Clinical trial NCT02700919
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Mereo BioPharma
Start date: 2016-08-01; Completion date: 2017-11-28
Enrollment: 282 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the efficacy and safety of BCT197 when added on to standard of care in adult subjects with acute respiratory exacerbations of chronic obstructive pulmonary disease requiring hospitalization. Additionally, the study will characterize the pharmacokinetics of BCT197 in adults with COPD. The total duration of the study will be 26 weeks. Subjects will receive study treatment administration over a period of 5 days after randomization. It is expected that approximately 255 subjects will complete the study and follow-up.

Detailed description:

Arms: arm 1: Drug: BCT197 Dose 1, Day 1 to Day 5 arm 2: Drug: BCT197 Dose 2, Day 1 to Day 5 arm 3: Placebo Day 1 to Day 5
Interventions: intervention 1: BCT197 intervention 2: Placebo
Intervention descriptions: intervention 1: Capsules will be taken orally with fluids over a 5 day period after randomization intervention 2: Capsules will be taken orally with fluids over a 5 day period after randomization

Protocol documents:
Prot_000.pdf: 
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, 
systolic and diastolic blood pressure) 


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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 
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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 
corticosteroids and/or antibiotics after completion of the initial regimen 


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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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20 
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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Protocol No. MBCT206 
 
 
 
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Page 83 of 95 
 
21 
REFERENCE LIST 
Albert RK, Martin TR, Lewis SW (1980) Controlled Clinical Trial of Methylprednisolone in 
Patients with Chronic Bronchitis and Acute Respiratory Insufficiency. Ann Intern Med; 
92:753-758 
Almagro P, Barreiro B, Ochoa de Echaguen A, et al (2006) Risk Factors for Hospital 
Readmission in Patients with Chronic Obstructive Pulmonary Disease. Respiration; 73:311-7 
Chapman KR, Mannino DM, Soriano JB et al (2006) Epidemiology and costs of chronic 
obstructive pulmonary disease. Eur Respir J;27(1):188-207 
Chin CL, Manzel LJ, Lehman EE, et al (2005) Haemophilus influenzae from patients with 
chronic inflammatory obstructive disease induce more inflammation than colonizers. Am J 
Resp Crit Care Med;172(1):85-91 
Davies L, Angus RM, Calverley PMA (1999). Oral corticosteroids in patients admitted to 
hospital with exacerbations of chronic obstructive pulmonary disease: a prospective 
randomized controlled trial. Lancet 354:456-60 
Donaldson GC, Seemungal TAR, Bhowmik A, et al (2002). The relationship between 
exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. 
Thorax:57:847–52 
European Medicines Agency (2012). Guideline on clinical investigation of medicinal 
products in the treatment of chronic obstructive pulmonary disease (COPD). Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/08/WC5
00130880.pdf 
Galimont-Collen AF, Vos LE, Lavrijsen AP, et al (2007). Classification and management of 
skin, hair, nail and mucosal side effects of epidermal growth factor receptor (EGFR) 
inhibitors. Eur J Cancer;43(5):845-51 
Global Initiative for Chronic Obstructive Lung Disease – GOLD (2015). Global Strategy for 
the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. 
Updated 2015. Available from http://www.goldcopd.org 
Garcia-Aymerich J, Farrero E, Felex MA et al (2003) Risk factors of readmission to hospital 
for a COPD exacerbation: a prospective study. Thorax;58:100-105 
Hurst R 2009: Management and prevention of chronic obstructive pulmonary disease 
exacerbations: a state of the art review. BMC Med;7:40 
Kumar S, Boehm J, Lee, JC (2003) P38 MAP kinases: Key signaling molecules as 
therapeutic targets for inflammatory diseases. Nat Rev Drug Discov 2: 717-726 
Langsetmo L, Platt RW, Ernst P (2008) Underreporting exacerbation of chronic obstructive 
pulmonary disease in a longitudinal cohort. Am J Respir Crit Care Med;177(4):396-401 
Lau A, Yam L, Poon E (2001) Hospital re-admission in patients with acute exacerbation of 
chronic obstructive pulmonary disease. Respir Med;95:876-884 


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Lee MR, Dominguez C (2005). MAP Kinase p38 Inhibitors: Clinical results and an intimate 
look at their interactions with p38 protein. Curr Med Chem;12:2979-94 
Leuppi JD, Schuetz P, Bingisser R, et al (2013). Short-term vs conventional glucocorticoid 
therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE 
randomized clinical trial. JAMA;309(21):2223-31 
Lopez AD, Shibuya K, Rao C (2006) Chronic obstructive pulmonary disease: current burden 
and future projections. Respir J;27(2):397-412 
Mackay AJ, Donaldson GC, Patel ARC, et al (2014) Detection and severity grading of COPD 
exacerbations using the exacerbations of chronic pulmonary tool (EXACT). Eur Respir 
J;43:735-44 
Mittmann N, Kuramoto L, Seung SJ, et al (2008) The cost of moderate and severe COPD 
exacerbations to the Canadian healthcare system. Respir Med. 2008 Mar;102(3):413-21 
Molinari N, Briand C, Vachier I, et al (2015). Hospitalizations for COPD exacerbations: 
Trends and determinants of death. COPD Journal of Chronic Obstructive Pulmonary Disease 
Aug 
11 
[Epub 
ahead 
of 
print]. 
Available 
from: 
http://www.tandfonline.com/doi/pdf/10.3109/15412555.2015.1007931 
Niewoehner DE, Erbland ML, Deupree RH et al. (1999) Effect of systemic glucocorticoids 
on exacerbations of chronic obstructive pulmonary disease. Department of Veteran Affairs 
Cooperative Study Group. N Engl J Med 340:1941-47 
Renda T, Baraldo S, Pelaia G, et al. (2008) Increased activation of p38 MAPK in COPD. Eur 
Respir J;31(1):62-9 
Rennard SI, Farmer SG (2004) Exacerbations and progression of disease in asthma and 
chronic obstructive pulmonary disease. Proc Am Thorac Soc;1(2):88-92 
Seemungal T, Donaldson G, Bhowmik A (2000) Time Course and Recovery of 
Exacerbations in Patients with Chronic Obstructive Pulmonary Disease. Am J Respir Crit 
Care Med;161:1608–1613 
Seemungal TAR, Wilkinson TMA, Hurst JR, et al (2008). Long-term erythromycin therapy is 
associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir 
Crit Care Med;178:1139-47 
Seemungal T, Hurst JR, Wedzicha J (2009) Exacerbation rate, health status and mortality in 
COPD – a review of potential interventions. Int J Chron Obstruct Pulmon Dis;4:203-223 
Toy EL, Gallagher KF, Stanley EL et al (2010) The economic impact of exacerbations of 
chronic 
obstructive 
pulmonary 
disease 
and 
exacerbation 
definition: 
a 
review. 
COPD;7(3):214- 28. 
 


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22 
APPENDICES 
 
 


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SAP_001.pdf: 
 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: MBCT206 
               Version: FINAL 2.0, Date:16 November 2017 
                                                                    Page 1 of 112 
 
Protocol Title: 
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 Number: 
MBCT206 
Protocol Version, Date 
Final V1.0, 05 November 2015 
Final V2.0 (Amendment 1), 23 December 2015 
Final V3.0 (Amendment 2), 10 March 2016 
Final V4.0 (Amendment 3), 26 May 2016 
Final V5.0 (Amendment 4), 08 November 2016 
ICON ID:  
3082/0004 
Document Version, Date: 
FINAL 1.0, 07 September 2017 
FINAL 2.0, 16 November 2017 
 
 
Prepared by: 
ICON Clinical Research Services 
 
On behalf of: 
Mereo BioPharma 1 Ltd 
 
 
 


 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: MBCT206 
               Version: FINAL 2.0, Date:16 November 2017 
                                                                    Page 2 of 112 
 
 
Confidentiality statement: 
 
The information provided in this document is strictly confidential.  
 
