthermore, the number of subjects 
reporting SAEs in the BCT197 group [12 (36%)] was higher than that on placebo [3 (9%)], 
but these were distributed over several types of SAEs that were also expected in the 
cardiopulmonary bypass population. None of the SAEs was related to a kidney disorder and 
none was suspected to be related to study medication. The BCT197 group had an average 
baseline weight 9.1 kg heavier than the placebo group, suggesting that there may have been 
some degree of unbalanced randomisation. Based on the IA data, the Data Monitoring 
Committee (DMC) recommended to put the study on hold for reasons of lack of efficacy and 
the higher rate of SAEs on BCT197. According to the DMC the data did not allow 
assessment for a possible nephrotoxicity. 
Based on the data available thus far, it appears that a regimen longer than a single dose would 
be required to sustain the effect of BCT197. Subjects will receive one of two oral dosing 
regimens of BCT197 or matching oral placebo administered according to the dosing 
schedules shown in Table 7-1. 
 
BCT197 is intended to be prescribed as a treatment added to standard of care (SoC) of acute 
exacerbations in COPD and is envisaged to be used for repeated administration. BCT197 is 
formulated as oral capsules. The two dose regimens proposed for this study are based on the 
efficacy, toxicology, pharmacokinetic and safety data available thus far. 
 
 
The rationales for the dose regimens 
proposed are based on the PK exposure and are explained in the Section 7.2 below. 

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7.2 
Rationale 
This study will be conducted in compliance with the protocol and with the International 
Conference on Harmonisation (ICH) guidelines on Good Clinical Practice (GCP). 
This study will investigate the efficacy, safety and tolerability of two different dosing 
regimens of BCT197 added to SoC (systemic corticosteroids and/or antibiotics) versus 
placebo added to SoC in subjects with severe acute exacerbations of COPD. The proposed 
doses take into account trough levels based on previous PK modelling to ensure that the study 
drug remains at effective concentrations between doses. 
The approach is to provide rapid attenuation of inflammatory responses which occur during a 
severe acute exacerbation, typically 3 to 5 days, and so multiple dosing will take place to 
ensure appropriate plasma levels are present to allow effective treatment of an exacerbation. 
As previously noted, acneiform rash occurred in a number of subjects treated once daily with 
BCT197 over a 14-day period at doses of 3 to 10 mg. On this basis there is a clear desire to 
ensure that prolonged continuous exposure to BCT197 is avoided. Overall, a dose-dependent 
reduction in TNF-α levels has been observed following doses ranging from 
BCT197, although flattening of this effect to between 45 to 50% of placebo levels occurred 
between doses of 
 A number of PK simulations have been performed looking at 
both dosing intervals 
, as well as dose levels 
. Based on predicted exposures 
of the various regimens, there is no perceived benefit in dosing beyond 
 for a typical 
exacerbation. However, in order to initiate suppression of the inflammatory response the 
 dose in both regimes is higher than the doses on 
. The ‘high’ dosing 
regimen (regimen 1) is initiated at 
 which is the highest dose which can be safely 
administered based on toxicology margins whereas the ‘low’ dose regimen is initiated at a 
40 mg dose which approximates to the mid-point in the TNF-α response curve. The doses in 
the two regimens have been designed to minimise overlap of PK exposure and to differentiate 
the doses to allow a better understanding of the exposure/clinical response relationship. 
The Ki values for p38 alpha and p38 beta are 49 and 72 nM, respectively, with IC50 values of 
37 nM and 106 nM, respectively. Based on the PK profiles the high dose regimen, dosing at 
 should maintain drug levels above 220 ng/mL out to approximately 
 This should achieve a plasma concentration of 5.7 µM. BCT197 has a very low 
first pass metabolism pre-clinically with the oral bioavailability estimated at 93% in the rat, 
87% in the dog and 90% in the monkey. The in vitro data show that it is only weakly protein 
bound with free fraction in man (human plasma samples) ranging from 13 to 25%. 
Using the most conservative estimate (13%), the concentration based on free fraction will be 
at or above 740 nM for the duration of the dosing interval. Cmax would be around 2 µM based 
on the first dose. Estimated drug levels are approximately 7 to 10 times higher in 
concentration than the Ki and IC50 values and therefore >99% enzyme inhibition would be 
expected to occur for 6 days. Assuming a PK variability of 50%, drug levels would still be 
expected to be 3 to 5 times above the Ki and so would produce high levels of inhibition, 
potentially in the range of 90 to 99%. 

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8 
STUDY OBJECTIVES 
8.1 
Primary Objectives 
The primary objective is to evaluate the efficacy of two different dosing regimens of BCT197 
added to SoC versus placebo added to SoC in the treatment of acute respiratory exacerbations 
of COPD that required hospitalisation by comparison of change in FEV1 from Baseline 
(pre-dose) to Day 7. 
8.2 
Secondary Objectives 
The secondary objectives are to evaluate the efficacy and tolerability of two different dosing 
regimens of BCT197 added to SoC versus placebo added to SoC in treatment of an acute 
exacerbation of COPD requiring hospitalisation by measuring the following: 
1. Comparison of FEV1 on Days 3, 10, and 14 
2. Normalisation evaluation of spirometry parameter (FEV1, forced vital capacity 
[FVC], and FEV1/FVC) response over time (performed daily from Days 1 to 7, 10, 
and 14, and Weeks 8, 12 and 26) compared with the most recent test performed within 
the last 12 months outside an exacerbation (pre-study FEV1, FVC, and FEV1/FVC 
value) 
3. Time taken to improvement of 100 mL in FEV1 compared to Baseline versus placebo 
4. Assessment of AUC of FEV1 over time among groups 
5. Respiratory rate (RR) normalisation over time (performed daily from Days 1 to 7, 10 
and 14) among groups 
6. RR at Days 3, 7, 10, and 14 among groups 
7. Time to improvement based on EXACT-PRO total score 
8. Assessment of AUC of EXACT-PRO over time among groups 
9. Evaluate the number of COPD-related deaths among groups 
10. Evaluate the number of moderate/severe COPD exacerbations (classified according to 
European Medicines Agency (EMA)/Committee for Medicinal Products for Human 
Use (CHMP) guidelines, refer to Section 11.2.3) over time among groups 
11. Evaluate time to next moderate/severe COPD exacerbation 
12. Change from Baseline at each inter-visit period and over the entire period of the study 
in the average EXACT-PRO total score and domain scores 
13. Evaluate the use of rescue therapy during the study 
14. Evaluate time from hospitalisation until subject is medically ready (COPD-related) for 
discharge 
15. To characterise the PK of BCT197 in adults with COPD. 
 

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Safety and tolerability of BCT197 
1. Evaluation of each treatment emergent adverse event (TEAE)/SAE (from first dose of 
study drug until study completion) 
2. Evaluation of the incidence of pneumonia from first dose of study drug until study 
completion 
3. TEAEs of special interest: rash, acneiform dermatitis, cervical/vaginal inflammation, 
headache, pruritus and liver enzymes (aspartate aminotransferase [AST], alanine 
aminotransferase [ALT], bilirubin) 
4. Evaluation of vital signs and laboratory parameters 
5. Evaluation of QTc intervals over time at Baseline, Day 1 to Day 7 (daily), Days 10 and 
14 
6. Quantitative sputum culture over Days 1 to 14 whenever sputum is collected for clinical 
purposes. 
8.3 
Exploratory Objectives 
Exploratory assessments will evaluate: 
1. Exploratory composite scale endpoints comparing among the three groups at Weeks 8, 12 
and 26 
o Number of events of worsening of symptoms warranting the addition of 
antibiotics 
o Number of events of worsening of symptoms warranting an increase of oral dose 
of corticosteroids or initiation of new oral corticosteroids 
o Number of events of worsening of symptoms requiring additional treatment with 
oral corticosteroids and/or antibiotics after completion of the initial regimen 
o Number of events of COPD exacerbations that required re-hospitalisation 
o Number of COPD-related deaths. 
2. Chronic respiratory questionnaire (CRQ) at Baseline, Day 14 and at Weeks 8, 12 and 26 
to evaluate recovery comparing among the three groups over time 
3. Cumulative oral /IV steroid dose on Days 1 to 14, and from Day 14 to Week 26 
4. Change in inflammatory blood biomarkers (IL-6, TNF-α, fibrinogen, high-sensitivity 
C-reactive protein [hs-CRP], and myeloperoxidase [MPO]) daily during Part 1 of the 
study, and at Weeks 8, 12 and 26 
5. Explore the relationship between BCT197 exposure and efficacy/safety endpoints 
6. Change from Baseline in modified Medical Research Council (mMRC) dyspnoea scale 
over time 
7. Body mass index, airflow Obstruction, Dyspnoea and Exercise (BODE) index among the 
three groups at Day 14. 

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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
9.1.1 
Description 
This is a phase IIa, two-part, randomised, multi-centre, multinational, double-blind, 
placebo-controlled, parallel-group study of 26 weeks duration in adult subjects with acute 
respiratory exacerbations in COPD. It will be conducted in approximately 90 centres in 
approximately 12 countries. It is planned that approximately 320 subjects will be screened to 
enrol approximately 270 subjects, and expected that approximately 255 subjects will 
complete the study and follow-up. Only hospitalised subjects will be recruited. 
Two regimens of BCT197 added to SoC (which includes at least steroids and/or antibiotics) 
will be compared with placebo added to SoC. 
Subjects that agree to participate in the study (informed consent form [ICF] process 
completed; subject has signed and dated the ICF) will be assessed for eligibility by 
confirming inclusion/exclusion criteria. 
After confirmation that all of the inclusion criteria and none of the exclusion criteria are met, 
the subject will be randomised on Day 1 in a 1:1:1 ratio to 1 of 2 BCT treatment schedules or 
placebo; all subjects will undergo SoC assessments regardless of treatment group. 
Randomisation will be via Interactive Response Technology (IRT) to ensure proper 
distribution among groups with respect to demographic data (age, gender), severity of 
disease, heart failure, oxygen saturation (without oxygen supplementation), and FEV1. 
After Randomisation, Part 1 (Acute Exacerbation Phase) of the study continues with daily 
evaluation up to Day 7. Further evaluations will be performed on Days 10 and 14. Subjects 
will receive their first dose of study treatment within a maximum of 24 hours after presenting 
with an acute exacerbation (Day 1). Subjects will be eligible only if their treatment (SoC) has 
been initiated less than 24 hours before Randomisation and dosing. Study treatment will be 
administered on Days 1, 3 and 5. Subjects will undergo all safety and efficacy assessments on 
Day 1. Physical examinations, 12-lead ECGs, pulmonary function test (PFT; spirometry), and 
blood sampling for blood biomarkers will be done every day during the Acute Exacerbation 
Phase (Days 1 to 7, Day 10 and Day 14). It is expected that subjects will be hospitalised 
during Part 1 (Day 1 - Day 7). However, if a subject improves and is discharged prior to Day 
7, the subject should return to the facility daily through to Day 7 and on Days 10 and 14 for 
completion of study assessments. Upon discharge the subject will be given a diary to 
document any occurrences of COPD and rescue medication use. 
Part 2 (Stabilisation Phase) of the study requires subject evaluations at Weeks 8, 12 and 26. 
During Part 2 of the study, the subject’s medical condition will be monitored at each visit and 
SoC medication adjusted as needed. 
The End of Study is defined as the last visit of the last global subject. 
Subjects will undergo sparse PK sampling (4 samples collected on any 2 of the 3 treatment 
days). 

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This study does not restrict the appropriate care of the subject and allows the use of the 
current institution SoC with respect to dose, regimens, duration of treatment for medical 
treatment of the subject. In agreement with the updated version of GOLD (2015) for the 
treatment of acute exacerbations of COPD, subjects must be receiving at least steroids and/or 
antibiotics. However medications that may interfere with metabolism of the study drug or that 
may bring additional risk to the subject should be avoided. These medications are referred as 
prohibited concomitant medications (Table 10-1) and are exclusionary from the study. 
A study schematic is provided in (Figure 9-1). 
 