The recipients of the SAP must not disclose the confidential information 
contained within this document or any related information to other persons 
without the permission of the sponsor. 
 
In addition, the recipients of the SAP must keep this confidential document in a 
controlled environment which prevents unauthorized access to the document. 
 
 
 


 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: MBCT206 
               Version: FINAL 2.0, Date:16 November 2017 
                                                                    Page 3 of 112 
 
SIGNATURE PAGE 
 
 
Prepared at ICON Clinical Research by:  
 
 
 
 
 
 
Date  
(DD Mmm YYYY) 
 
 
 
 
 
Reviewed at ICON Clinical Research by:  
 
 
 
 
 
 
 
 
Date  
(DD Mmm YYYY) 
 
 
 
 
 
 
 
Approved at Mereo BioPharma 1 Ltd by: 
 
 
 
 
 
 
 
 
Date  
(DD Mmm YYYY) 
 
 
 
 


 
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Protocol Number: MBCT206 
               Version: FINAL 2.0, Date: 16 November 2017 
                                                                Page 4 of 112 
 
REVISION HISTORY 
 
 
Version/Date 
Version name 
Section 
Changes implemented 
Version 1.0/ 
07-Sep-2017 
Initial approved 
version 
N/A 
N/A 
Version 2.0/ 
16-Nov-2017 
2.0 
7.1.4.13 Clinical treatment failure 
(exploratory composite endpoint) 
 
7.2 Handling of missing data and 
outliers 
 
Medical review clarification added. 
 
 
A new section for time since last documented COPD exacerbation 
has been added to define the imputation rules in case of partial 
date for the last documented COPD exacerbation. 


 
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Protocol Number: MBCT206 
               Version: FINAL 2.0, Date: 16 November 2017 
                                                                  Page 5 of 112 
 
TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................3 
REVISION HISTORY.....................................................................................................................4 
TABLE OF CONTENTS.................................................................................................................5 
LIST OF ABBREVIATIONS ..........................................................................................................9 
1 INTRODUCTION ...................................................................................................................13 
2 STUDY OBJECTIVES............................................................................................................14 
2.1 Primary objective ............................................................................................................14 
2.2 Secondary objectives.......................................................................................................14 
2.3 Exploratory objectives ....................................................................................................15 
3 STUDY DESIGN.....................................................................................................................16 
3.1 General study design .......................................................................................................16 
3.2 Randomisation and blinding ...........................................................................................17 
3.2.1 Randomisation ....................................................................................................17 
3.2.2 Blinding...............................................................................................................17 
3.2.3 Unblinding ..........................................................................................................17 
3.3 Study treatments and assessments ..................................................................................17 
4 STUDY ENDPOINTS .............................................................................................................23 
4.1 Primary efficacy endpoint ...............................................................................................23 
4.2 Secondary efficacy endpoints .........................................................................................23 
4.3 Exploratory endpoints .....................................................................................................23 
4.4 Safety endpoints ..............................................................................................................24 
5 SAMPLE SIZE AND POWER................................................................................................25 
6 ANALYSIS POPULATIONS .................................................................................................26 
6.1 Intention-To-Treat population (ITT)...............................................................................26 
6.2 Safety population (Safety) ..............................................................................................26 
6.3 Per-Protocol population (PP) ..........................................................................................26 
6.4 PK population .................................................................................................................27 
6.5 Other Populations Defined for Tables and Listings........................................................27 
6.6 Protocol deviations/violations and exclusions from analysis sets ..................................27 
7 Statistical Considerations and analysis ....................................................................................28 
7.1 Derived Variables ...........................................................................................................28 
7.1.1 Study days ...........................................................................................................28 
7.1.2 Follow-up time ....................................................................................................28 
7.1.3 Definitions relative to demographic and other baseline characteristics..............28 
7.1.3.1 Age ......................................................................................................................28 
7.1.3.2 Weight, height and BMI......................................................................................28 
7.1.3.3 Temperature ........................................................................................................28 
7.1.3.4 Smoking duration ................................................................................................28 
7.1.3.5 COPD disease duration .......................................................................................28 
7.1.3.6 Current COPD exacerbation duration .................................................................29 
7.1.3.7 Times from start/stop of current COPD exacerbation to first dosing .................29 


 
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7.1.3.8 Time since last documented COPD exacerbation...............................................29 
7.1.4 Definitions relative to efficacy criteria ...............................................................29 
7.1.4.1 COPD exacerbation (moderate and severe) ........................................................29 
7.1.4.2 FEV1 normalisation ............................................................................................29 
7.1.4.3 FEV1/FVC normalisation ...................................................................................30 
7.1.4.4 Time to improvement in FEV1 value .................................................................30 
7.1.4.5 Standardised Area Under Curve (AUC) of FEV1 ..............................................31 
7.1.4.6 Respiratory Rate (RR) normalisation..................................................................32 
7.1.4.7 Questionnaire EXACT-PRO...............................................................................32 
7.1.4.8 Time to improvement/recovery based on EXACT-PRO total score ..................33 
7.1.4.9 Standardised AUC of EXACT-PRO Total Score ...............................................33 
7.1.4.10 
Time to next COPD exacerbation ..................................................35 
7.1.4.11 
Time from hospitalisation admission until subject is medically 
ready for discharge (current COPD) ...................................................................36 
7.1.4.12 
Percentage of days with intake of COPD rescue therapy ..............36 
7.1.4.13 
Clinical treatment failure (exploratory composite endpoint) .........37 
7.1.4.14 
Time to clinical treatment failure...................................................39 
7.1.4.15 
Chronic Respiratory Questionnaire (CRQ)....................................40 
7.1.4.16 
Cumulative oral/IV steroid dose ....................................................41 
7.1.4.17 
BODE index ...................................................................................41 
7.1.5 Definitions relative to safety parameters ............................................................42 
7.1.5.1 Adverse Event (AE) ............................................................................................42 
7.1.5.2 Serious Adverse Event (SAE).............................................................................43 
7.1.5.3 Duration of AEs ..................................................................................................43 
7.1.5.4 Relationship of AEs ............................................................................................43 
7.1.5.5 Intensity of AEs ..................................................................................................44 
7.1.5.6 Adverse Event of Special Interest (AESI) ..........................................................44 
7.2 Handling of missing data and outliers ............................................................................44 
7.2.1 Missing data analysis methods............................................................................44 
7.2.2 Handling of missing or incomplete dates............................................................44 
7.2.2.1 Partial dates of first COPD diagnosis .................................................................44 
7.2.2.2 Partial dates of current COPD exacerbation symptoms start/stop ......................44 
7.2.2.3 Concomitant medications definitions and handling of missing or incomplete 
dates ....................................................................................................................45 
7.2.2.4 Definition of treatment-emergent AEs and handling of missing or 
incomplete dates..................................................................................................45 
7.2.2.5 Time since last documented COPD exacerbation...............................................46 
7.2.3 Missing items in a questionnaire (CRQ) within a patient/visit ...........................46 
7.2.4 Handling of changes in study endpoints due to protocol amendments...............46 
8 STATISTICAL METHODS ....................................................................................................47 
8.1 General statistical conventions........................................................................................47 
8.1.1 Populations for analysis ......................................................................................47 
8.1.2 Treatment groups ................................................................................................47 


 
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8.1.3 Descriptive statistics ...........................................................................................47 
8.1.4 Statistical significance.........................................................................................48 
8.1.5 Definitions of Baseline........................................................................................48 
8.1.6 Visit dates............................................................................................................48 
8.1.7 Data re-allocation ................................................................................................49 
8.1.8 Exclusion of data from the statistical analysis ....................................................49 
8.1.9 Data listings.........................................................................................................49 
8.2 Subject disposition ..........................................................................................................49 
8.3 Protocol deviations..........................................................................................................50 
8.4 Demographics and baseline characteristics.....................................................................50 
8.4.1 Demographics .....................................................................................................50 
8.4.2 Smoking status ....................................................................................................50 
8.4.3 COPD history ......................................................................................................51 
8.4.4 Baseline treatment for COPD .............................................................................51 
8.4.5 Current COPD exacerbation data........................................................................51 
8.4.6 Spirometry at Screening and Visit 1 Pre-dose ....................................................51 
8.4.7 EXACT-PRO at Visit 1 Pre-dose .......................................................................52 
8.4.8 CRQ at Visit 1 Pre-dose......................................................................................52 
8.4.9 BODE index at Visit 1 Pre-dose .........................................................................52 
8.4.10 Other Baseline and disease characteristics..........................................................52 
8.4.11 Medical history and concomitant diseases..........................................................52 
8.4.12 Prior and concomitant medications.....................................................................52 
8.4.13 Vital signs at Screening and Visit 1 Pre-dose .....................................................53 
8.4.14 12-lead ECG at Screening and Visit 1 Pre-dose .................................................53 
8.4.15 Eosinophils at Screening and Visit 1 Pre-dose ...................................................53 
8.5 Extent of exposure ..........................................................................................................54 
8.5.1 Treatment duration ..............................................................................................54 
8.5.2 Treatment compliance.........................................................................................54 
8.6 Efficacy analyses.............................................................................................................54 
8.6.1 Analysis methods ................................................................................................54 
8.6.1.1 Multiplicity..........................................................................................................55 
8.6.1.2 Treatment by center interaction analysis (multi-center study)............................55 
8.6.2 Analysis of primary efficacy endpoint(s)............................................................55 
8.6.2.1 Primary analysis ..................................................................................................55 
8.6.2.2 Descriptive analysis ............................................................................................57 
8.6.2.3 Sensitivity analyses .............................................................................................58 
8.6.3 Analysis of secondary efficacy endpoint(s) ........................................................59 
8.6.3.1 Comparison of FEV1 on Days 3, 10, and 14 ......................................................59 
8.6.3.2 Normalisation of spirometry parameters over time compared with the most 
recent test performed within the last 12 months outside an exacerbation ..........60 
8.6.3.3 Time to improvement in FEV1 value over time .................................................60 
8.6.3.4 Standardised AUC of FEV1 over time ...............................................................61 
8.6.3.5 Normalisation of RR over time (daily from Days 1 to 7, 10 and 14) .................61 


 
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8.6.3.6 Change in RR on Days 3, 7, 10 and 14 ...............................................................62 
8.6.3.7 Time to improvement based on EXACT-PRO total score..................................62 
8.6.3.8 Time to recovery based on EXACT-PRO total score .........................................63 
8.6.3.9 Standardised AUC of EXACT-PRO over time ..................................................63 
8.6.3.10 
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......................................................................................................64 
8.6.3.11 
Number of COPD-related exacerbations during the study 
derived from ‘Acute Exacerbation COPD’ form of the eCRF ...........................64 
8.6.3.12 
Number of COPD-related deaths during the study ........................66 
8.6.3.13 
Time to next COPD exacerbation ..................................................66 
8.6.3.14 
Time from hospitalisation admission until the subject is 
medically ready for discharge (current COPD) ..................................................67 
8.6.3.15 
Percentage of days with intake of COPD rescue therapy ..............68 
8.6.4 Analysis of exploratory endpoint(s)....................................................................68 
8.6.4.1 Exploratory composite scale endpoints at Weeks 8, 12 and 26 ..........................68 
8.6.4.2 Change in CRQ from Baseline at Day 14 and Weeks 8, 12 and 26 ...................69 
8.6.4.3 Cumulative oral/IV steroid dose during the duration of current COPD 
exacerbation ........................................................................................................70 
8.6.4.4 Change in inflammatory blood biomarkers ........................................................71 
8.6.4.5 Change from Baseline in mMRC dyspnoea scale over time ..............................71 
8.6.4.6 BODE index at Day 14 .......................................................................................72 
8.7 Safety analyses ................................................................................................................72 
8.7.1 Adverse events ....................................................................................................73 
8.7.2 Clinical laboratory evaluations ...........................................................................74 
8.7.3 Vital signs ...........................................................................................................77 
8.7.4 Physical examinations.........................................................................................77 
8.7.5 Electrocardiograms .............................................................................................77 
8.7.6 Sputum for microbiology culture ........................................................................77 
8.7.7 Other safety assessments.....................................................................................78 
8.8 Other analysis..................................................................................................................78 
8.8.1 Efficacy analyses based on acute exacerbations of COPD adjudication ............78 
8.8.2 PK/PD analyses...................................................................................................79 
8.8.3 Subgroup analysis ...............................................................................................79 
8.9 Interim analysis ...............................................................................................................80 
9 CHANGES TO PLANNED ANALYSIS FROM STUDY PROTOCOL ...............................81 
10 REFERENCES ........................................................................................................................82 
11 APPENDICES .........................................................................................................................83 
 
 


 
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Protocol Number: MBCT206 
               Version: FINAL 2.0, Date: 16 November 2017 
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LIST OF ABBREVIATIONS 
 
The following abbreviations will be used within this SAP. 
 
Abbreviation or 
special term 
Explanation 
ADaM 
Analysis Dataset Model 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
BODE 
Body mass index, airflow Obstruction, Dyspnoea and Exercise index 
BUN 
Blood Urea Nitrogen 
CDISC 
Clinical Data Interchange Standards Consortium 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Confidence Interval 
COPD 
Chronic Obstructive Pulmonary Disease 
CRF 
Case Report Form 
CRQ 
Chronic Respiratory Questionnaire 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
CTF 
Clinical Treatment Failure 
CTMS 
Clinical Trial Management System 
DBL 
Database Lock 
DBP 
Diastolic Blood Pressure 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 


 
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ER 
Emergency Room 
E-R 
Exposure-Response 
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 
GOLD 
Global initiative for chronic Obstructive Lung Disease 
HR 
Heart Rate 
Hs-CRP 
High-sensitivity C-Reactive Protein 
IAC 
Independent Adjudication Committee 
ICH 
International Conference on Harmonisation 
ICS 
Inhaled Corticosteroid 
ICU 
Intensive Care Unit 
IL-6 
interleukin-6 
IMP 
Investigational Medicinal Product 
INR 
International Normalised Ratio 
IRT 
Interactive Response Technology 
ITT 
Intention-To-Treat 
IV 
intravenous 
kg 
Kilogram 
LABA 
Long-Acting β2-Agonist 
LLOQ 
Lower Limit of Quantification 
LS 
Least Square 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
millilitre 
mMRC 
modified Medical Research Council 
MMRM 
Mixed Model for Repeated Measurements 
MOV 
Maximum Observed Value 
MPO 
Myeloperoxidase 