Figure 9-1: Schematic of Study Design 
 
9.1.2 
Schedule of Assessments 
The schedule of assessments is presented in Table 9-1. 
 

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Table 9-1 
Schedule of Assessments 
 
Acute Exacerbation Phase 
Stabilisation phase 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Screening1 
Randomisation/
Baseline1 
Day 1 
Day 2 
Day 3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 
Day 10 
(± 1 
day) 
Day 14 
(± 1 
day) 
Week 
8 
(± 3 
days) 
Week 
12 
(± 3 
days) 
Week 
26 
(± 3 
days) 
Written Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history including 
current medical conditions17 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical examination2, 15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG3,4,7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Assessment of inflammation of 
cervix and vagina16 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
Pregnancy test4 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Clinical laboratory tests2,5,6 
(haematology, blood chemistry 
and urinalysis laboratory 
assessments) 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
PK assessment7 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
PFT (Spirometry) 
X9,13 
X8,13 
X8 
X8 
X8 
X8 
X8 
X8 
X8 
X8 
X8,14 
X8,14 
X8,14 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
mMRC,  
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
X 

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1 
Ideally subjects should be screened and randomised and dosed on the same day. There will be no separate Screening Visit as subjects will receive their first dose of study 
treatment within 24 hours of presenting with an acute exacerbation.  Subjects will be eligible only if their treatment (SoC) has been initiated less than 24 hours before 
Randomisation and dosing (Day 1). For screen failures, re-screening may be performed 1 month after complete recovery from a previous acute exacerbation of COPD. 
2 
Vital signs and laboratory assessments should where feasible be performed before salbutamol intake. Height is to be measured at Screening only. Vital signs include 
body temperature, RR, pulse rate, blood oxygen (measured using a pulse oximeter), systolic and diastolic blood pressure. If Screening and Day 1 are on the same day and 
there is no medical indication, then vital signs and physical examination noted for Visit 1 do not need to be repeated. If Visit 1 is performed over different days, vital 
signs and physical examination should be repeated on Day 1 prior to randomisation only if the subject’s condition has deteriorated. 
3 
12-lead ECG will be performed after 10 minutes rest. If the Screening Visit and Day 1 are on the same day and there is no medical indication then the ECG noted for 
Visit 1 does not need to be repeated. If Visit 1 is performed over different days, the ECG should be repeated on Day 1 prior to randomisation. 
4 
For women of child-bearing potential only. Urine dipstick pregnancy tests carried out by site at Screening and at all indicated visits; serum pregnancy tests will be 
performed centrally at the Screening and last visit only. Urine pregnancy tests will be used for the purposes of inclusion into the study due to the acute nature of the 
study. 
5 
Prior to entry into the study (Visit 1), clinical laboratory tests will be performed at a local laboratory to confirm eligibility for randomisation. These tests will also be 
performed by the central laboratory. If Screening and Day 1 are on the same day and there is no medical indication, then the clinical laboratory tests noted for Visit 1 do 
not need to be repeated. If Visit 1 is performed over different days, the local laboratory should repeat clinical laboratory tests on Day 1 if the subject’s condition has 
deteriorated. 
6 
All blood samples are to be collected at least 6 hours after SABA intake whenever possible (times of sample collection and SABA intake must be recorded), 8 hours 
fasting (where possible) and after ECG and vital signs (including RR). INR and prothrombin time not required during the Stabilisation phase. 
7 
There will be sparse PK sampling in all subjects to be taken on any 2 of the 3 dosing occasions (Days 1, 3, or 5): one sample to be taken pre-dose, one sample taken 0-2 h 
post-dose, one sample taken 4-8 hours post-dose, and one sample no earlier than 12 hours post-dose. ECG will be taken at approximately the same time as with PK 
sample. ECGs should be taken before the PK sample. 
6MWT/BMI10 
 
 
 
 
 
 
 
 
 
X 
 
 
 
CRQ 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
Blood biomarkers6,11 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exploratory composite scale 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
EXACT-PRO 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study treatment 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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8 
Spirometry will be taken ‘on bronchodilator’ and ideally in the morning.  For an individual spirometry should be taken at approximately the same time of day (during the 
acute phase ± 1 hour and in the stabilisation phase ± 2 hour window). Ideally this will be taken at least 1 hour after regular long acting bronchodilators and 30 minutes 
after short acting bronchodilator medication. Time of last short and long acting bronchodilators will be documented.  
9 
Spirometry at Screening should be performed ‘on bronchodilator’. This will be taken after any regular long acting bronchodilator administration and 30 minutes after 
short acting bronchodilator medication.  
10 Perform BMI and 6MWT at Day 14. BODE will then be calculated.  
11 Please refer to the Laboratory Manual for clarification of whether the biomarker is to be analysed in either serum or plasma. 
12 If the subject is discharged before Day 7, they will return to the hospital daily for assessment. 
13 If screening and Day 1 occur on different days spirometry will be repeated on day 1 before dosing with study treatment and result obtained on  day 1 may be used as 
baseline. 
14 If historical spirometry data within last 12 months does not include pre and post SABA value this should be obtained during the stabilisation phase, for demographic 
purposes. 
15 Physical examination at screening should include a minimum of chest, cardiovascular and abdominal examination. At all other time points a minimum of chest 
auscultation is required. Additional examination is at the discretion of the Investigator as indicated by the subjects’ clinical condition. 
16 A gynaecological history should be taken (from females only) with subjects specifically asked about vaginal bleeding, discharge or pain. Any new vaginal bleeding 
(other than normal menstruation), vaginal discharge or pain after dosing should be investigated by vaginal examination and any required specialist assessment. 
17 Document in eCRF which symptoms of the acute exacerbation are present out of increased sputum, increased cough and increased dyspnoea. 
 
Abbreviations: BMI = body mass index; BODE = Body mass index, airflow Obstruction, Dyspnoea and Exercise index; COPD: chronic obstructive pulmonary disease; CRQ = chronic 
respiratory questionnaire; ECG = electrocardiogram; eCRF: electronic case report form; EXACT-PRO: The EXAcerbations of Chronic pulmonary disease Tool-Patient Reported Outcome; INR: 
international normalised ratio; mMRC = modified Medical Research Council; PFT = pulmonary function test; PK = pharmacokinetics; RR = respiratory rate; SABA = short-acting β2 agonist; 
SoC: standard of care; 6MWT = 6-minute walking test 
 
 

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9.1.3 
Study Assessments 
9.1.3.1 
Screening (Visit 1) 
Subjects will be screened on the day that they present with an acute exacerbation (Day 1); 
there will be no separate Screening Visit as subjects will receive their first dose of study 
treatment within 24 hours of presenting with an acute exacerbation. Subjects will be eligible 
only if their treatment (SoC) has been initiated less than 24 hours before Randomisation and 
dosing (Day 1). For screen failures, re-screening may take place 1 month after complete 
recovery from a previous acute exacerbation of COPD. 
The following procedures/assessments will be done: 
1. Collection of the written informed consent signed by the subject, after the study has been 
fully explained by the investigator. The investigator or his/her designee should provide 
enough time and opportunity to inquire about details of the study and to decide whether 
or not to participate in the study, however respecting the study timelines defined in the 
inclusion and exclusion criteria 
2. Collection of demographic data and medical/surgical/psychiatric history, including 
smoking history and gynaecological history (females) 
3. Exacerbation assessment to verify a documented history of at least one exacerbation in 
the 12 months preceding Screening 
4. Verification that spirometry has been performed within the last 12 months and outside of 
an exacerbation 
5. Physical examination, including vital signs (body temperature, RR, pulse rate, blood 
oxygen [measured using a pulse oximeter], systolic and diastolic blood pressure), height, 
and weight 
6. 12-lead electrocardiogram (ECG); recorded after 10 minutes at rest  
7. Urine and serum pregnancy test, women of child-bearing potential only 
8. Blood sample for clinical laboratory tests (haematology and biochemistry) to be taken at 
least 6 hours after SABA (whenever possible; times of sample collection and SABA 
intake must be recorded), after 8 hours of fasting (whenever possible), and after 
completion of ECG and vital signs (body temperature, RR, pulse rate, systolic and 
diastolic blood pressure). These clinical laboratory tests will performed both at the local 
and central laboratory to confirm eligibility for Randomisation 
9. Urinalysis (specific gravity, pH, protein, glucose, blood) 
10. ‘On bronchodilator’ spirometry. This will be taken after regular long acting 
bronchodilators and 30 minutes after short acting bronchodilator 
11. Confirm inclusion and exclusion criteria 
12. Document in eCRF which of the following three symptoms of the acute exacerbation are 
present  

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- 
Increased sputum 
- 
Increased cough 
- 
Increased dyspnoea. 
 
Adverse events (AEs) and concomitant medications will be documented from the time the 
subject has signed the ICF. 
9.1.3.2 
Day 1 to Day 14 – Acute Exacerbation Phase 
All subjects will initially be hospitalised. However, if a subject improves and is discharged 
prior to Day 7, the subject should return to the study facility daily up to and including Day 7 
for study drug administration and completion of study assessments. 
The subject should receive a diary on Day 1 after Randomisation and be instructed in its use. 
Prior to hospital discharge, the subject should be reminded about the use of the diary and 
need to bring their diary to all visits. 
Study Day 1, Visit 1 (prior to study drug administration) 
Once Screening has been completed, the following assessments/procedures will be done for 
all subjects: 
1. Concomitant medication 
2. If the Screening visit and Day 1 are performed on different days, the following 
assessments should be repeated at Day 1 prior to Randomisation only if the subject’s 
condition has deteriorated: 
o Physical examination, including vital signs (body temperature, RR, pulse rate, blood 
oxygen [measured using a pulse oximeter], systolic and diastolic blood pressure) and 
weight 
o Blood sample for clinical laboratory tests (haematology and biochemistry) to be taken 
at least 6 hours after SABA (whenever possible; times of sample collection and 
SABA intake must be recorded), after 8 hours of fasting (wherever possible), and 
after completion of ECG and vital signs (body temperature, RR, pulse rate, systolic 
and diastolic blood pressure). These clinical laboratory tests will be performed at both 
the local and central laboratory to confirm eligibility for Randomisation 
o Urinalysis (specific gravity, pH, protein, glucose, blood) 
3. 12-lead ECG; recorded after 10 minutes at rest 
4. Randomisation via IRT to allocate subjects to a treatment group. All necessary data for 
completing the IRT system, per IRT manual, should be available 
5. Chronic respiratory questionnaire (CRQ); Visit 1 questionnaire will be considered the 
Baseline score 
6. Collection of mMRC dyspnoea scale 

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7. Blood sample for clinical laboratory tests (inflammatory blood biomarkers) to be taken at 
least 6 hours after SABA (whenever possible; times of sample collection and SABA 
intake must be recorded), after 8 hours of fasting (not essential if this is the initial visit), 
and after completion of ECG and vital signs (body temperature, RR, pulse rate, blood 
oxygen [measured using a pulse oximeter], systolic and diastolic blood pressure) 
8. PK assessment (There will be sparse PK sampling in all subjects, to be taken on any 2 of 
the 3 
): one sample to be taken pre-dose, one sample 
taken 0-2 hours post-dose, one sample taken 4-8 hours post-dose, and one sample no 
earlier than 12 hours post-do
9. 12 lead ECG to be performed at the same time as PK sample (ECG should be conducted 
before the blood sample is taken) 
10. Delivery of diary and training for use 
11. EXACT-PRO completed by the subject in the evening; the Visit 1 questionnaire will be 
considered the Baseline score 
12. Spirometry. If Day 1 and screening occur on different days spirometry will be done on 
Day 1 (and may be used as the baseline value). This should be done ideally in the 
morning, at least 1 hour after regular long acting bronchodilator administration and 
30 minutes after short acting bronchodilator medication. 
 
Study Day 1 (study drug administration) 
 
2. Adverse event monitoring. 
 
Study Days 2, 4 and 6 
The following assessments will be done for all subjects, regardless of treatment group: 
1. Adverse event monitoring 
2. Concomitant medication 
3. Physical examination, including vital signs (body temperature, RR, pulse rate, blood 
oxygen [measured using a pulse oximeter], systolic and diastolic blood pressure) and 
weight 
4. 12-lead ECG; recorded after 10 minutes at rest 
5. Blood sample for clinical laboratory tests (inflammatory blood biomarkers) to be taken at 
least 6 hours after SABA (whenever possible; times of sample collection and SABA 
intake must be recorded), after 8 hours of fasting (wherever possible), and after 
completion of ECG and vital signs (body temperature, RR, pulse rate, systolic and 
diastolic blood pressure) 

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6. If sputum or bronchoalveolar culture is collected for any medical reason (qualitative or 
quantitative culture) the result should be recorded in the electronic case report form 
(eCRF) 
7. ‘On bronchodilator’ spirometry. Spirometry will ideally be performed in the morning, at 
least 1 hour after regular long acting bronchodilator administration and 30 minutes after 
short acting bronchodilator medication 
8. COPD exacerbation reporting (EXACT-PRO) completed by the subject in the evening in 
the Diary. 
 
Study Days 3 and 5 
The following assessments will be done for all subjects, regardless of treatment group: 
1. Adverse event monitoring 
2. Concomitant medication 
3. Physical examination, including vital signs (body temperature, RR, pulse rate, blood 
oxygen [measured using a pulse oximeter], systolic and diastolic blood pressure) and 
weight 
4. 12-lead ECG; recorded after 10 minutes at rest before dose with study treatment and at 
the same time as PK sample (ECG will be done before the blood sample) 
5. Blood sample for clinical laboratory tests (haematology, biochemistry, and inflammatory 
blood biomarkers) to be taken at least 6 hours after SABA (whenever possible; times of 
sample collection and SABA intake must be recorded), after 8 hours of fasting (wherever 
possible), and after completion of ECG and vital signs (body temperature, RR, pulse rate, 
systolic and diastolic blood pressure) 
6. Urinalysis (specific gravity, pH, protein, glucose, blood) 
7. PK assessment (There will be sparse PK sampling in all subjects, to be taken on any 2 of 
the 3 dosing occasions (Days 1, 3, or 5): one sample to be taken pre-dose, one sample 
taken 0-2 hours post-dose, one sample taken 4-8 hours post-dose, and one sample no 
earlier than 12 hours post-dose) 
8. If sputum or bronchoalveolar culture is collected for any medical reason (qualitative or 
quantitative culture), the result should be recorded in the eCRF 
9. ‘On bronchodilator’ spirometry. This will ideally be performed in the morning, at least 
1 hour after regular long acting bronchodilator administration and 30 minutes after short 
acting bronchodilator medication 
1
 
11. COPD exacerbation reporting (EXACT-PRO) completed by the subject in the evening. 
 

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Study Day 7 
The following assessments will be done for all subjects, regardless of treatment group: 
1. Adverse event monitoring 
2. Concomitant medication 
3. Physical examination, including vital signs (body temperature, blood oxygen [measured 
using a pulse oximeter], RR, pulse rate, systolic and diastolic blood pressure) and weight  
4. Gynaecological symptoms questions (change in bleeding (other than normal 
menstruation), discharge or pain. Any new symptoms should be followed up with a 
vaginal examination and specialist assessment as indicated (Females only) 
5. 12-lead ECG; recorded after 10 minutes at rest 
6. Blood sample for clinical laboratory tests (haematology, biochemistry, and inflammatory 
blood biomarkers) to be taken at least 6 hours after SABA (whenever possible; times of 
sample collection and SABA intake must be recorded), after 8 hours of fasting (wherever 
possible), and after completion of ECG and vital signs (oral body temperature, RR, pulse 
rate, systolic and diastolic blood pressure) 
7. Urinalysis (specific gravity, pH, protein, glucose, blood) 
8. If sputum or bronchoalveolar culture is collected for any medical reason (qualitative or 
quantitative culture), the result should be recorded in the eCRF 
9. ‘On bronchodilator’ spirometry. This will ideally be performed in the morning, at least 
1 hour after regular long acting bronchodilator administration and 30 minutes after short 
acting bronchodilator medication 
10. Collect mMRC dyspnoea scale 
11. COPD exacerbation reporting (EXACT-PRO) completed by the subject in the evening. 
 