 
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NCS 
Not Clinically Significant 
OC 
Observed Cases 
PD 
Pharmacodynamic 
PFT 
Pulmonary Function Test 
PK 
Pharmacokinetic 
PoC 
Proof of Concept 
PP 
Per-Protocol 
PR 
Time interval between the onset of the P wave and the beginning of the QRS 
complex 
PRO 
Patient Reported Outcome 
PT 
Preferred Term 
QRS 
Time interval between the beginning of the Q wave and the termination of the 
S wave 
QTc 
corrected QT interval of the electrocardiogram 
QTcB 
Bazett-corrected time interval between the Q and T waves 
QTcF 
Fridericia-corrected time interval between the Q and T waves 
RBC 
Red Blood Cell 
RR 
Respiratory Rate 
SABA 
Short-Acting 2-Agonist 
SAMA 
Short-Acting Muscarinic Antagonist 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SE 
Standard Error 
SI 
Standard International 
SoC 
Standard of Care 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TFLs 
Tables, Figures and Listings 
TNF- 
Tumour Necrosis Factor-alpha 


 
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ULN 
Upper Limit Normal 
ULOQ 
Upper Limit of Quantification 
WBC 
White Blood Cell 
WHO 
World Health Organisation 
6MWT 
6-Minute Walk Test 
β-HCG 
Beta-Human Chorionic Gonadotropin 


 
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1 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide detailed descriptions of the statistical 
methods, data derivations and data displays for study protocol No. MBCT206: 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.  
This analysis plan is based on the final protocol version 1.0 dated 05 November 2015, final protocol 
version 2.0 (amendment 1) dated 23 December 2015, final protocol version 3.0 (amendment 2) dated 
10 March 2016, final protocol version 4.0 (amendment 3) dated 26 May 2016, and final protocol 
version 5.0 (amendment 4) dated 08 November 2016.  
A summary of the key changes to each protocol amendment is presented in Appendix A. 
The table of contents and templates for the Tables, Figures and Listings (TFLs) will be produced in a 
separate document.  
Any deviations from this SAP will be described and justified in the Clinical Study Report (CSR). 
The preparation of this SAP has been based on International Conference on Harmonisation (ICH) 
E91. 
All data analyses and generation of TFLs will be performed using SAS 9.4® or higher. 
Note: This plan does not address the pharmacokinetic (PK)/pharmacodynamic (PD) analyses of 
BCT197 (nonlinear mixed effects PK/PD modelling) for this study. These analyses will be detailed in 
a separate analysis plan and results from the PK/PD modelling will be reported separately from the 
CSR. 
 
 


 
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2 
STUDY OBJECTIVES 
2.1 
Primary objective 
The primary objective is 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 one second (FEV1) from baseline (pre-dose) to Day 7. 
2.2 
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: 
Efficacy of BCT197: 
1. Comparison of FEV1 on Days 3, 10, and 14 
2. Normalisation evaluation of spirometry parameter (FEV1 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 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) 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 admission until subject is medically ready (COPD-related) 
for discharge 
15. To characterize 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)/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 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. 
2.3 
Exploratory objectives 
Exploratory assessments will evaluate: 
1. Exploratory composite scale endpoints comparing among the three groups at Weeks 8, 12 and 
26: 
 
Number of events of worsening of symptoms warranting the addition of antibiotics 
 
Number of events of worsening of symptoms warranting an increase of oral dose of 
corticosteroids or initiation of new oral corticosteroids 
 
Number of events of worsening of symptoms requiring additional treatment with oral 
corticosteroids and/or antibiotics after completion of the initial regimen  
 
Number of events of COPD exacerbations that required re-hospitalisation  
 
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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3 
STUDY DESIGN 
3.1 
General study design 
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 100 centres in 12 countries (includes 
Europe [Germany, Italy, UK and some Central and Eastern European countries], Argentina and US). 
It is planned that approximately 320 subjects will be screened to randomise approximately 270 
subjects, and expected that approximately 255 subjects will complete the study and follow-up. Only 
hospitalised subjects will be recruited. 
Study is divided into 2 parts: 
Acute Exacerbation Phase: from Day 1 (Randomisation day) until Day 14. Drug Administration will 
be done at days 1, 3 and 5. 
Stabilisation Phase: requires subject evaluations at Weeks 8, 12 and 26. 
The Study Flow Chart is presented in Figure 1. 
 
Figure 1: Study Flow Chart 
 
 
 


 
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3.2 
Randomisation and blinding 
3.2.1 Randomisation 
This is a double-blind and randomised study. Each patient will be randomised in a 1:1:1 ratio to 
receive 1 of 2 BCT197 treatment schedules or Placebo. At Visit 1 all eligible subjects will be 
randomised via Interactive Response Technology (IRT) to one of the treatment regimens. The 
investigator or his/her delegate will contact the IRT after confirming that the subject meets all the 
inclusion criteria and none of the 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. 
3.2.2 Blinding 
Study Blinding is done 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. 
3.2.3 Unblinding 
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. Unblinding is 
permissible after database lock or in case of emergency only (with the exception of unblinded DMC 
staff/members - Refers to SAP Section 8.9 ‘Interim analysis’). Emergency treatment code breaks 
should only be undertaken when it is essential to treat the subject safely and efficaciously. Emergency 
code breaks are performed using the IRT.  
Moreover, the randomisation codes associated with each subject will be disclosed to PK analysts who 
will keep PK results confidential until database lock. 
3.3 
Study treatments and assessments 
Study is planned for 26 weeks duration in adult subjects with acute respiratory exacerbations in 
COPD and divided into two parts: Acute Exacerbation Phase and Stabilisation Phase. All subjects are 
planned to be treated with test product or placebo on 
 after randomisation. Subjects 
will be screened for up to 24 hours and will be followed daily in the first week, at days 10 and 14, and 
up to 8, 12 and 26 weeks (+/- 3 days) post-treatment. A total of 12 visits are planned for the two parts 
of the study. 
 


 
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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 and fulfilling the study entry criteria. 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. 
Day 1 to Day 14 – Acute Exacerbation Phase: 
Subjects will undergo all safety and efficacy assessments on Day 1. Physical examinations, 12-lead 
electrocardiograms (ECGs), pulmonary function test (PFT; spirometry), and blood sampling for 
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 Days 1-7. 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. The subject should receive a diary 
on Day 1 after Randomisation to document any occurrences of COPD and rescue medication 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. 
Subjects randomised to the placebo arm will be administered two matching placebo capsules that are 
identical to the test product in appearance but contain no active treatment. The placebo should be 
taken orally with fluids on days 1, 3 and 5 after randomisation, preferably at the same time each day. 
Weeks 8, 12 and 26 – Stabilisation Phase: 
Subjects will return to the facility for 3 follow-up visits at Weeks 8, 12 and 26, at which time the 
required assessments/procedures will be done. 
Rescue Medication: 
All subjects will be treated as per institution SoC, 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 during the study. 


 
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A detailed description of procedures and assessments to be conducted during this study is summarised 
in the Schedule of Study Assessments in Table 1 below (refers to study protocol Final V5.0). 
 


 
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Table 1: Schedule of Study Assessments 
 


 
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4 
STUDY ENDPOINTS 
4.1 
Primary efficacy endpoint 
The primary efficacy endpoint of this study is the change in FEV1 from baseline (pre-dose) to 
Day 7. 
4.2 
Secondary efficacy endpoints 
The secondary efficacy endpoints of this study are: 
1. Comparison of FEV1 on Days 3, 10, and 14 
2. Normalisation evaluation of spirometry parameter (FEV1 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 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 normalisation 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 
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 admission until the subject is medically ready (COPD-related) 
for discharge 
15. Nonlinear mixed effects pharmacokinetic/pharmacodynamic (PK/PD) models evaluating 
the relationship between BCT197 exposure and efficacy/safety endpoints. 
4.3 
Exploratory endpoints 
The exploratory endpoints of this study are: 
1. Exploratory composite scale comparing the following among the three groups at Week 8, 
12 and 26: 
 
Number of events of worsening symptoms warranting the addition of antibiotics 
 
Number of events of worsening symptoms warranting an increase in dose of oral 


 
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corticosteroids or initiation of new oral corticosteroids 
 
Number of events of worsening symptoms requiring additional treatment of oral 
corticosteroids and/or antibiotics after completion of the initial regimen 
 
Number of events of COPD exacerbation requiring re-hospitalisation 
 
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-, 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. 
4.4 
Safety endpoints 
The safety endpoints of this study are: 
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. 
 
 


 
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5 
SAMPLE SIZE AND POWER 
The sample size is based on a formal statistical calculation using the following assumptions: 
1. Endpoint: Absolute change in FEV1 (mL) from baseline to Day 7 
2. Minimum clinically significant difference between regimens: absolute change of 100 mL 
3. Standard deviation (SD) of the difference = 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. 


 
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6 
ANALYSIS POPULATIONS 
All primary and secondary efficacy endpoints will be analysed using the intention-to-treat (ITT) 
population. The Per-Protocol (PP) population will be used for the analysis of the primary endpoint 
to examine the robustness of the primary analyses. A PP analysis will also be performed on the 
secondary and exploratory efficacy endpoints for this Proof of Concept (PoC) and hypothesis-
generating study. 
Safety and tolerability will be analysed using the safety population.  
Pharmacokinetic data will be analysed using the PK population. 
6.1 
Intention-To-Treat population (ITT) 
The ITT population includes all subjects who: 
 
Are randomised, and 
 
Receive at least one dose of study medication, and 
 
Provide a Baseline and at least one post-Baseline FEV1 value. 
Patients will be included in the analysis per the treatment to which they were randomised. 
Note: the ‘Baseline’ FEV1 value refers to the last non-missing FEV1 value assessed prior to the 
first dose of study medication. 
6.2 
Safety population (Safety) 
The safety population includes all subjects who received at least one administration of the study 
medication. 
Patients will be included in the analysis per the treatment actually/1st received. 
6.3 
Per-Protocol population (PP) 
The PP population is a subset of the ITT population and includes all randomised subjects who have 
been treated according to the protocol and fulfil the following criteria (i.e. no major protocol 
deviations): 
 
Key inclusion/exclusion criteria met with respect to factors likely to affect the assessment 
of efficacy in the intended target population 
 
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 
 
Adequate study medication compliance (i.e. full treatment regimen; all 3 doses of study 
drug received on Days 1, 3, and 5) 
 
Adequate measurement of the primary variable (i.e. Baseline and Day 7 FEV1 values 
provided). 


 
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Patients will be included in the analysis per the treatment to which they were randomised. 
6.4 
PK population 
For the nonlinear mixed effects modelling, all subjects who received at least one dose 
administration and have at least one quantifiable plasma concentration will be included. 
6.5 
Other Populations Defined for Tables and Listings 
For the purposes of tables and listings a further three populations are defined: 
 
All screened patients 
 
Screening failure patients 
 
Randomised population (all randomised patients). 
6.6 
Protocol deviations/violations and exclusions from analysis sets 
All violations and exclusions of patients from analysis populations will be finalised at the 
Classification Meeting prior to the final database lock (DBL)/study unblinding, through clinical 
review input provided by Mereo, using the following sources of information: 
 
Supportive patient listings, provided by the ICON lead statistician ahead of the 
Classification Meeting, based on data recorded on the eCRF. 
The protocol deviations criteria are detailed in Appendix B and specific protocol deviations 
will be identified by programming. 
 
Protocol Deviation Logs, retrieved from Clinical Trial Management System (CTMS). 
Further, deviations from protocol will be classified as major or minor.  


 
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7 
STATISTICAL CONSIDERATIONS AND ANALYSIS 
7.1 
Derived Variables 
7.1.1 Study days 
Study days will be based on the date of first IMP administration (Study Day 1) and calculated as:  
 
(assessment date – date of first IMP administration) + 1, for assessments on or after the 
first IMP administration date 
 
(assessment date – date of first IMP administration), for assessments prior to first IMP 
administration date. 
7.1.2 Follow-up time 
Follow-up time (days) will be calculated as:  
(date of last contact - date of first IMP administration) + 1 
7.1.3 Definitions relative to demographic and other baseline characteristics 
7.1.3.1 Age 
Age at informed consent will be calculated as:  
Age (years) = (date of informed consent - date of birth + 1) / 365.25 
7.1.3.2 Weight, height and BMI 
Weight, recorded in pounds on the eCRF, will be converted in kilograms (1 pound = 0.45359 kg). 
Height, recorded in inches on the eCRF, will be converted in centimetres (1 inch = 2.54 cm) 
(International System of Units). 
Body mass index (BMI) will be calculated in kg/m2 as: weight (kg)/(height (m))2. 
7.1.3.3 Temperature 
Temperature, recorded in Fahrenheit degrees on the eCRF, will be converted in Celsius degrees: 
Celsius degrees = (Fahrenheit degrees - 32) x (5/9) 
7.1.3.4 Smoking duration 
Duration of smoking will be calculated in years as: 
 
Current smoker: (Current Year - Year when subject started smoking) + 1 
 
Ex-smoker: (Year when subject stopped smoking - Year when subject started smoking) + 1 
7.1.3.5 COPD disease duration 
Duration of COPD disease will be calculated in years as: 
(date of informed consent – date of first diagnosis of COPD + 1) / 365.25 


 
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7.1.3.6 Current COPD exacerbation duration 
 
Duration of current COPD exacerbation symptoms will be calculated in days as:  
(date when symptoms stopped – date when symptoms started + 1) 
 
Time until complete recovery from the current COPD exacerbation will be calculated in 
days as:  
(date when patient achieved complete recovery from the current exacerbation – date when 
symptoms started). 
Where ‘Date when symptoms started’, ‘Date when symptoms stopped’, and ‘Date when patient 
achieved complete recovery from the current exacerbation’ are recorded on the ‘Current COPD 
Exacerbation’ form of the eCRF. 
7.1.3.7 Times from start/stop of current COPD exacerbation to first dosing 
Times from start/stop of current COPD exacerbation symptoms to first dose of study medication 
will be calculated in days as: 
(date of first study treatment dose – date when symptoms started/stopped). 
7.1.3.8 Time since last documented COPD exacerbation 
Time since last documented COPD exacerbation will be calculated in months as: 
(date of informed consent – date of last documented COPD exacerbation + 1) / 30.4375 
7.1.4 Definitions relative to efficacy criteria 
7.1.4.1 COPD exacerbation (moderate and severe) 
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: 
 
Moderate: exacerbations that require treatment with systemic corticosteroids and/or 
antibiotics 
 
Severe: exacerbations that require hospitalisation or result in death. 
7.1.4.2 FEV1 normalisation 
FEV1 normalisation is achieved if FEV1 returns to a value ≥ 89%3 of the most recent FEV1 value 
measured within the last 12 months outside an exacerbation (pre-study FEV1 value). 
 