Study Day 10 
1. Adverse event monitoring 
2. Concomitant medication 
3. Physical examination, including vital signs (body temperature, RR, pulse rate, blood 
oxygen [measured using a pulse oximeter], systolic and diastolic blood pressure) and 
weight 
4. 12-lead ECG; recorded after 10 minutes at rest 
5. Blood sample for clinical laboratory tests (haematology, biochemistry, and inflammatory 
blood biomarkers) to be taken at least 6 hours after SABA (whenever possible; times of 
sample collection and SABA intake must be recorded), after 8 hours of fasting (wherever 
possible), and after completion of ECG and vital signs (body temperature, RR, pulse rate, 
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6. Urinalysis (specific gravity, pH, protein, glucose, blood) 
7. If sputum or bronchoalveolar culture is collected for any medical reason (qualitative or 
quantitative culture), the result should be recorded in the eCRF 
8. ‘On bronchodilator’ spirometry. This will ideally be performed in the morning, at least 
1 hour after regular long acting bronchodilator administration and 30 minutes after short 
acting bronchodilator medication 
9. COPD exacerbation reporting (EXACT-PRO) completed by the subject in the evening. 
 
Study Day 14 
1. Adverse event monitoring 
2. Concomitant medication 
3. CRQ 
4. Collect data for the exploratory composite scale 
5. Physical examination, including vital signs (body temperature, RR, pulse rate, blood 
oxygen [measured using a pulse oximeter], systolic and diastolic blood pressure) and 
weight 
6. Gynaecological symptoms questions (new bleeding except normal menstruation, 
discharge, pain). Any new symptoms should be assessed by vaginal examination and 
specialist assessment as indicated (females only) 
7. 12-lead ECG; recorded after 10 minutes at rest 
8. Blood sample for clinical laboratory tests (haematology, biochemistry, and inflammatory 
blood biomarkers) to be taken at least 6 hours after SABA (whenever possible; times of 
sample collection and SABA intake must be recorded), after 8 hours of fasting (wherever 
possible), and after completion of ECG and vital signs (body temperature, RR, pulse rate, 
systolic and diastolic blood pressure) 
9. Urinalysis (specific gravity, pH, protein, glucose, blood) 
10. If sputum or bronchoalveolar culture is collected for any medical reason (qualitative or 
quantitative culture), the result should be recorded in the eCRF 
11. ‘On bronchodilator’ spirometry. This will ideally be performed in the morning, at least 
1 hour after regular long acting bronchodilator administration and 30 minutes after short 
acting bronchodilator medication 
12. Collect mMRC dyspnoea scale 
13. Perform the 6 minute walk test (6MWT) and BMI (for calculation of the BODE) 
14. COPD exacerbation reporting (EXACT-PRO) completed by the subject in the evening. 
 

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9.1.3.3 
Weeks 8, 12 and 26 – Stabilisation Phase 
Subjects will return to the facility for 3 follow-up visits, at which time the following 
assessments/procedures will be done: 
1. Adverse event monitoring 
2. Concomitant medication 
3. CRQ 
4. Collect data for the exploratory composite scale 
5. Physical examination, including vital signs (body temperature, RR, pulse rate, blood 
oxygen [measured using a pulse oximeter], systolic and diastolic blood pressure) and 
weight 
6. Urine and serum (Week 26 only) pregnancy test, women of childbearing potential only 
7. Blood sample for clinical laboratory tests (haematology [INR and prothrombin time not 
required], biochemistry, and inflammatory blood biomarkers) to be taken at least 6 hours 
after SABA (whenever possible; times of sample collection and SABA intake must be 
recorded), after 8 hours of fasting (wherever possible), and after completion of ECG and 
vital signs (body temperature, RR, pulse rate, systolic and diastolic blood pressure) 
8. Urinalysis (specific gravity, pH, protein, glucose, blood) 
9. If sputum or bronchoalveolar culture is collected for any medical reason (qualitative or 
quantitative culture), the result should be recorded in the eCRF 
10. ‘On bronchodilator’ spirometry. This will ideally be performed in the morning, at least 
1 hour after regular long acting bronchodilator administration and 30 minutes after short 
acting bronchodilator medication 
11. Collect mMRC dyspnoea scale 
12. COPD exacerbation reporting (EXACT-PRO) completed by the subject in the evening 
13. Pre and post bronchodilator spirometry (week 8, 12 or 26). Where this is not available 
from historical spirometry this will be collected during the stabilisation period, for 
demographic purposes. 
 
9.2 
Discussion of Study Design 
There are two components to a COPD exacerbation; one is related to the cause of the 
exacerbation and the other to the intensity of the inflammatory response of the airways and 
lungs. This inflammatory response of the airways results in local oedema and increased 
constriction of airway muscle, leading to an increased airway resistance to airflow, worsening 
dyspnoea, and fatiguing respiratory musculature. The natural course of COPD exacerbation 
indicates that inflammation is most intense at the initial stages. Anti-inflammatory treatment 
with steroids for as little as three days has been shown to improve FEV1 (Albert et al, 1980), 
and a recent trial (Leuppi et al, 2013) suggests that a 5-day treatment course is as effective as 

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the current practice of continuing anti-inflammatory therapy for two weeks or longer 
(Niewoehner et al, 1999). 
The aim of treatment with BCT197 is to reduce the intensity of the inflammatory response 
and its effect on airways, thus increasing the rate of recovery of pulmonary function without 
the side effects associated with corticosteroids. The intention is to minimise the 
complications associated with COPD exacerbations, reduce the requirement for ventilator 
support, decrease the incidence of relapses over time, and restore previous functional status 
more quickly. 
The objectives of this study are to prove the concept that the addition of BCT197 to SoC for 
COPD exacerbation improves subject recovery at two different regimen doses. As a 
secondary objective, two different dosing regimens of BCT197 added to SoC will be 
evaluated to compare efficacy and tolerability versus placebo added to SoC on pulmonary 
function recovery, stabilisation of airways and impact on subject well-being. FEV1 will be 
the primary variable as they reflect airway inflammation and respiratory effort. The study is 
designed in 2 parts. The first part is the Acute Exacerbation Phase, during which the subject 
will be evaluated daily for 7 days, then at Days 10 and 14. The second part is the Stabilisation 
Phase, designed to detect recurrences of exacerbations and to measure recovery of the subject 
to previous respiratory status and subject well-being. 
9.2.1 
Risk/Benefit and Ethical Assessment 
The study explores the effect of BCT197 as add-on therapy to current therapies versus 
placebo added to SoC, thus all enrolled subjects will continue to receive standard of care for 
their severe acute exacerbation of COPD, including systemic corticosteroids and/or 
antibiotics, as defined by GOLD updated version 2015. 
BCT197 thus far has been investigated in two healthy volunteer studies, as well as in a PoC 
study in COPD [CBCT197A2201] and in another PoC study in acute kidney injury (AKI) 
[CBCT197A2202]. Rash, gastrointestinal (GI) toxicity, hepatotoxicity, headache and 
dizziness are some of the class effects of p38 MAPK inhibitors. 
In the multiple dose-ascending study [CBCT197A2101] the percentage of rash has been 
proportionately high in healthy volunteers treated with both placebo and BCT197 doses of 
. 
In the CBCT197A2201 study in acute exacerbation COPD subjects, no acneiform rashes 
were observed. 
The benefit/risk assessment of using BCT197 to treat COPD exacerbations is positive if 
BCT197 proves to be efficacious. COPD exacerbations can be life threatening, whereas the 
occurrence of a rash which is mild and transient in nature, is not serious compared with the 
COPD exacerbation. The risk to subjects in this study will be minimised by compliance with 
the inclusion/exclusion criteria, close clinical monitoring, including signs and symptoms 
related to the potential risks of p38 MAPK inhibitors for at least 25 weeks following the last 
dose of study medication. Additional stringent monitoring for inclusion in the study with 
specific observation for any class effects will be performed throughout the study. 

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9.3 
Selection of Study Population 
9.3.1 
Inclusion criteria 
1. Male and female adults aged ≥ 40 years 
2. Written informed consent obtained prior to any study-related procedure 
3. Presence of an active exacerbation of the ongoing COPD requiring hospitalisation for 
treatment: 
“A sustained worsening of the patient’s condition (dyspnoea, cough and/or sputum 
production/purulence), from the stable state and beyond normal day-to-day variations, 
that is acute in onset and necessitates a change in regular medication in a patient with 
underlying COPD that includes prescriptions of systemic corticosteroids and/or 
antibiotics and need for hospitalisation”. 
4. Subjects with a diagnosis of COPD with spirometry performed outside an exacerbation 
within the last12 months prior to the Screening Visit  
5. Current smokers or ex-smokers with a smoking history of at least 10 pack years 
(pack-years = [number of cigarettes per day x number of years/20]) 
6. A FEV1 < 65% of the predicted normal value 
7. A documented history of at least one moderate or severe COPD exacerbation in the 
12 months preceding the Screening Visit that required antibiotics and/or systemic 
corticosteroid (addition or increment on subject current use) as defined below: 
o “A sustained worsening of the patient’s condition (dyspnoea, cough and/or sputum 
production/purulence), from the stable state and beyond normal day-to-day 
variations, that is acute in onset and necessitates a change in regular medication in a 
patient with underlying COPD that includes prescriptions of systemic corticosteroids 
and/or antibiotics or need for hospitalisation” 
o Also, documented visits to an emergency department due to COPD exacerbation are 
considered acceptable to fulfil this criterion. 
8. Current regular treatment for COPD (categories C and D according to GOLD guidelines, 
updated 2015) for at least 2 months prior to the Screening Visit with either: 
o Inhaled corticosteroids/long-acting β2-agonist combination, long-acting muscarinic 
antagonist without regular use of any short-acting bronchodilator (any short-acting 
bronchodilator allowed if used as needed [PRN]) or 
o Inhaled corticosteroids/long-acting β2-agonist combination, without regular use of any 
short-acting bronchodilator (any short-acting bronchodilator allowed if used PRN or 
o Inhaled corticosteroids/long-acting muscarinic antagonist combination, without 
regular use of any short-acting bronchodilator (any short-acting bronchodilator 
allowed if PRN) or 

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o Inhaled long-acting β2-agonist and inhaled long-acting muscarinic antagonist (with 
any PRN short acting bronchodilator) or 
o Subjects under monotherapy with long-acting muscarinic antagonist (with any PRN 
short acting bronchodilator). 
9. Ideally, subjects should be screened, randomised and dosed on the same day. Where 
information is not available, the Screening period can be extended to a maximum of 
24 hours before Randomisation and dosing. 
9.3.2 
Exclusion Criteria 
1. Current diagnosis of asthma 
2. Subjects who have already completed treatment for the current exacerbation of COPD 
o Subjects whose treatment for the current exacerbation (systemic corticosteroids or 
antibiotics) was initiated longer than 24 hours before Randomisation. 
3. Subjects who have been treated with or require use of the following medications (Refer to 
Table 10-1): 
o A course of systemic steroids longer than 3 days for COPD exacerbation in the 
4 weeks prior to the current exacerbation 
o A course of antibiotics for COPD exacerbation longer than 7 days in the 4 weeks prior 
to the current exacerbation 
o Phosphodiesterase type 3/4 (PDE3/4) inhibitors 
o Any p38 MAPK p38 inhibitor treatment) 
o Use of antibiotics for a lower respiratory tract infection (e.g. pneumonia) in the 
4 weeks prior to the current exacerbation (except for treatment of the current 
exacerbation, but not longer than 2 days). 
4. Subjects currently requiring intensive care unit (ICU) and/or mechanical ventilation 
5. Subjects treated with non-cardioselective β-blockers in the 10 days preceding the 
Screening Visit. Those subjects may enter the study after non-selective β-blockers 
withdrawal and/or cardioselective β-blockers intake for at least 10 days before 
Randomisation 
6. Subjects treated with long-acting anti-histamines unless taken at stable regimen at least 
2 months prior to Screening and to be maintained constant during the study, or if taken as 
PRN 
7. Known respiratory disorders other than COPD which may impact the efficacy of the 
study drug according to the investigator’s judgement. This can include but is not limited 
to α-1 antitrypsin deficiency, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, 
lung fibrosis, pulmonary hypertension and interstitial lung disease 
8. Subjects who have had pulmonary lobectomy or lung volume reduction surgery or lung 
transplantation 

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9. Subjects who have had a live vaccination in the last 30 days prior to study start 
10. Subjects who have a clinically significant cardiovascular condition (including, but not 
limited to, unstable ischemic heart disease, New York Heart Association (NYHA) Class 
III/IV, left ventricular failure, acute myocardial infarction); or the current exacerbation is 
due to a cardiovascular condition 
11. An abnormal and clinically significant 12-lead ECG which may impact the safety of the 
subject according to the investigator’s judgement at Screening or Baseline 
12. Subjects whose 12-lead ECG shows QTcF > 450 msec at Screening and at Randomisation 
visits; ECG does not need to be repeated if Screening and Randomisation visit are on the 
same day 
13. Current diagnosis of pneumonia (clinical or radiographic), pulmonary embolus or 
pneumothorax 
14. History of hypersensitivity to anti-cholinergics, β2-agonist, corticosteroids or any of the 
excipients contained in any of the formulations used in the study which may raise contra-
indications or impact the efficacy of the study drug according to the investigator’s clinical 
judgement 
15. Clinically significant laboratory abnormalities indicating a significant or unstable 
concomitant disease which may impact the efficacy or the safety of the study drug 
according to the investigator’s clinical judgement 
16. Subjects with liver enzyme alterations (serum alanine aminotransferase and/or aspartate 
aminotransferase > 2 x upper limit of normal [ULN], bilirubin > 1.5 ULN) 
17. Impairment of renal function (defined as creatinine clearance [CrCL] < 60 mL/min 
[estimated by Cockcroft-Gault]) 
18. Concomitant/recent use of the CYP3A inhibitors or P-gp inhibitors including, but not 
limited to macrolide antibiotics troleandomycin, erythromycin, clarithromycin, 
roxithromycin and chloramphenicol (with the exception of azithromycin, which is not 
prohibited), and of the calcium channel blockers verapamil and diltiazem; consumption of 
grapefruit will also be excluded (Refer to Table 10-1) 
19. Unstable concurrent disease: e.g. uncontrolled hyperthyroidism, uncontrolled diabetes 
mellitus or other endocrine disease; significant hepatic impairment; significant renal 
impairment; uncontrolled gastrointestinal disease (e.g. active peptic ulcer); uncontrolled 
neurological disease; uncontrolled haematological disease; uncontrolled auto-immune 
disorders, or other which may impact the efficacy or the safety of the study drug 
according to the investigator’s judgement 
20. History of alcohol abuse and/or substance/drug abuse within 12 months prior to the 
Screening Visit 
21. Participation in another interventional clinical study where the investigational drug was 
received within < 5 x half-lives of the drug or 8 weeks (whichever is longer) (6 months in 

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the case of a monoclonal antibody) prior to the Screening Visit. Participation in 
observational/non-interventional studies is allowed 
22. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
urine test at Screening 
23. Sexually active men unless they are using double barrier method for the period of dosing 
and the 5 half-lives (8 days) afterwards 
24. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during the study and for 8 days after treatment with investigational medication. Highly 
effective contraception methods include: 
o Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
o Female sterilisation (surgical bilateral oophorectomy with or without hysterectomy) 
or tubal ligation at least six weeks before taking study treatment. In case of 
oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow-up hormone level assessment 
o Male sterilisation (at least 6 months prior to Screening). For female subjects on the 
study, the vasectomised male partner must be the sole partner for that subject 
o Combination of the following: 
a) Use of oral, injected or implanted hormonal methods of contraception or 
other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal 
hormone contraception. In case of use of oral contraception women should 
have been stable on the same pill for 3 months before taking study treatment. 
b) Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
o Women are considered post-menopausal and not of child-bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhoea with an appropriate 
clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had a 
surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at 
least six weeks ago. In the case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow-up hormone level assessment is 
she considered not of child-bearing potential. Sexually active men must use double 
barrier method while taking drug and for 5 half-lives (8 days) after completing 
investigational medication and should not father a child in this period. A condom is 
required to be used also by vasectomised men in order to prevent delivery of the drug 
via seminal fluid. 
 

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9.3.3 
Withdrawal of Subjects from the Study 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. 
Withdrawal of consent occurs when a subject does not want to participate in the study 
anymore and does not want to attend any further visits or assessments, have further study 
related contact, or allow analysis of already obtained biologic material. 
If a subject withdraws consent, the investigator must make every effort to determine the 
primary reason for this decision and record this information. Investigational treatment must 
be discontinued and no further assessments conducted. All biological material that has not 
been analysed at the time of withdrawal must not be used. Further attempts to contact the 
subject are not allowed unless safety findings require communication or follow-up. 
The investigator should discontinue participation of a given subject if, on balance, he/she 
believes that continuation would be detrimental to the subject’s well-being. However the 
subject should be followed up to the end of the study and all study procedures should be 
performed per protocol. As a minimum, all assessments for Week 26 should be performed 
according to the Schedule of Assessments Table 9-1. 
9.3.4 
Study Drug Discontinuation 
Subjects may voluntarily discontinue investigational treatment for any reason at any time. 
Subject decision on discontinuation of study drug does not imply an automatic withdrawal 
from the study. If the subject does not want to take study drug but desires to continue in the 
study he/she may remain in the study and continue to undergo all assessments/procedures. 
Investigational treatment must be discontinued under the following circumstances: 
1. Emergence of the following adverse events: 
o Absolute QTcF > 500 msec 
o Occurrence of class effects i.e., rash Grade 4 as defined by exfoliations and 
ulcerations (Galimont-Collen et al 2007) 
2. Any of the following laboratory abnormalities: 
o Renal function values that require discontinuation: 
• 
Discontinue investigational treatment for a subject if individual serum creatinine 
increases ≥ 50% compared to Baseline (and is considered clinically significant), 
or in the event of treatment emergent proteinuria (albumin:creatinine ratio 
(ACR) > 300 mg/g or >30 mg/mmol; protein creatinine ration (PCR) ≥ 500 mg/g 
or >50 mg/mmol), unless the event is not drug related,  or if the benefit/risk 
assessment supports continuing investigational treatment 
• 
A renal event leading to subject discontinuation should be followed up until event 
resolution (serum creatinine within 10% of Baseline, protein-creatinine ratio 
within 50% of Baseline), stabilises or becomes not clinically significant, or is 
assessed as being chronic. 

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o Liver laboratory values that require discontinuation 
• 
ALT or AST > 5 times the ULN 
• 
ALT or AST > 3 times the ULN and bilirubin total > 2 times ULN or 
international normalised ratio (INR) > 1.5 or the appearance of worsening fatigue, 
nausea, vomiting, right upper quadrant (RUQ) pain/tenderness, fever, rash, or 
eosinophilia 
3. Pregnancy as confirmed by a positive urine test at any time during Part 1 (Acute 
Exacerbation Phase) 
4. Clinically significant change in cardiac rhythm or other clinically significant 
cardiovascular abnormality or an increase in QTcF ≥ 60 msec above baseline 
5. Use of prohibited treatment 
6. Any other protocol deviation that results in a significant risk to the subject’s safety 
7. Withdrawal of informed consent. 
9.3.5 
Continued study participation 
If premature discontinuation of investigational treatment occurs, the subject should continue 
to attend the follow-up visits until the end of study for collection of data on treatment failure. 
The subject should NOT be considered withdrawn from the study due to interrupting or 
discontinuing investigational treatment. For this study it is very important to continue 
collecting data, especially outcome data, on all subjects whether or not they complete 
treatment. The investigator must determine the primary reason for the subject’s premature 
discontinuation of investigational treatment and record this information on the treatment 
disposition eCRF page. The investigator and study staff must discuss with the subject, the 
subject’s continued participation in the study and request subjects to continue attending 
follow-up study visits according to the study visit schedule. 
If the subject cannot or is unwilling to attend the follow-up visits, all assessments for Week 
26 (refer to Schedule of Assessment Table 9-1) should be performed and the site staff should 
request to maintain regular phone contact with the subject, or with a person pre-designated by 
the subject. This phone contact should preferably be done according to the study visit 
schedule. Data will continue to be collected concerning the subject’s health status, including 
information regarding new / concomitant treatments, adverse events, events of special interest 
i.e., rash etc., and vital status. 
If the subject decides to completely withdraw from the study (refuses any further study 
participation or contact), all study participation for that subject will cease and data to be 
collected at subsequent visits will be considered missing. 
The appropriate personnel from the site and ICON will assess whether investigational 
treatment should be discontinued for any subject whose treatment code has been broken 
inadvertently for any reason. 

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The investigator must also contact the IRT to register the subject’s discontinuation from 
investigational treatment. 
9.3.6 
Discontinuation of Study Sites 
Study site participation may be discontinued if Mereo BioPharma or designee, the 
investigator or IRB/IEC of the study site judges it necessary for medical, safety, regulatory or 
other reasons consistent with applicable laws, regulations and GCP. 
9.3.7 
Discontinuation of Study 
The study will be discontinued if Mereo BioPharma or designee, including through DMC 
recommendation, judges it necessary for medical, safety, regulatory or other reasons 
consistent with applicable laws, regulation and GCP. 
9.3.8 
Lost to Follow-up 
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorised by the subject. Lost to follow-up is 
defined by the inability to reach the subject after a minimum of three documented phone 
calls, faxes or emails as well as lack of response by the subject to one registered mail letter. 
All attempts should be documented in the subject’s medical records. If it is determined that 
the subject has died, the site will use permissible local methods to obtain the date and cause 
of death. 
If the investigator’s use of a third-party representative to assist in the follow-up portion of the 
study has been included in the subject’s informed consent, then the investigator may use a 
sponsor-retained third-party representative to assist site staff with obtaining the subject’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study. The site staff and representative will consult publicly available sources, 
such as public health registries and databases, in order to obtain updated contact information. 
If after all attempts, the subject remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the subject’s medical 
records. Data to be collected at subsequent visits will be considered missing. 
10 
TREATMENT OF SUBJECTS 
10.1 
Identity of Study Treatment(s) 
10.1.1 
Administration of Study Treatment(s) 
The investigational treatment BCT197 is prepared as gelatine capsules (white to near white 
powder in hard gelatine capsules) in doses of 
. Those subjects 
randomised to the placebo regimen will be administered two matching placebo capsules that 
are identical to the test product in appearance but contain no active ingredient. 
BCT197 or placebo capsules should be taken orally with fluids at the same time of the day 
according to the randomised regimens detailed in Table 7-1. 
All subjects will be treated with test product or placebo on 
after 
Randomisation. Subjects will be screened for not more than one day and followed daily in the 

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first week and on Days 10 and 14 (Acute Exacerbation Phase), and then at 8, 12 and 
26 weeks in the Stabilisation Phase. 
All subjects will be treated as per institution SoC, since in agreement with GOLD 2015 
updated version for treating COPD exacerbations, open label corticosteroids and/or 
antibiotics may be administered at the investigator’s discretion. Subjects will be permitted to 
use SoC short-acting bronchodilators as rescue medication on an ‘as needed’ basis. 
10.2 
Study Treatment Packaging and Labelling 
10.2.1 
Packaging 
Each study site will be supplied with investigational treatment in packaging of identical 
appearance. 
Investigator staff will identify the investigational treatment package(s) to dispense to the 
subject by contacting the IRT and obtaining the medication number(s). This number should 
be recorded in the subject’s notes and in the Pharmacy file. 
10.2.2 
Labelling 
Medication labels will comply with the legal requirements of each country and be printed in 
the local language. They will supply no information about the subjects. 
10.2.3 
Storage 
Based on available stability data, 
 should be 
stored at ≤ 25°C. The storage conditions for the study drug will be described on the 
medication label. 
10.2.4 
Blinding and Randomisation of Study Treatments 
At Visit 1 all eligible subjects will be randomised via IRT to one of the treatment regimens. 
The investigator or his/her delegate will contact the IRT after confirming that the subject 
fulfils all the inclusion/exclusion criteria. The IRT will assign a medication number to the 
subject which will be used to link the subject to a treatment regimen and will specify a unique 
medication number for the package of investigational treatment to be dispensed to the 
subject. The randomisation number will not be communicated to the caller. 
The randomisation numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A 
subject randomisation list will be produced by ICON Biostatistics using a validated system 
that automates the random assignment of subject numbers to randomisation numbers. These 
randomisation numbers are linked to the different treatment regimens, which in turn are 
linked to medication numbers. A separate medication list will be produced using a validated 
system that automates the random assignment of medication numbers to packs containing the 
investigational drug. 
Should a situation arise where unblinding is required, the investigator at that site may 
perform immediate unblinding without the need for communication with the sponsor. 

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10.3 
Procedure for Breaking the Randomisation Code 
Subjects, investigator staff, persons performing the assessments, and data analysts will 
remain blind to the identity of the treatment from the time of randomisation until database 
lock, using the following methods: 
o Randomisation data are kept strictly confidential until the time of blinding, and will not 
be accessible by anyone involved in the study 
o The identity of the treatments will be concealed by the use of investigational treatment 
that is identical in packaging, labelling, schedule of administration and appearance. 
Emergency treatment code breaks should only be undertaken when it is essential to treat the 
subject safely and efficaciously. Most often, investigational treatment discontinuation and 
knowledge of the possible treatment assignments are sufficient to treat a study subject who 
presents with an emergency condition. Emergency code breaks are performed using the IRT. 
When the investigator contacts the system to break a treatment code for a subject, he/she 
must provide the requested subject identifying information and confirm the necessity to break 
the treatment code for the subject. The investigator will then receive details of the 
investigational drug treatment for the specified subject and a fax or email confirming this 
information. The system will automatically inform the ICON site monitor, the medical 
monitor, and the ICON Project Manager that the code has been broken. 
It is the investigator’s responsibility to ensure that there is a procedure in place to allow 
access to the IRT in case of emergency. The investigator will inform the subject how to 
contact his/her backup in cases of emergency when he/she is unavailable. The investigator 
will provide the protocol number, investigational treatment name if available, subject 
number, and instructions for contacting the local entity which has responsibility for 
emergency code breaks to the subject in case an emergency treatment code break is required 
at a time when the investigator and backup are unavailable. 
The randomisation codes associated with each subject will be disclosed to PK analysts who 
will keep PK results confidential until database lock. 
10.4 
Subject Compliance 
Study drug compliance will be assessed by the investigator and/or centre personnel by 
recording capsule counts of study treatments from the previously dispensed blister strips. The 
investigator and/or centre personnel will also assess whether the subject has been given the 
capsules in the prescribed order. The total number of doses administered to each subject will 
be derived from dosing information recorded in the eCRF. 
10.5 
Study Treatment Accountability 
Records shall be maintained of the delivery of study treatments to the study centres, the 
inventory at the study centres, the use of each subject and the return to the sponsor. 
These records shall include dates, quantities, batch numbers, expiry dates and the unique code 
numbers assigned to the study medication and to the study subjects. 