 


 
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7.1.4.3 FEV1/FVC normalisation 
FEV1/FVC normalisation is achieved if FEV1/FVC returns to a value ≥ 89%3 of the most recent 
FEV1/FVC value measured within the last 12 months outside an exacerbation (pre-study 
FEV1/FVC value). 
7.1.4.4 Time to improvement in FEV1 value 
7.1.4.4.1 Time to improvement of 100 mL in FEV1 
This is defined as the time (in days) from initiation of study treatment until the change in FEV1 is ≥ 
+ 100 mL (improvement). 
Change in FEV1 = FEV1 value (time T) – FEV1 value (baseline). 
Table 2-1: Criteria for event/censored for assessment of Time to improvement of 100 mL 
(FEV1) 
Situation 
Date of event or 
Censoring 
Time to improvement of 100 mL 
Outcome 
Subjects who meet criteria 
of change in FEV1 ≥ + 100 
mL 
Date when the 
criteria is met 
Time from initiation of study 
treatment until Date when the 
aforesaid criteria is met 
Event 
Subjects who never meet 
change in FEV1 ≥ + 100 
mL 
Date of the last 
evaluable 
spirometry  
Time from initiation of study 
treatment until Date of the last 
evaluable spirometry  
Censored 
Subjects who died 
Death date 
Time from initiation of study 
treatment until Date of death 
Censored 
Subjects who withdrew or 
were lost to follow-up 
during the study 
Withdrawal or last 
contact date 
Time from initiation of study 
treatment until Date of withdrawal or 
last contact date 
Censored 
7.1.4.4.2 Time to improvement of 80 mL in FEV1 
This is defined as the time (in days) from initiation of study treatment until the change in FEV1 is ≥ 
+ 80 mL (improvement). 
Change in FEV1 = FEV1 value (time T) – FEV1 value (baseline). 
 
 


 
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Table 2-2: Criteria for event/censored for assessment of Time to improvement of 80 mL 
(FEV1) 
Situation 
Date of event or 
Censoring 
Time to improvement of 80 mL 
Outcome 
Subjects who meet criteria 
of change in FEV1 ≥ + 80 
mL 
Date when the 
criteria is met 
Time from initiation of study 
treatment until Date when the 
aforesaid criteria is met 
Event 
Subjects who never meet 
change in FEV1 ≥ + 80 mL 
Date of the last 
evaluable 
spirometry  
Time from initiation of study 
treatment until Date of the last 
evaluable spirometry  
Censored 
Subjects who died 
Death date 
Time from initiation of study 
treatment until Date of death 
Censored 
Subjects who withdrew or 
were lost to follow-up 
during the study 
Withdrawal or last 
contact date 
Time from initiation of study 
treatment until Date of withdrawal or 
last contact date 
Censored 
7.1.4.5 Standardised Area Under Curve (AUC) of FEV1 
AUC will be calculated according to the trapezoidal rule. The trapezoidal rule is a numerical 
method to be used to approximate the integral or the area under a curve. Using trapezoidal rule to 
approximate the area under a curve first involves dividing the area into a number of strips of equal 
width. Then, approximating the area of each strip by the area of the trapezium formed when the 
upper end is replaced by a chord. The sum of these approximations gives the final numerical result 
of the area under the curve. 
The (standardised) AUC of the FEV1 will be calculated from Day (a) to Day (b) using the 
trapezoidal rule as follows: 
 
 
Missing values for the calculation of FEV1 AUC will be handled as follows: 
- 
If single or more intermediate values are missing between two non-missing values, they 
will be ignored and the component of the AUC will be calculated between 2 days for this 
part of the curve.  
- 
If FEV1 value at Day 1 pre-dose (baseline) is missing then the AUC will be missing. 


 
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- 
For the Day 1 – 3 AUC, Day 1 – 7 AUC, Day 1 – 10 AUC and Day 1 – 14 AUC: if < 50% 
of values are available from Day 1 pre-dose (baseline), then the AUC will be set as 
missing. 
7.1.4.6 Respiratory Rate (RR) normalisation 
RR is normalised if RR returns to a baseline plateau level achieved after the acute COPD 
exacerbation during the Stabilisation Phase. This baseline plateau value is defined on a patient 
basis, and corresponds to the mean of the 3 RR values recorded during the Stabilisation Phase for 
each patient (mean of RR at Weeks 8, 12 and 26). Only 1 of the 3 data points needs to be present 
for this computation. In the case that all three RR values are missing during the Stabilisation Phase 
for a patient, the baseline plateau value will be set to 20 breaths/min2. 
To summarise, RR is normalised if RR returns to a value ≤ P breaths/min; where P (“Plateau”) 
equals to: 
 
mean of RR at Weeks 8, 12 and 26 (on a patient basis) 
 
20 breaths/min, if all three RR values at Weeks 8, 12 and 26 are missing. 
7.1.4.7 Questionnaire EXACT-PRO 
The EXACT is a 14-item patient reported outcome (PRO) daily diary used to quantify and measure 
exacerbations of COPD (Mackay 20144). 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 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. 
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. 
EXACT Total Score 
An EXACT Total score is computed for each day of diary collection. The EXACT Total score is 
based on a logit scoring system with conversion to a 0 to 100 scale for ease of interpretation and 
use. The total score is used in the determination of exacerbation frequency, severity and duration of 
exacerbation. Specifically, changes in the total score are used to define onset and recovery from an 
exacerbation event and the magnitude of that event. 
 
 


 
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EXACT Domain Scores 
Additional information regarding the patient’s condition can be obtained through 3 domain scores 
embedded within the EXACT measure: Breathlessness, Cough & Sputum, and Chest Symptoms. 
These scores also range from 0 to 100 with higher scores indicating more severe symptoms. 
Appendix C describes the EXACT raw scores and EXACT scoring instructions to compute the 
EXACT daily scores and event frequency, duration and severity. 
7.1.4.8 Time to improvement/recovery based on EXACT-PRO total score 
Table 3: 
Criteria for event/censored for assessment of Time to improvement/recovery 
(EXACT-PRO) 
Situation 
Date of event or 
Censoring 
Time 
to 
improvement/recovery 
(EXACT-PRO) 
Outcome 
Subjects who had current 
COPD 
exacerbation 
improved/recovered 
over 
the observed period 
Date 
of 
improvement/ 
recovery 
of 
current 
COPD 
exacerbation 
Time from initiation of study treatment 
until Date of improvement/recovery of 
current COPD exacerbation 
Event 
Subjects who never had 
current COPD exacerbation 
improved/recovered 
over 
the observed period 
Date of the last 
evaluable 
EXACT-PRO 
assessment 
Time from initiation of study treatment 
until 
Date of the last evaluable 
EXACT-PRO assessment 
Censored 
Subjects who died over the 
observed period 
Death date 
Time from initiation of study treatment 
until Date of death 
Censored 
Subjects who withdrew or 
were lost to follow-up over 
the observed period 
Withdrawal or last 
contact date 
Time from initiation of study treatment 
until Date of withdrawal or last contact 
date 
Censored 
7.1.4.9 Standardised AUC of EXACT-PRO Total Score 
The (standardized) AUC of the EXACT-PRO will be calculated from Day (a) to Day (b) using the 
trapezoidal rule as follows: 
 


 
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AUCs for EXACT-PRO subscores will also be calculated. 
Missing values for the calculation of EXACT-PRO score and subscores AUCs will be handled as 
follows:  
- 
If single or more intermediate value is missing between two non-missing values, they will 
be ignored and the component of the AUC will be calculated between 2 days for this part 
of the curve.  
- 
If baseline EXACT-PRO rolling average (i.e. EXACT-PRO score at Day 1) is missing then 
the AUC will be missing. 
- 
For the Day 1 – 3 AUC:  
o if < 50% of rolling average values are available from Day 1, then the AUC will be 
set as missing. 
o if the rolling average is missing at Day 3 then the average between the Rolling 
Average at Day 2 and the Rolling Average at Day 4 will be used in the AUC 
calculation in place of the Rolling Average at Day 3. 
- 
For the Day 1 – 5 AUC:  
o if < 50% of rolling average values are available from Day 1, then the AUC will be 
set as missing. 
o if the rolling average is missing at Day 5 then the average between the Rolling 
Average at Day 4 and the Rolling Average at Day 6 will be used in the AUC 
calculation in place of the Rolling Average at Day 5. 
- 
For the Day 1 – 7 AUC:  
o if < 50% of rolling average values are available from Day 1, then the AUC will be 
set as missing. 
o if the rolling average is missing at Day 7 then the average between the Rolling 
Average at Day 6 and the Rolling Average at Day 8 will be used in the AUC 
calculation in place of the Rolling Average at Day 7. 
- 
For the Day 1 – 10 AUC:  
o if < 50% of rolling average values are available from Day 1, then the AUC will be 
set as missing. 
o if the rolling average is missing at Day 10 then the average between the Rolling 
Average at Day 9 and the Rolling Average at Day 11 will be used in the AUC 
calculation in place of the Rolling Average at Day 10. 
- 
For the Day 1 – 14 AUC:  
o if < 50% of rolling average values are available from Day 1, then the AUC will be 
set as missing. 
o if the rolling average is missing at Day 14 then the average between the Rolling 
Average at Day 13 and the Rolling Average at Day 15 will be used in the AUC 
calculation in place of the Rolling Average at Day 14. 