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The investigator shall be responsible for ensuring that the records adequately document that 
the subjects were provided the doses specified in the protocol and that all study medication 
received from the sponsor is reconciled. All study medication must be returned to the sponsor 
or sponsor designee according to the procedures described in the Pharmacy Manual. 
10.6 
Concomitant Therapy 
10.6.1 
Permitted Concomitant Medication for COPD 
1. Long-acting anti-histamines if taken at stable regimen at least 2 months prior to Screening 
or if taken PRN. For subjects not on stable, long-acting anti-histamines, short courses are 
allowed during the study period (≤ 7 days). Other anti-histamines are allowed during the 
study period for a short course (≤ 10 days) or if taken PRN 
2. If required for respiratory symptoms or a COPD exacerbation: 
o Systemic corticosteroid (oral/IV/intramuscular) 
o Inhaled short-acting β2-agonists and/or short acting muscarinic antagonists or 
combination of both 
o Nebulised β2-agonists, anti-cholinergics and/or steroids 
o Antibiotics 
o Oxygen. 
3. Mechanical ventilation at the investigator’s discretion 
o Mechanical ventilation is exclusionary at Screening. However, if the subject requires 
mechanical ventilation during the course of the study, they should remain on the study 
until Week 26, even if further study drug cannot be administered or assessments 
carried out. 
4. Short courses (≤ 10 days) of nasal corticosteroids (maximum two courses) are allowed 
5. Current regular therapy for COPD as stated in inclusion criterion 8 
6. Current regular theophylline. 
 
10.6.2 
Prohibited Therapy 
The class of medications listed in Table 10-1 are not permitted to be taken for the specified 
time before dosing with study treatment. Medications excluded for Drug-Drug interaction 
potential (e.g. CYP3A4 inhibitors) should be excluded until Day 14. Medications excluded 
for potential to affect respiratory efficacy end points should be excluded for the duration of 
the study unless required to treat worsening of clinical condition. Live vaccines should be 
excluded from the time specified in Table 10-1 before dosing, during dosing and up to Week 
8. Each concomitant drug must be individually assessed against all exclusion criteria and the 
table below. If in doubt, the investigator should contact the ICON medical monitor before 
randomising a subject or allowing a new medication to be started. Whilst not prohibited, 
killed vaccines may be less efficacious if administered in the period 14 days prior to study 

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drug dosing and up to Week 8. Consideration should be made to assess vaccine response 
and/or revaccinate during this period. 
Table 10-1 
Prohibited Medication 
Class of medication 
Subject will not be included in the study if the 
following prohibited medications have been taken 
within 
CYP3A4 inhibiting drugs (including chloramphenicol) 
14 days prior to randomisation 
Ingestion of grapefruit juice 
14 days prior to randomisation 
CYP3A4 inducers including carbamazepine, 
phenytoin, rifampicin and St John’s Wort 
14 days prior to randomisation 
Non-cardioselective β blockers 
10 days prior to randomisation 
Multi drug resistance protein 1 (P-gp) inhibiting drugs 
including the calcium channel blockers verapamil and 
diltiazem (with the exception of azithromycin, which 
is not prohibited) 
14 days prior to randomisation 
Monoamine-oxidase inhibitors 
14 days prior to randomisation 
Live attenuated vaccine 
30 days prior to randomisation 
Monoclonal antibodies 
6 months prior to randomisation 
p38 mitogen activated protein kinase inhibitor 
6 months prior to randomisation 
PDE3/4 inhibitors 
6 months prior to randomisation 
IgE inhibitors (e.g. xolair) 
6 months prior to randomisation 
Leukotriene antagonists and leukotriene synthesis 
inhibitors 
7 days prior to randomisation 
This table is not considered all-inclusive. Medications should be assessed for adherence to the indication and 
other inclusion/exclusion criteria. The washout of these prohibited medications is not to be encouraged. 
 
 

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11 
ASSESSMENT OF EFFICACY 
11.1 
Efficacy Variables 
1. FEV1, FVC and FEV1/FVC on Days 1 to 7 (daily), 10, 14, and at Weeks 8,12 and 26 
2. FEV1, FVC and FEV1/FVC form the most recent test performed within the last 
12 months outside an exacerbation 
3. Time to improvement of 100 mL in FEV1 compared to Baseline versus placebo 
4. AUC of FEV1 
5. RR on Days 1 to 7 (daily), Days 10, 14, and at Weeks 8,12 and 26 
6. EXACT-PRO score daily from Baseline up to the end of subject participation 
7. AUC of EXACT-PRO 
8. Number of COPD-related deaths from first dose intake up to the end of study 
participation (Week 26) 
9. Number of moderate/severe COPD exacerbations over time among groups 
10. Time to next moderate/severe COPD exacerbation (in days) 
11. Number of uses of rescue therapy during the study 
12. Time from hospitalisation until the subject is medically ready for discharge 
13. Exploratory composite endpoints: 
o Number of events of worsening of symptoms warranting the addition of antibiotics 
o Number of events of worsening of symptoms warranting an increase of oral dose of 
corticosteroids or initiation of new oral corticosteroids 
o Number of events of worsening of symptoms requiring additional treatment with oral 
corticosteroids and/or antibiotics after completion of the initial regimen 
o Number of events of COPD exacerbations that required re-hospitalisation 
o Number of COPD-related deaths. 
14. CRQ scores at Baseline, Day 14 and at Weeks 8, 12 and 26 
15. Cumulative oral/IV steroid dose Days 1 to 14, and from Day 14 to Week 26 
16. Blood biomarkers (IL-6, TNF-α, fibrinogen, hs-CRP, and MPO) 
17. BCT197 exposure on Days 1, 3, and 5 
18. Body Mass Index at Baseline, Days 7, 14, and Weeks 8, 12 and 26 
19. Dyspnoea (mMRC dyspnoea scale) at Baseline, Days 7, 14, and Weeks 8, 12 and 26 
20. 6MWT and BMI Day 14 (for BODE index calculation). 
 

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11.2 
Efficacy Assessments 
Primary 
1. Change in FEV1 from Baseline (pre-dose) to Day 7. 
Secondary 
1. Comparison of FEV1 on Days 3, 10, and 14 
2. Normalisation evaluation of spirometry parameter (FEV1, FVC and FEV1/FVC) response 
over time (performed daily from Days 1 to 7, 10, and 14, and Weeks 8, 12 and 26) 
compared with the most recent test performed within the last 12 months outside an 
exacerbation (pre-study FEV1, FVC, and FEV1/FVC value) 
3. Time to improvement of 100 mL in FEV1 compared with Baseline versus placebo 
4. Comparison of AUC of FEV1 over time among groups 
5. Change in RR over time (performed daily from Days 1 to 7, 10 and 14) among groups 
6. Change on RR on Day 3, 7, 10 and 14 among groups 
7. Time to improvement based on EXACT-PRO total score 
8. Comparison of AUC of EXACT-PRO among groups 
9. Number of COPD-related deaths during the study 
10. Number of moderate/severe COPD-related exacerbations during the study 
11. Time to next moderate/severe COPD exacerbation 
12. Change from Baseline at each inter-visit period and over the entire period of the study in 
the average EXACT-PRO total score and domain scores 
13. Number of times each subject required rescue therapy during the study 
14. Time from hospitalisation until the subject is medically ready (COPD-related) for 
discharge 
15. Nonlinear mixed effects pharmacokinetic/pharmacodynamics (PK/PD) models evaluating 
the relationship between BCT197 exposure and efficacy/safety endpoints. 
 
Exploratory 
1. Exploratory composite scale endpoints comparing among the three groups at Weeks 8, 12 
and 26: 
o Number of events of worsening of symptoms warranting the addition of antibiotics 
o Number of events of worsening of symptoms warranting an increase of oral dose of 
corticosteroids or initiation of new oral corticosteroids 
o Number of events of worsening of symptoms requiring additional treatment with oral 
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o Number of events of COPD exacerbations that required re-hospitalisation 
o Number of COPD-related deaths. 
2. Change in CRQ from Baseline at Day 14 and Weeks 8, 12 and 26 to evaluate recovery, 
comparing among the three groups over time 
3. Cumulative oral/IV steroid dose from Day 1 to Day 14, and from Day 14 to Week 26 
4. Change in inflammatory blood biomarkers (IL-6, TNF-α, fibrinogen, hs-CRP, and MPO) 
daily during Part 1 of the study, and at Weeks 8, 12 and 26 
5. Relationship between BCT197 exposure and efficacy/safety endpoints 
6. Change from Baseline in mMRC dyspnoea scale over time 
7. BODE index among the three groups at Day 14. 
 
11.2.1 
Spirometry 
Pulmonary function tests will be carried out under medical supervision in either a clinic or 
hospital and will be recorded using a computer-operated spirometer. 
Lung function measurements and daily calibration of the spirometer will be done to the 
recommendations of the official Statement of the European Respiratory Society (ERS) and 
the American Thoracic Society (ATS). All sites will be provided with equipment and a 
central spirometry laboratory will be used. Investigator sites will be trained to the use of the 
system during the investigator meeting. All calibration reports should be printed and kept 
with the source study documents. 
The specific procedures for the central spirometry will be provided to the investigator by the 
central spirometry company. 
Forced Expiratory Volume in the 1st second in litres (FEV1, L) and Forced Vital Capacity 
(FVC, L) will be recorded daily from Days 1 to 7 and on Days 10 and 14 during Part 1 of the 
study and at all visits of the Part 2 of the study. At either Week 8, 12, and 26 pre and post 
bronchodilator spirometry will be performed, for demographic purposes, if this information is 
not available from historical spirometry. This is additional to the ‘on bronchodilator’ 
spirometry, with the ‘on bronchodilator’ measurement being the priority.  
The chosen value should not exceed the next by more than 150 mL. If the difference is larger, 
up to 8 measurements will be made and the highest value reported. The ratio FEV1/FVC will 
be derived from this highest value of each parameter. 
Predicted values will be automatically calculated with the demographics data recorded in the 
centralised system. 
If more than one spirometry has been conducted within the 12 months before the study the 
most recent result, outside the exacerbation, will be used as the pre study value. 
 

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11.2.2 
Body mass index, airflow obstruction, dyspnoea, and exercise (BODE) index 
BMI 
The BMI is to be calculated from the weight and height obtained at Day 14 where the BODE 
index is required. BODE uses the binary classification for BMI > 21 kg/m2 or ≤ 21 kg/m2. 
Obstruction 
The level of obstruction for the BODE index will be collected from the spirometry done at 
the time points where the BODE index is specified. The index to be used is the FEV1% (in 
relation to the predicted value). 
Dyspnoea (mMRC score) 
The mMRC dyspnoea scale is a questionnaire that consists of five statements about perceived 
breathlessness: grade 0, “I only get breathless with strenuous exercise”; grade 1, “I get short 
of breath when hurrying on the level or up a slight hill”; grade 2, “I walk slower than people 
of the same age on the level because of breathlessness or have to stop for breath when 
walking at my own pace on the level”; grade 3, “I stop for breath after walking 100 yards or 
after a few minutes on the level”; grade 4, “ I am too breathless to leave the house”. 
The investigator or his designee who will apply the mMRC should orient how the scale is 
graded, explain to the subject that he/she should choose the one option that best reflects the 
current dyspnoea limitation and then let the subject choose his/her own score without any 
suggestion or interference by the investigator/designee. 
Exercise (6MWT) 
The 6MWT to achieve the BODE index will be performed at Day 14 when BODE index is 
required. It will be documented if it is not medically possible for the subject to perform the 
6MWT. The subject will be required to walk as fast as he/she can without stopping for 
6 minutes, in a pre-defined and scaled circuit supervised by a physician and with oxygen 
saturation monitoring. This test should follow the ATS 2002 guidelines for 6MWT. The ATS 
guidelines for the 6MWT recommend use of a 30-metre or 100-foot walkway with the length 
of the corridor marked every 3 metres. Turnaround points should be marked by a cone or 
similar to avoid interruption during the test (ATS, 2002). 
The distance covered over 6 minutes will be recorded as well the speed (if available) and the 
oxygen saturation. 
Assistive devices can be used but must be kept consistent from test to test; the subject may 
use a device but should be able to walk without physical assistance. 
BODE Index 
The BODE index is used to evaluate the functional status of subjects with COPD. It will be 
assessed at Day 14. Each parameter of the index (obstruction, dyspnoea score per mMRC and 
exercise through the 6MWT) is graded from 0 to 3 with the exception of BMI which is 
graded as 0 or 1. The overall BODE score can vary from 0 to 10. 
 

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11.2.3 
COPD exacerbations 
A COPD exacerbation is defined as “A sustained worsening of the patient’s condition 
(dyspnoea, cough and/or sputum production/purulence), from the stable state and beyond 
normal day-to-day variations, that is acute in onset and necessitates a change in regular 
medication in a patient with underlying COPD that includes prescriptions of systemic 
corticosteroids and/or antibiotics or need for hospitalisation”. 
The exacerbations will be classified as moderate or severe as per the EMA/CHMP guideline 
definition: 
o Moderate: exacerbations that require treatment with systemic corticosteroids and/or 
antibiotics. 
o Severe: Exacerbations that require hospitalisation or result in death. 
Emergency room (ER) attendance includes any unscheduled visit at any healthcare institution 
requiring urgent advice associated with systemic steroids (addition or increment of dose). If 
an ER stay is longer than 24 hours it will be considered severe. If the ER visit is shorter than 
24 hours and not related to any prescription of systemic steroids or antibiotics it will not be 
considered moderate or severe exacerbation. 
For the Screening Visit, a current active COPD exacerbation is classified as one that requires 
hospitalisation, systemic corticosteroids (start of systemic corticosteroid, or increase in the 
dose of the systemic corticosteroid) and/or antibiotics. 
For the documented history of COPD, moderate and severe COPD exacerbations are defined 
above. Documentation of previous COPD exacerbation could be, but is not limited to, ER or 
hospital discharge summary, source document notes at the time of the exacerbation, reference 
letter from the attending physician of the COPD exacerbation, or the medical prescription of 
the previous COPD exacerbation with antibiotics or systemic steroids prescribed. 
For Part 2 (Stabilisation phase) of the study, COPD exacerbation will be considered all 
moderate and severe COPD exacerbations per the definition above. Exacerbations that do not 
fulfil these criteria should be reported as an AE (e.g. worsening of symptoms). A COPD 
exacerbation during Part 2 of the study is not a reason to withdraw the subject from the study, 
unless deemed necessary by the investigator. 
11.2.4 
Number of COPD-related deaths 
The number of COPD-related deaths will be determined at the end of the study. It is the 
responsibility of the investigator to define whether death was COPD-related. The rationale 
used in this causality assessment should be recorded in the source documents and in the 
eCRF. 
11.2.5 
Exploratory composite endpoints 
These endpoints are to be collected in the subject’s eCRF at Day 14, and Weeks 8, 12 and 26. 
This evaluates treatment failure as defined by: 
1. Worsening of symptoms warranting the addition of antibiotics 

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2. Worsening of symptoms warranting an increase in dose of oral corticosteroids or 
initiation of new oral corticosteroids 
3. Worsening of symptoms requiring additional treatment of oral corticosteroids and/or 
antibiotics after completion of the initial regimen 
4. Re-hospitalisation due to worsening of COPD and requiring additional treatment during 
the duration of the study due to exacerbations of respiratory symptoms 
5. COPD-related death. 
11.2.6 
Chronic Respiratory Questionnaire 
The CRQ is used to evaluate four dimensions: dyspnoea, fatigue, emotional function, and 
mastery (the subject’s feeling of control over their disease). The questions covering the 
dimensions of fatigue, emotional function, and mastery are standardised and the subject is 
offered an appropriate 7-point scale for each question. The dyspnoea component is not 
standardised. The subject is required to identify everyday activities which make them 
breathless and then select, rank, and score the five most important activities on a 7-point scale 
which spans from 1 (extremely short of breath) to 7 (not at all short of breath). Every subject 
will have a unique list of activities. In each dimension the lower the score, the greater the 
degree of dysfunction. 
An interviewer administered standardised CRQ will be used for the study. The investigator or 
designee who will apply the CRQ should orient how the scale is graded, explain to the 
subject that he/she should choose the one option that better reflects the current dyspnoea 
limitation and then let the subject choose his/her own score without any suggestion or 
interference by the instructor. 
The score will be applied at Baseline at Day 14, and Weeks 8, 12 and 26 and will allow an 
evaluation of the improvement of subject well-being throughout the study. 
11.2.7 
Blood Biomarkers 
Blood biomarkers (IL-6, TNF-α, fibrinogen, hs-CRP, and MPO) will be measured on Days 1 
to 7, and Days 10 and 14 during Part 1 of the study, and at Weeks 8, 12 and 26. 
11.2.8 
EXACT-PRO 
The EXACT is a 14-item patient reported outcome (PRO) daily diary used to quantify and 
measure exacerbations of COPD (Mackay 2014). This instrument provides a single, 
standardised approach for assessing the symptomatic manifestations of COPD exacerbations, 
with a development and validation history consistent with guidelines proposed by the Food 
and Drug Administration (FDA), EMA and well-known measurement principles. 
The questionnaire is composed of 14 items covering various domains such as breathlessness, 
cough and sputum, chest symptoms, and overall status (tiredness, weakness, sleep 
disturbances). Each question is individually weighted to provide a total score varying from 
0 to 100. The health status of the subject is correlated to the global score, meaning a higher 
score corresponds to a more severe health status of the subject. 

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The EXACT-PRO will be completed once a day in the evening by the subject. The EXACT 
score will be monitored and will raise an alert to the investigator in case of relevant increases. 
11.3 
Pharmacokinetics 
Sparse PK sampling for BCT197 and metabolite(s) (4 samples) will be done on any 2 of the 
3 dosing occasions: one sample will be taken pre-dose, one between 0 and 2 hours post-dose, 
one between 4 and 8 hours post-dose and one no earlier than 12 hours post-dose. 

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12 
ASSESSMENT OF SAFETY 
The timing and frequency of safety assessments are described in Section 9.1.2 and 
Section 9.1.3. 
12.1 
Adverse Events 
12.1.1 
Definitions 
The definitions for AEs and SAEs are given below. It is of the utmost importance that all 
staff involved in the study are familiar with the content of this section. The principal 
investigator is responsible for ensuring this. 
Adverse Event/Reaction 
An AE is defined as any untoward medical occurrence in a subject, or clinical investigation 
subject administered a pharmaceutical product, and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended 
sign, symptom or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) product. 
Any relevant observations made at the Screening Visit (prior to signing the ICF) are to be 
recorded as a pre-existing condition; an AE will only be recorded if there is a worsening of 
the pre-existing condition during study conduct with regards to nature, severity, or frequency. 
An adverse drug reaction is an “untoward and unintended response to an investigational 
medicinal product related to any dose administered”. 
All AEs judged by either the reporting investigator or the sponsor as having a reasonable 
causal relationship to a medicinal product qualify as adverse reactions. The expression of 
“reasonable causal relationship” means to convey in general that there are facts or arguments 
meant to suggest a causal relationship. 
Serious Adverse Event 
An SAE is defined as an AE that results in one of the following outcomes: 
1. Results in death 
Death is not an adverse event itself, but an outcome. The cause of the death is currently 
the AE which resulted in death. 
2. Is life-threatening 
Life-threatening means that the subject was at immediate risk of death at the time of the 
SAE, it does not refer to a SAE that hypothetically might have caused death if it were 
more severe. 
3. Requires in-patient hospitalisation or prolongs existing hospitalisation (This does not 
include prolonged hospitalisation for study purposes) 
Hospitalisation is defined as at least one overnight formal admission into hospital, 
usually to perform additional tests, provide treatment that it is not possible to provide at 

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home and/or to allow specific monitoring of the subject due to their unstable medical 
condition. Current hospitalisation due to the COPD and pre-planned hospitalisations 
(known already prior to signing the ICF) will not be considered an SAE, unless any of 
the above criteria are fulfilled over the course of the hospitalisation due to unplanned 
complications. Following the initial discharge from hospital, subsequent hospitalisations 
due to COPD are to be considered an SAE. “Social” hospitalisation, defined as 
administrative impossibility to discharge the subject is not necessarily an SAE. 
Complications that occur during hospitalisation are AEs unless they would qualify as an 
SAE for any of the above criteria. If the complication delays the subject’s release from 
hospital, then the AE becomes an SAE. Hospitalisations due to diagnostic procedures 
which are not performed due to an AE are not regarded as SAE. 
4. Results in persistent or significant disability/incapacity 
The term significant disability refers to any condition that impairs physical/psychological 
well-being to the extent that the subject is unable to function normally. Physical 
disability may include, but is not limited to, permanent disability of locomotion or 
motility, but also systemic permanent dysfunction as development of heart failure, liver 
insufficiency or pulmonary fibrosis. 
5. Is a congenital anomaly/birth defect 
6. Is an important medical event 
Important medical events that may not result in death, be life-threatening or require 
hospitalisation may be considered an SAE, when based on appropriate medical 
judgement, they may jeopardise the subject or the subject may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
Treatment Emergent Adverse Event (TEAE) 
TEAEs are defined as any AE occurring or worsening on or after the first dose of study 
medication. 
Adverse Events of Special Interest (AESI) 
Refer to Section 12.1.7. 
12.1.2 
Recording of Adverse Events 
Any relevant observations made at the Screening Visit (prior to signing the ICF) are to be 
recorded as a pre-existing condition. For the purposes of this study, any detrimental change in 
the subject's condition, after signing the informed consent form and up to completion of the 
26 week follow-up period after the last administration of study drug, should be considered an 
AE/SAE. 
The following variables will be recorded for each AE: verbatim/AE description and date for 
AE start and stop, severity, seriousness, causality rating, whether or not the AE caused the 
subject to discontinue, and the outcome. If the severity of the AE changes, a new AE must be 
recorded. 

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SAEs and AEs will be recorded starting after signing of informed consent. All SAEs and AEs 
have to be recorded, whether or not considered causally related to the investigational product 
or to the study procedure(s). 
All ongoing AEs/SAEs should be followed up until resolution or stabilisation or the last visit 
if in the investigator's opinion, the AE is unlikely to resolve due to the subject's underlying 
disease. 
At any time after the follow-up visit, if an investigator learns of an SAE that can be 
reasonably related to study drug, he/she should promptly notify the sponsor. 
The investigator will assess the intensity of AEs based on the following definitions: 
1. Mild (awareness of sign or symptom, but easily tolerated) 
2. Moderate (discomfort sufficient to cause interference with normal activities) 
3. Severe (incapacitating, with inability to perform normal activities). 
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 12.1.8. 
An AE of severe intensity need not necessarily be considered serious. For example, nausea 
that persists for several hours may be considered severe nausea, but not an SAE. On the other 
hand, a stroke that results in only a limited degree of disability may be considered a mild 
stroke but would be an SAE. 
For an AE to be a suspected drug-related event, there should be at least a reasonable 
possibility of a causal relationship between the study drug and the AE. 
12.1.3 
Causal Assessment 
The following “binary” decision choice will be used by the investigator to describe the 
causality assessment: 
o Reasonable possibility of a relatedness 
o No reasonable possibility of relatedness. 
The term “reasonable possibility of relatedness” is meant to convey, in general, that there is 
enough evidence or argument to suggest the causal relationship. The investigator should 
consider, before reaching up to a decision on causality assessment: 
o Time relationship between study drug intake and event’s onset 
o Dechallenge 
o Rechallenge 
o Medical History 
o Study treatment 
o Mechanism of action of study drug 
o Class effect 

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o Concomitant treatments in use 
o Withdrawal of study treatment 
o Lack of efficacy/worsening of existing condition 
o Erroneous treatment with study medication or concomitant medication 
o Protocol related process. 
 
Action taken with study drug due to the AE: 
o None 
o Drug permanently discontinued 
o Unknown/not applicable. 
 
Other action taken: 
o Specific therapy/medication 
o Surgical medical procedure 
o (Prolonged) hospitalisation. 
 
Outcome 
Each single AE must be rated by choosing one of the following: 
o Recovered/resolved 
o Recovering/resolving 
o Not recovered/not resolved 
o Recovered with sequelae/resolved with sequelae 
o Fatal 
o Unknown. 
 
12.1.4 
Abnormal Laboratory Values/Vital Signs/Electrocardiograms 
Laboratory/vital signs/ECG abnormalities should be reported as an AE/SAE if any one of the 
following criteria is met: 
1. Result is clinically significant or associated with signs/symptoms 
2. Requires additional diagnostic testing and/or interventions 
3. Leads to a change in dose, discontinuation of or interruption to the study drug. 

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Repeats of an abnormal test result without any of the above criteria do not constitute an AE. 
Any test result determined to be an error is not required to be reported as an AE. 
12.1.5 
Overdose 
A drug overdose is defined as the accidental or intentional use of a drug or medicine in an 
amount that is higher than is normally used. Every overdose must be reported to ICON 
Medical and Safety Services (MSS) within 24 hours of awareness, irrespective of whether the 
overdose was associated with an AE/SAE. In case of overdose in which decreasing the 
systemic concentration of BCT197 may be deemed as being of possible clinical benefit, the 
investigator should consider haemodialysis or other filtration method to decrease the systemic 
concentration. This is based on BCT197 being a small molecule with low protein binding and 
moderate volume of distribution. 
12.1.6 
Pregnancy 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study drug may 
have interfered with the effectiveness of a contraceptive medication. If a pregnancy is 
reported for a subject, no further study drug will be administered to this subject and the 
outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented. Follow-up should be done up 
to delivery and after the examination of the newborn when a follow up report should be sent 
with any new information regarding the pregnancy and the outcome of the newborn. 
All congenital abnormalities/birth defects should be classified as SAEs. Spontaneous 
miscarriages should also be reported and handled as SAEs. Elective abortions without 
complications should not be handled as SAEs, but should be reported as an AE. All outcomes 
of pregnancy must be reported to the sponsor on a pregnancy outcomes report form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the female partner. 
Pregnancies must be reported to ICON MSS using the reporting details provided in 
Section 12.1.8 within 24 hours of awareness. 
12.1.7 
Adverse Event of Special Interest 
Some AEs, despite their severity or outcome, will be expedited due to the relevance for 
subject safety or study drug safety profile. These events should be reported to ICON MSS 
within 24 hours of awareness: 
1. Pneumonia 
o The diagnosis of pneumonia should be confirmed with a chest radiography (two 
positions) or a CT scan. Whenever possible, microbiologic confirmation should be 
obtained and the corresponding form in the eCRF should be completed. 