 
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- 
For the Day 1 – 29 AUC: 
o  if the rolling average is missing at Day 29 no further imputation will be performed 
and the Day 29 will be considered missing in the calculation of the AUC. 
7.1.4.10 Time to next COPD exacerbation 
The time to next COPD exacerbation (in days) is defined as: 
(Date when first COPD exacerbation symptoms started – Date when current COPD exacerbation 
symptoms stopped), 
where COPD exacerbations experienced during the study are recorded on the ‘Acute Exacerbation 
COPD’ form of the eCRF, i.e.: 
 
Start date of COPD exacerbation is the ‘date when symptoms started’ recorded on the form 
 
COPD exacerbation has an intensity recorded as ‘Mild’, ‘Moderate’ or ‘Severe’ on the 
form. 
Table 4: 
Criteria for event/censored for assessment of Time to next COPD exacerbation 
Situation 
Date of event or 
Censoring 
Time to next COPD exacerbation 
Outcome 
Subjects who had next 
COPD exacerbation 
Date 
of 
next 
COPD 
exacerbation after 
entering in study 
Time 
from when current COPD 
exacerbation symptoms stopped until 
Date of next COPD exacerbation after 
entering in study 
Event 
Subjects who never had 
COPD 
exacerbation 
in 
study period 
Withdrawal or last 
contact date 
Time 
from when current COPD 
exacerbation symptoms stopped until 
Date of withdrawal or last contact date 
Censored 
Subjects who died 
Death date 
Time 
from when current COPD 
exacerbation symptoms stopped until 
Date of death 
Censored 
Subjects who withdrew or 
were 
lost 
to 
follow-up 
during the study 
Withdrawal or last 
contact date 
Time 
from when current COPD 
exacerbation symptoms stopped until 
Date of withdrawal or last contact date 
Censored 
 
 


 
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7.1.4.11 Time from hospitalisation admission until subject is medically ready 
for discharge (current COPD) 
This time (in days) will be calculated as: 
(Date subject is medically ready for discharge from hospital – Date of hospitalisation admission), 
where ‘Date of hospitalisation admission’ and ‘Date subject is medically ready for discharge from 
hospital’ are recorded on the ‘Current COPD Exacerbation’ form of the eCRF. 
Table 5: 
Criteria for event/censored for assessment of Time from hospitalisation admission 
until subject is medically ready for discharge (current COPD) 
Situation 
Date of event or 
Censoring 
Time from hospitalisation admission 
until subject is medically ready for 
discharge 
Outcome 
Subjects 
who 
were 
medically 
ready 
for 
discharge from hospital 
Date 
subject is 
medically 
ready 
for discharge 
Time from hospitalisation admission 
until Time subject is medically ready 
for discharge 
Event 
Subjects who were not 
medically 
ready 
for 
discharge from hospital 
Withdrawal or last 
contact date 
Time from hospitalisation admission 
until Date of withdrawal or last contact 
date 
Censored 
Subjects who died 
Death date 
Time from hospitalisation admission 
until Date of death 
Censored 
Subjects who withdrew or 
were 
lost 
to follow-up 
during the study 
Withdrawal or last 
contact date 
Time from hospitalisation admission 
until Date of withdrawal or last contact 
date 
Censored 
7.1.4.12 Percentage of days with intake of COPD rescue therapy 
Patients will complete the EXACT-PRO starting from Study Day 1 and will record rescue 
medication use and any occurrences of COPD once a day (evening) in the diary. The percentage of 
days with intake of rescue medications will be evaluated on the basis of the information recorded 
daily by the patient on the diaries. 
A day will be considered with intake of rescue medications if the answer to the question “How 
many puffs of rescue medication did you take since last evening?” is > 0.  
Inter-Visit Period: 
For the calculation of the percentage of days, the inter-visit periods are defined as below: 
 
 


 
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Inter-visit period visit i - visit i+1 (1 ≤ i ≤ 11) 
Date of start of the period 
Date of end the period 
 If i=1 then date of start = date of Study 
Day 1. 
 
Else date of start = date of visit i. 
 
If visit i is NOT the last clinic visit 
performed before the End of Study then 
date of end = date of visit i+1 – 1 day (i.e., 
the day before visit i+1). 
 
Else date of end = date of End of Study. 
This includes the case date of visit i+1 = 
date of End of Study. 
On a per patient basis, the percentage of days in each inter-visit period will be calculated using the 
following formula:  
 
% of days with rescue medication (inter-visit period) = (Number of days with rescue 
medication during the inter-visit period / Number of days with data recorded during the 
inter-visit period)*100. 
Acute Exacerbation Phase: 
 
Percentage of days: data recorded from Study Day 1 to the day before Visit 9/Day 14 will 
be considered as data of the Acute Exacerbation Phase. 
On a per patient basis, the percentage of days in the Acute Exacerbation Phase will be calculated 
using the following formula:  
 
% of days with rescue medication (Acute Exacerbation Phase) = (Number of days with 
rescue medication during the Acute Exacerbation Phase/Number of days with data 
recorded during the Acute Exacerbation Phase)*100. 
Stabilisation Phase: 
 
Percentage of days: data recorded from the day of Visit 9/Day 14 to the day of End of 
Study will be considered as data of the Stabilisation Phase. 
On a per patient basis, the percentage of days in the Stabilisation Phase will be calculated using the 
following formula: 
 
% of days with rescue medication (Stabilisation Phase) = (Number of days with rescue 
medication during the Stabilisation Phase/Number of days with data recorded during the 
Stabilisation Phase)*100. 
7.1.4.13 Clinical treatment failure (exploratory composite endpoint) 
Clinical treatment failure (CTF) is defined as a composite endpoint in which a patient meets any 
one of the following criteria (a medical review will be also performed to review each patient 
meeting these criteria because these selections can select non-CTF patients): 
 
Worsening of symptoms warranting the addition of another antibiotic or initiation of a new 


 
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antibiotic (Criterion 1) 
 
Worsening of symptoms warranting an increase in dose of oral corticosteroids or initiation 
of new oral corticosteroids (Criterion 2) 
 
Worsening of symptoms requiring additional treatment regimen of oral corticosteroids 
and/or antibiotics after completion of the initial regimen (Criterion 3) 
 
Re-hospitalisation due to worsening of COPD and requiring additional treatment during the 
duration of the study due to an exacerbation of respiratory symptoms (emergency room 
admission for longer than 24 hours will qualify as a hospitalisation) (Criterion 4) 
 
COPD-related death (Criterion 5). 
Criterion 1: Worsening of symptoms warranting the addition of another antibiotic or initiation of a 
new antibiotic will be derived from the ‘Prior (Last 6 months medication) and Concomitant 
Medication’ form of the eCRF. The medications recorded on this form to be considered for this 
criterion will verify: 
 