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2. Liver injury 
o For subject safety and to ensure that the hepatotoxic potential of the study drug 
can be determined, a standardised procedure for identification, monitoring and 
evaluation of liver events must be followed: 
a) In the event of: i) ALT or AST elevations > 5 x ULN or ii) ALT or 
AST > 3 x ULN and bilirubin total > 2 x ULN or INR > 1.5 or the appearance 
of worsening fatigue, nausea, vomiting, RUQ pain/tenderness, fever, rash, or 
eosinophilia, the study drug should be withdrawn and testing repeated within 
2 days. An investigation of the liver event should be carried out in order to 
evaluate other causes for liver injury. These investigations can include 
serology 
tests, 
imaging 
and 
pathology 
assessments, 
hepatologist’s 
consultancy, based on investigator’s discretion. The subject should be 
hospitalised if required. The appropriate form in the eCRF should be 
completed. 
b) In the case of ALT and AST elevations < 5 x ULN or ALT and 
AST < 3 x ULN and bilirubin total < 2 x ULN, the tests should be repeated to 
confirm the elevation and report as an AE if clinically significant. 
3. Dermatologic events (Rash/Acneiform dermatitis/Pruritus) 
o The appropriate diagnosis should be confirmed with a dermatologist evaluation 
and appropriate treatment provided to the subject. The corresponding eCRF form 
should be completed. 
4. Headache 
o If the event starts during the study, the corresponding eCRF form should be 
completed. Subjects who have a migraine or tension headache will fulfil this 
criteria only if it is noted as a worsening in the frequency or intensity. 
5. Inflammation of cervix and vagina 
o If the event starts during the study, the corresponding eCRF form should be 
completed. The diagnosis should be confirmed with a gynaecologist evaluation 
and appropriate treatment provided to the subject. The gynaecologist assessment 
should be recorded in the source documents and a summary of the findings 
recorded in the eCRF. 
 
12.1.8 
Reporting of Serious Adverse Events and Adverse Events of Special Interest 
Investigators and other site personnel must inform ICON MSS of any SAE/AESI that occurs 
(whether or not attributable to the study drug) during the course of the study (from the time of 
informed consent until the End of Study Visit) within 24 hours of when he or she becomes 
aware of it. 

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Follow-up information on SAEs/AESIs must also be reported by the investigator within the 
same time frames. 
If a non-serious AE becomes serious, this and other relevant follow-up information must also 
be provided to ICON MSS within 24 hours as described above. 
All SAEs/AESIs must be reported, whether or not considered causally related to the 
investigational product or to the study procedure(s). All SAEs/AESIs will also be recorded in 
the eCRF. The investigator is responsible for informing the Ethics Committee of the 
SAE/AESI as per local requirements. 
Paper SAE/AESI forms should be completed at the site and faxed to the relevant MSS 
Department at ICON Clinical Research or e-mailed to the global email distribution list within 
24 hours of awareness of the event. 
SAE/AESI reports should be sent by all participating investigational sites to the 
following email address: 
STUDY-MSS-DL-3082-0004-Global@iconplc.com 
 
If the report is sent via email then the completed and signed SAE/AESI or Pregnancy report 
form must be attached to the email. A notification email of the event describing it in the email 
text is not sufficient. 
 
Alternatively, the following fax numbers can be used for transmission of the completed 
SAE/AESI reporting form: 
For European sites: 
Telefax: +49 (0) 6103 904 217 
 
For North and South American sites 
Telefax: + 1 215-240-6991 
 
There may be situations when an SAE/AESI has occurred and the investigator has minimal 
information to include in the initial SAE/AESI report. However, it is very important that the 
investigator always makes an assessment of causality for every event prior to transmission of 
the SAE/AESI report form. Minimum criteria are identifiable subject (number), a suspect 
product (i.e. study drug or concomitant medication), an identifiable reporting source 
(investigator/study site identification), and an event or outcome that can be identified as 
serious or as an AESI. The investigator may change his/her opinion of causality in the light of 
follow-up information, amending the SAE/AESI report form accordingly. The causality 
assessment is one of the criteria used when determining regulatory reporting requirements for 
SAEs. 

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Suspected Unexpected Serious Adverse Reactions (SUSARS) will be collected and reported 
to the competent authorities and relevant ethics committees in accordance with Directive 
2001/20/EC or as per national requirements in participating countries. 
12.2 
Safety Endpoints 
Assessment will include assessment of: 
1. TEAEs/SAEs (from first dose of study drug until study completion) 
2. TEAEs of special interest (pneumonia) 
3. TEAEs of special interest (liver enzymes [ALT, AST, bilirubin total and fractions], 
rash, acneiform dermatitis, cervical/vaginal inflammation, headache and pruritus) 
4. Vital signs (body temperature, RR, pulse rate, blood oxygen [measured using a pulse 
oximeter], systolic and diastolic blood pressure) 
5. QTc intervals and ECG findings (arrhythmias, conduction blocks, changes in ST 
segment) at Baseline, from Day 1 to Day 7, Days 10 and 14 
6. Laboratory data including sputum cultures and blood eosinophil percentages. 
 
12.3 
Laboratory Assessments 
Haematology, blood chemistry, and urinalysis will be conducted at Screening, on Days 1, 3, 
5, 7, 10 and 14, and at each visit in the Stabilisation phase. 
Haematology, blood chemistry and pregnancy tests done at the Screening visit of the study 
should be sent to both the local laboratory and central laboratory for analysis. Haematology, 
blood chemistry and pregnancy done at all other visits of the study should be sent only to the 
central laboratory for analysis, with the exception of urine dipstick pregnancy test that should 
be done at the local laboratory. 
Local laboratory normal ranges will be collected prior to first patient first visit (FPFV) at 
each site and provided to data management via the study team. Laboratory results collected 
from the local laboratory should be entered in the eCRF by the investigator. 
The following parameters will be assessed: 
o Haematology: red blood cell count, white blood cell count with differential counts and 
percentages, total haemoglobin, haematocrit, platelets count, INR and prothrombin 
time (INR and prothrombin time not required during the Stabilisation phase) 
o Blood chemistry: creatinine, blood urea nitrogen [BUN], fasting serum glucose, AST, 
ALT, gamma-glutamyl transpeptidase, total bilirubin, albumin, chloride, calcium, 
phosphorous, uric acid, total protein, sodium and potassium 
o Urinalysis (specific gravity, pH, protein, glucose, blood) 
o Pregnancy test: serum β-HCG and urinary pregnancy test. 

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Blood collection and sample preparation will be performed according to procedures from the 
local and central laboratories. 
If sputum or bronchoalveolar culture is collected for any medical reason (qualitative or 
quantitative culture), the result should be recorded in the eCRF and included in the safety 
analysis. 
12.4 
Medical Evaluation/Physical Examination 
A full medical evaluation and physical examination should be performed at each visit in order 
to evaluate the medical condition of the subject and also detect any sign/symptom of AEs, 
and to perform all the procedures required per protocol. Height will only be measured at the 
Screening Visit.  
12.5 
Vital Signs 
Vital signs include body temperature, systolic and diastolic blood pressure, pulse, blood 
oxygen (using a pulse oximeter), and respiratory rate. After the subject has been sitting for 
five minutes with back supported (in a chair or in bed), pulse rate and systolic and diastolic 
blood pressure will be measured. Respiratory rate will be measured after the subject has been 
resting for 10 minutes. 
12.6 
12-lead ECG 
The 12-lead ECG measurement will be done under medical supervision in either a clinic or 
hospital at all visits. All sites will be provided with equipment and a central ECG laboratory 
will be used. Investigator sites will be trained in the use of the system. 
ECG should be done before any blood sample collection scheduled for the same time. 
Before recording, subjects should be resting in a quiet supervised setting with minimal 
stimulation (e.g. no television, loud music, computer games) and lie in a resting position for 
10 minutes before ECG recording. 
QTc value will be calculated using the Fridericia formula (QTc=QT/3√RR). The QTc interval 
will be automatically calculated. 
In the case of clinically significant ECG abnormalities, the investigator should report these as 
an AE if not due to a pre-existing condition or if a pre-existing condition worsens in 
frequency or intensity. 
12.7 
24/7 Medical Emergency Coverage 
In a study related emergency situation, when the assigned Medical Monitors for a study 
cannot be reached by a caller, an on-call Physician can be reached 24 hours per day, 7 days 
per week via an ICON Call Centre: 
o Telephone: +1 919 674 5468 
(chargeable telephone number allowing a global reach from both landlines and mobile 
phones) 
o https://icophone.iconplc.com 

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On this internet page, a list of country-specific toll-free telephone numbers is provided. It 
should be noted that not all countries globally have access to toll-free numbers as indicated 
on the “24/7 Medical Helpdesk” index. Countries without toll-free numbers need to dial the 
chargeable number as indicated above. Furthermore, toll-free numbers are not available from 
mobile phones. 
12.8 
Data Monitoring Committee (DMC) 
An independent, external DMC will periodically review accumulating safety data. Full details 
of composition, operational aspects, and data to be reviewed and recommendation to be made 
by the DMC will be described in a separate DMC charter. 
12.9 
Independent Adjudication Committee (IAC) 
Once subjects have completed study treatment, all new reports of exacerbation of COPD and 
events of hospitalisations due to new exacerbations of COPD will be evaluated by an external 
IAC. Specific details regarding procedures for clinical adjudication of the components of the 
endpoint will be described in a separate charter. 

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13 
STATISTICAL EVALUATION 
13.1 
Sample Size and Power 
The sample size is based on a formal statistical calculation using the following assumptions: 
1. Endpoint: Change in FEV1 from Baseline to Day 7 
2. Minimum clinically significant difference between regimens: 100 mL 
3. Standard deviation = 230 mL (based on a previous study [CBCT197A2201] with 
BCT197) 
4. Superiority design of two BCT197 doses compared to placebo 
5. Two-sided alpha (Type 1) error = 0.05 
6. No adjustment for multiplicity 
7. Beta error (Type 2) = 0.20 (Power = 80%). 
Based on the above assumptions, 85 subjects will need to be analysed per dose regimen, 
resulting in a total of 255 evaluable subjects. 
Assuming a dropout rate of approximately 5%, a total of approximately 270 subjects will be 
randomised to the study. 
13.2 
Randomisation 
ICON Biostatistics will prepare the randomisation list based on a randomisation scheme 
blocked by site. Each subject will be assigned to one of three dosing regimens defined in 
Section 10.1.1 in a 1:1:1 ratio. 
See Section 10.2.4 for further details of the Randomisation procedures to be applied. 
13.3 
Analysis Sets 
All primary and secondary efficacy endpoints will be analysed using the intention to treat 
(ITT) population. The per protocol (PP) population will be used only for the analysis of the 
primary endpoint to examine the robustness of the primary analyses. 
Safety and tolerability will be analysed using the safety population. 
Pharmacokinetic data will be analysed using the PK population. 
13.3.1 
Intention to treat (ITT) (Full Analysis Set) 
The intention to treat population includes all subjects who: 
1. Are randomised, and 
2. Receive at least one dose of study medication, and 
3. Provide a Baseline and at least one post-Baseline FEV1 value. 

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13.3.2 
Per protocol (PP) 
The PP population is a subset of the ITT population and includes all randomised subjects as 
randomised who have been treated according to the protocol and fulfil the following criteria 
(to be further described in the statistical analysis plan [SAP]): 
1. All inclusion/exclusion criteria satisfied 
2. Absence of relevant protocol violations with respect to factors likely to affect the efficacy 
of treatment where the nature of protocol violation will be defined before breaking the 
blind 
3. Adequate study medication compliance 
4. Adequate measurement of the primary variable. 
13.3.3 
Safety population 
The safety population includes all subjects who received at least one administration of the 
study medication. 
13.3.4 
PK population 
For the nonlinear mixed effects modelling, all subjects who received at least one 
administration and have at least one quantifiable concentration will be included. 
13.4 
Endpoints 
13.4.1 
Primary Efficacy Endpoint(s) 
The primary assessment of efficacy will be made based on the change in FEV1 between 
Baseline (pre-dose) and Day 7. 
13.4.2 
Secondary Efficacy Endpoint(s) 
Efficacy will be further assessed based on the following secondary endpoints: 
 
1. Comparison of FEV1 on Days 3, 10, and 14 
2. Normalisation evaluation of spirometry parameter (FEV1, FVC and FEV1/FVC) response 
over time (performed from Days 1 to 7, 10, 14, and at Weeks 8, 12 and 26) compared 
with the most recent test performed within the last 12 months outside and exacerbation 
(pre-study FEV1, FVC, and FEV1/FVC value) 
3. Time taken to improvement of 100 mL in FEV1 compared to Baseline versus placebo 
4. Comparison of AUC of FEV1 over time among groups 
5. Change in RR over time (performed daily from Days 1 to 7, 10 and 14) among groups 
6. Change in RR on Days 3, 7, 10 and 14 among groups 
7. Time to improvement based on EXACT-PRO total score 
8. Comparison of AUC of EXACT-PRO over time among groups 
9. Number of COPD-related deaths during the study 

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10. Number of moderate/severe COPD-related exacerbations during the study 
11. Time to next moderate/severe COPD exacerbation 
12. Change from Baseline at each inter-visit period and over the entire period of the study in 
the average EXACT-PRO total score and domain scores 
13. Number of times each subject required rescue therapy during the study 
14. Time from hospitalisation until the subject is medically ready (COPD-related) for 
discharge 
15. Nonlinear mixed effects PK/PD models evaluating the relationship between BCT197 
exposure and efficacy/safety endpoints. 
More details and the time points for collection are given in Section 9.1.3 and in the Schedule 
of assessments (Table 9-1). A complete list of efficacy endpoints is given in Section 11.2. 
These secondary efficacy parameters will be assessed using the ITT population. 
 
13.4.3 
Exploratory Endpoints(s) 
The following data were collected as exploratory endpoints: 
1. Exploratory composite scale comparing the following among the three groups at Week 8, 
12 and 26: 
o Number of events of worsening symptoms warranting the addition of antibiotics 
o Number of events of worsening symptoms warranting an increase in dose of oral 
corticosteroids or initiation of new oral corticosteroids 
o Number of events of worsening symptoms requiring additional treatment of oral 
corticosteroids and/or antibiotics after completion of the initial regimen 
o Number of events of COPD exacerbation requiring re-hospitalisation 
o Number of COPD-related deaths. 
2. Change in CRQ from Baseline at Day 14 and Weeks 8, 12 and 26 to evaluate recovery, 
comparing among the three groups over time 
3. Cumulative oral/IV steroid dose from Day 1 to Day 14, and from Day 14 to Week 26 
4. Change in inflammatory blood biomarkers (IL-6, TNF-α, fibrinogen, hs-CRP, and MPO) 
daily during Part 1 of the study, and at Weeks 8, 12 and 26 
5. Relationship between BCT197 exposure and efficacy/safety endpoints 
6. Change from Baseline in mMRC overtime 
7. BODE index among the three groups at Day 14. 
13.4.4 
Safety Endpoint(s) 
The following data will be collected for assessment of safety: 

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1. TEAEs/SAEs (from first dose of study drug until study completion) 
2. Evaluation of the incidence of pneumonia from first dose of study drug until completion 
3. TEAEs of special interest (liver enzymes [ALT, AST, bilirubin total and fractions]; rash, 
acneiform dermatitis, cervical/vaginal inflammation, headache and pruritus) 
4. Vital signs (body temperature, RR, pulse rate, blood oxygen [measured using a pulse 
oximeter], systolic and diastolic blood pressure) and laboratory parameters 
5. QTc intervals and ECG findings (arrhythmias, conduction blocks, changes in ST 
segment) at Baseline, from Days 1 to 7, 10 and 14 
6. Laboratory data including sputum cultures and blood eosinophil percentages. 
 
These safety parameters will be assessed using the safety population. A complete list of 
efficacy endpoints is given in Section 11.2. 
 
13.5 
Description of Statistical Analyses 
13.5.1 
General Considerations 
The statistical evaluation will be performed by ICON using SAS®, Version 9.3 or later. Data 
will be analysed by either enumeration of subjects displaying distinctive characteristics 
within each treatment regimen or by descriptive statistical summaries such as means, SD, 
medians, and ranges for continuous measures. Categorical variables will be presented by the 
number of observations and absolute and relative (%) frequency. 
For efficacy data, summary statistics (N, mean, SD, median minimum and maximum for 
continuous data, and N [%] for categorical data) will be presented at each visit. 
Similarly, changes from Baseline (or percentage change from Baseline if appropriate) will be 
summarised in a similar manner. 
The main population for efficacy analysis will be the ITT population. 
Unless stated otherwise, the Baseline value for a variable will be the latest value taken prior 
to the first dose of study medication. 
Data in summary tables will generally be presented on an Observed Cases basis. 
Unless stated otherwise, all statistical tests will be two-sided and conducted at the 5% level, 
and all quoted confidence intervals will be two-sided 95% confidence intervals. All three 
treatment regimens will be assessed by pairwise comparisons, no adjustment for multiplicity 
will be made and all analyses will be considered as exploratory analyses. 
Full details of the statistical analysis will be given in the SAP. 

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13.5.2 
Analysis of Primary Endpoint 
FEV1 results (absolute values and changes from Baseline) will be summarised by treatment 
regimen and visit. Formal statistical analysis will be restricted to data collected up to and 
including Day 7. 
The primary analysis of efficacy will be performed with the ITT population. Additionally for 
exploring the robustness of the intent-to-treat results, a supportive analysis using the PP 
population will be carried out. 
Change of FEV1 from Baseline up to and including Day 7 will be assessed with a mixed-
model repeated measures (MMRM) analysis, with treatment regimen as a factor and Baseline 
FEV1 as a covariate. The adjusted mean difference between regimens will be presented along 
with 95% confidence intervals for the Day 7 time-point. 
13.5.3 
Analysis of Secondary Endpoints 
The analysis of secondary efficacy endpoints will be performed on the ITT population. 
For the secondary efficacy endpoints, data will be summarised by treatment regimen and 
visit. 
For each continuous parameter, change from Baseline will be assessed with a MMRM 
analysis, with treatment regimen as a factor and the Baseline value as a covariate. The 
adjusted mean difference between treatments will be presented along with a 95% confidence 
interval for the time-points of interest. 
The proportion of subjects with a COPD-related death will be summarised and compared 
between treatment regimens using Fisher’s Exact Test. 
The pharmacokinetic parameters will be summarised by dose group and visit day. 
A more detailed description will be presented in the SAP. 
13.5.4 
Analysis of Exploratory Endpoints 
13.5.4.1 
Population PK/PD modelling 
Nonlinear mixed effects modelling will be utilised to develop a population PK model for 
BCT197 from which exposure metrics will be derived, which will be used subsequently to 
explore exposure-response (E-R) relationships with selected exposure and efficacy/safety 
endpoints. 
A separate Modelling and Simulation Analysis Plan (MSAP) will be prepared and results 
from the PK/PD modelling will be reported separately from the CSR. 
13.5.5 
Safety Analyses 
The analysis of safety parameters will be based on the safety population. In general, missing 
safety data will not be replaced. A more detailed description will be presented in the SAP. 
Adverse Events 
Adverse events will be coded using the most recent version available of the Medical 
Dictionary for Regulatory Activities (MedDRA). Summaries will be by system organ class 

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and preferred term. TEAEs are defined as any AE occurring or worsening on or after the first 
dose of study medication. If a subject experiences the same preferred term multiple times, the 
event will be counted only once and by the greatest severity. 
The frequency and incidence of treatment emergent adverse events will be presented by 
system organ class and preferred term for each treatment regimen (number and percentage of 
subjects experiencing at least one AE per preferred term as well as the number of observed 
events per preferred term). Separate tables will be presented by severity and by relationship. 
All AEs will be presented in full in a comprehensive listing including subject number, 
treatment regimen, severity, seriousness, action taken, outcome, relationship to treatment, 
onset/stop and duration. Details of SAEs and AEs leading to withdrawal will be listed 
separately. 
Concomitant Medication 
Concomitant medication will be tabulated and summarised by treatment regimen. 
 
Physical Examination 
Physical examination results will be listed by subject and body system. 
 
Vital signs 
Vital signs will be summarised as actual values and change from Baseline by treatment 
regimen and visit. 
ECG 
The overall ECG interpretation will be summarised by presenting the number and percentage 
of subjects with “Normal” “Abnormal, not clinically significant‟ and “Abnormal, clinically 
significant”. 
ECG parameter values (e.g. QTcF) will be summarised as actual values and change from 
Baseline by treatment regimen and visit. 
 
Clinical Laboratory 
Descriptive statistics will be presented for quantitative laboratory parameters for each 
treatment regimen and time-point. Similarly, changes from Baseline will be summarised. 
Values outside the normal range will be categorised as H (above the normal range) or L 
(below the normal range) based on the laboratory’s reference range and these will be flagged 
in the listings of individual subject data. 
 
Withdrawals 
Subjects who withdraw from the study will be summarised by treatment regimen according to 
their reason for withdrawal. 
 

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13.5.6 
Analysis of Further Endpoints 
Demographic data and subjects’ characteristics at Screening will be listed and summarised 
using descriptive statistics. Formal statistical analysis will not be performed on Baseline 
demographic data. 
Medical history will be coded using MedDRA. An incidence table by body system and 
preferred term will be presented by treatment regimen. 
Compliance with study medication will be summarised descriptively by treatment regimen. 
13.6 
Interim Analysis 
No interim analysis is planned. 

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14 
DIRECT ACCESS TO SOURCE DATA/NOTES 
The investigator/institution shall provide direct access to source data/documents for 
study-related monitoring, audits, Independent Ethics Committee (IEC)/Institutional Review 
Board (IRB) review and regulatory inspection. 
15 
QUALITY CONTROL AND QUALITY ASSURANCE 
15.1 
Conduct of the Study 
ICON shall implement and maintain quality control and quality assurance procedures with 
written standard operating procedures (SOPs) to ensure that the study is conducted and data 
are generated, documented and reported in compliance with the protocol, ICH GCP and 
applicable regulatory requirements. 
This study shall be conducted in accordance with the provisions of the Declaration of 
Helsinki (October 2013) and all revisions thereof, and in accordance with FDA regulations 
(CFR, Sections 312.50 and 312.56) and with ICH GCP (CPMP 135/95). 
The investigator may not deviate from the protocol without a formal protocol amendment 
having been established and approved by an appropriate IEC/IRB, except when necessary to 
eliminate immediate hazards to the subject or when the change(s) involve(s) only logistical or 
administrative aspects of the study. Any deviations may result in the subject having to be 
withdrawn from the study and render that subject non-evaluable. 
15.2 
Study Monitoring 
The investigator shall permit the ICON Site Monitor to review study data as frequently as 
deemed necessary to ensure that data are being recorded in an adequate manner and that 
protocol adherence is satisfactory. 
The investigator shall access medical records for the Monitor in order that entries in the 
eCRF may be verified. The investigator, as part of his/her responsibilities, is expected to 
co-operate with ICON in ensuring that the study adheres to GCP requirements. 
The investigator may not recruit subjects into the study until such time that a visit, or with the 
agreement of the sponsor, attendance at the investigator meeting, has been made by a 
sponsor/ICON monitor to conduct a detailed review of the protocol and eCRF. 

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16 
ETHICS 
16.1 
Independent Ethics Committee/Institutional Review Board 
Prior to the start of the study, the investigator is responsible for ensuring that the protocol and 
consent form have been reviewed and approved by a relevant IEC/IRB. The IEC/IRB shall be 
appropriately constituted and perform its functions in accordance with FDA, ICH GCP and 
local requirements as applicable. 
The IEC/IRB shall approve all protocol amendments (except for logistical or administrative 
changes), written informed consent documents and document updates, subject recruitment 
procedures (e.g., advertisements), written information to be provided to the subjects, 
Investigator's Brochure, available safety information, information about payment and 
compensation available to subjects, the investigator's curriculum vitae and/or other evidence 
of qualifications and any other documents requested by the IEC/IRB and Regulatory 
Authority (Competent Authority) as applicable. 
16.2 
Written Informed Consent 
The nature and purpose of the study shall be fully explained to each subject (or their legally 
responsible guardian). 
Written informed consent must be obtained from each subject (or guardian) prior to any study 
procedures being performed. The process of obtaining informed consent must be documented 
in the subject source documents. 
The consent documents to be used for the study shall include all the elements of informed 
consent in accordance with FDA, ICH GCP and local requirements as applicable and be 
reviewed and approved by the appropriate IEC/IRB prior to use. 

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17 
DATA HANDLING AND RECORD KEEPING 
17.1 
Case Report Forms/Source Data Handling 
All required study data must be entered in the eCRF created for the study. This data 
collection tool is a validated electronic data capture (EDC) system that contains a system 
generated audit trail. Data required according to this protocol are recorded by investigational 
site personnel via data entry into the internet based EDC software system. The investigator 
shall ensure that all data from subject visits are promptly entered into the eCRFs in 
accordance with the specific instructions given. The investigator must sign each eCRF to 
verify the integrity of the data recorded. All internal ICON and external investigational site 
personnel seeking access to the eCRF are supported by a Service Desk (if applicable). At the 
end of the study all data captured electronically will be provided to the investigator on 
CD-ROM for archiving at the investigational site. 
A list of the normal ranges for all laboratory tests to be undertaken forms part of the 
documentation to be collated prior to study start. If a central laboratory has been selected to 
conduct any or all tests, it is essential that all samples be analysed at that laboratory. 
The investigator must maintain source documents, such as laboratory reports, X-rays, ECGs, 
consultation reports, and complete medical history and physical examination reports. All 
information in the eCRF must be traceable to the source documents in the subject’s file. 
Data such as the CRQ and EXACT-PRO may be recorded directly in the eCRFs (i.e., no prior 
written or electronic record of data) and considered to be source data. 
17.2 
Retention of Essential Documents 
The investigator/institution should maintain the study documents as specified in the ICH 
guidelines on GCP and as required by the applicable regulatory requirements. The 
investigator/institution should take measures to prevent accidental or premature destruction of 
these documents. 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to 
inform the investigator/institution as to when these documents no longer need to be retained. 

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18 
FINANCING AND INSURANCE 
The sponsor shall carry an insurance policy to cover compensation of subjects’ health injuries 
arising from the study. If a subject incurs a study-related injury, the subject may be treated 
(and other necessary measures taken) at the study site and/or another medical institution. If it 
is necessary to compensate for the treatment, the sponsor will cover the cost. The sponsor 
shall not impose on the subject the burden of proving the causal relation between the study 
and the injury. 
If any of the following is confirmed, the sponsor may refuse or restrict the payment of the 
compensation: 
1. A serious GCP or protocol deviation by the investigator or sub-investigator (except 
deviation medically necessary to avoid an immediate hazard to study subjects) 
2. Intentional act or negligence on the part of the investigator or sub-investigator or 
malpractice thereby 
3. Injury caused by unlawful act or delinquency of a third party 
4. Injury caused by intentional act or negligence of the subject. 
If compensation becomes necessary for a study-related injury, the site will promptly notify 
the sponsor and will co-operate with the sponsor and its insurer (or their legal representatives) 
in their handling thereof. 
 

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19 
PUBLICATION POLICY 
The sponsor shall retain the ownership of all data. When the study is complete the sponsor 
shall arrange the analysis and tabulation of data. A clinical study report shall then be 
prepared, which may be used for publication, presentation at scientific meetings or 
submission to regulatory authorities. All proposed publications based on this study must be 
subject to the sponsor's approval requirements. 
The sponsor assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalisation of the study report, the results of this study will be submitted for publication 
and/or posted in a publicly accessible database of clinical trial results. 

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SIGNATURE OF INVESTIGATOR 
I agree to conduct the study outlined above in accordance with the terms and conditions of 
the protocol, ICH guidelines on GCP and with applicable regulatory requirements. All 
information pertaining to the study shall be treated in a confidential manner. 
 
 
 
 
 
 
((Type name and job title))   
 
 
 
 
 
Date (day/month/year) 
 

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21 
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22 
APPENDICES 
 
 

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