Antibiotics: Anatomical Therapeutic Chemical (ATC) code ‘J01’ 
 
Medication administered for COPD exacerbations only, i.e. with indication = ‘COPD 
exacerbation: current/during the study’ 
 
Medication started after Study Day 1 (i.e. ≥ Randomisation date + 1) and prior to or on 
completion of the initial treatment (systemic corticosteroids or antibiotics) for the current 
COPD exacerbation (started no longer than 24 hours before randomisation). 
Criterion 2: Worsening of symptoms warranting an increase in dose of oral corticosteroids or 
initiation of new oral corticosteroids will be derived from the ‘Prior (Last 6 months medication) 
and Concomitant Medication’ form of the eCRF. The medications recorded on this form to be 
considered for this criterion will verify: 
 
Systemic corticosteroids: ATC code ‘H02’ 
 
Route ‘PO = oral’ 
 
Medication administered for COPD exacerbations only, i.e. with indication = ‘COPD 
exacerbation: current/during the study’ 
 
Medication started after Study Day 1 (i.e. ≥ Randomisation date + 1) and prior to or on 
completion of the initial treatment (systemic corticosteroids or antibiotics) for the current 
COPD exacerbation (started no longer than 24 hours before randomisation). 
Criterion 3: Worsening of symptoms requiring additional treatment regimen of oral corticosteroids 
and/or antibiotics after completion of the initial regimen will be derived from the ‘Prior (Last 6 
months medication) and Concomitant Medication’ form of the eCRF. The medications recorded on 
this form to be considered for this criterion will verify: 
 
Systemic oral corticosteroids (ATC code ‘H02’ and Route ‘PO = oral’) or Antibiotics 
(ATC code ‘J01’) 
 
Medication administered for COPD exacerbations only, i.e. with indication = ‘COPD 


 
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exacerbation: current/during the study’ 
 
Medication started after completion of the initial treatment (systemic corticosteroids or 
antibiotics) for the current COPD exacerbation (started no longer than 24 hours before 
randomisation). 
Criterion 4: Re-hospitalisation due to worsening of COPD and requiring additional treatment 
during the duration of the study due to an exacerbation of respiratory symptoms will be determined 
based on the COPD exacerbations experienced after the initial study COPD exacerbation and 
recorded on the ‘Acute Exacerbation COPD’ form of the eCRF. This criterion will verify: 
 
“Has the patient experienced any COPD exacerbations after the initial qualifying study 
exacerbation subsided?” = ‘Yes’ 
 
Treatment: Systemic corticosteroids = ‘Yes’ or Antibiotics = ‘Yes’ 
 
Hospitalisation = ‘Yes’ or (Emergency room = ‘Yes’ with admission longer than 24 hours). 
Criterion 5: COPD-related death will be determined based on the COPD exacerbations experienced 
during the study (including the initial study COPD exacerbation) and recorded on the ‘Adverse 
Event’ form of the eCRF. This criterion will verify: 
 
AE Preferred Term ‘Chronic obstructive pulmonary disease’ 
 
Serious AE that ‘Results in death’. 
The cumulative incidence of CTF as well as each of the individual criteria will be evaluated at Day 
30, Day 60, Day 90, Day 120, Day 150 and Day 180. 
7.1.4.14 Time to clinical treatment failure 
The time to clinical treatment failure (in days) is defined as: 
(Date when any one of the criteria defining the composite endpoint occurred for the first time – 
Date of initiation of study treatment), 
where acute COPD exacerbations experienced during the study and their characteristics are 
recorded on the ‘Acute Exacerbation COPD’ form of the eCRF, i.e. in particular: 
 
Date of first antibiotic intake and/or first systemic corticosteroid intake for treating the 
COPD exacerbation 
 
Date of hospitalisation admission for the COPD exacerbation 
 
Date of emergency room admission (emergency room admission for longer than 24 hours 
will qualify as a hospitalisation) for the COPD exacerbation 
 
Date the COPD exacerbation (assessed as an AE) results in death. 
 
 


 
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Table 6: 
Criteria for event/censored for assessment of Time to clinical treatment failure 
Situation 
Date of event or 
Censoring 
Time to clinical treatment failure 
Outcome 
Subjects who had any one 
of the criteria defining the 
composite endpoint 
Date of clinical 
treatment 
failure 
after entering in 
study 
(Time 
from 
initiation 
of 
study 
treatment 
until 
Date 
of 
clinical 
treatment failure after entering in 
study) 
Event 
Subjects who never had 
any one of the criteria 
defining 
the 
composite 
endpoint in study period 
Withdrawal or last 
contact date 
(Time 
from 
initiation 
of 
study 
treatment until Date of withdrawal or 
last contact date) 
Censored 
Subjects who died (not 
COPD-related) 
Death date 
(Time 
from 
initiation 
of 
study 
treatment until Date of death) 
Censored 
Subjects who withdrew or 
were 
lost 
to follow-up 
during the study 
Withdrawal or last 
contact date 
(Time 
from 
initiation 
of 
study 
treatment until Date of withdrawal or 
last contact date) 
Censored 
7.1.4.15 Chronic Respiratory Questionnaire (CRQ) 
The CRQ is an instrument developed to measure quality of life of patients with COPD. The CRQ 
contains 20 questions which can be divided into four domains: dyspnoea (5 questions), fatigue (4 
questions), emotional function (7 questions) and mastery (4 questions; the subject’s feeling of 
control over their disease). The dyspnoea component is “individualised” (not standardised) which 
means that it is made up of five activities chosen by a patient to cause the greatest shortness of 
breath. The patient then rates the dyspnoea on these 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. 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 ranging from 1 (maximum impairment) to 7 (no impairment). The results are 
expressed as the mean score for each domain (i.e. the total score per domain divided by the 
corresponding number of items) and the mean total score (i.e. the mean of the scores from the 3 
domains fatigue, emotional function and mastery). (Refer Appendix D). 
The four domain scores will be calculated based on: 
 
Dyspnoea from questions 1, 2, 3, 4, 5 
 
Fatigue from questions 8, 11, 15, 17 
 
Emotional function from questions 6, 9, 12, 14, 16, 18, 20 


 
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 
Mastery from questions 7, 10, 13, 19. 
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. 
7.1.4.16 Cumulative oral/IV steroid dose 
The cumulative oral/IV steroid dose during the duration of current COPD exacerbation will be 
derived on a patient level from the ‘Prior (Last 6 months medication) and Concomitant Medication’ 
form of the eCRF. The medications recorded on this form to be considered for this exploratory 
endpoint will verify: 
 
Systemic corticosteroids: ATC code ‘H02’ 
 
Route ‘IV = intravenous’ or ‘PO = oral’ 
 
Medication administered for COPD exacerbations only (i.e. with indication = ‘COPD 
exacerbation: current/during the study’) and taken during the duration of current COPD 
exacerbation (i.e. from the date when symptoms started until the date when symptoms 
stopped). 
Moreover, the dose of treatment recorded on the form for selected systemic corticosteroids will be 
converted to ‘mg’, in case the unit recorded on the form is not ‘mg’. 
Then a correction factor will apply on the oral/IV steroid dosages (mg) using dosing equivalencies, 
i.e.: 
 
1 mg of betamethasone = +/- 7 mg of prednisone equivalence 
 
1 mg of cortisone = +/- 0.2 mg of prednisone equivalence 
 
1 mg of dexamethasone = +/- 7 mg of prednisone equivalence 
 
1 mg of hydrocortisone = +/- 0.25 mg of prednisone equivalence 
 
1 mg of methylprednisolone = +/- 1 mg of prednisone equivalence 
 
1 mg of prednisolone = +/- 1 mg of prednisone equivalence 
 
1 mg of triamcinolone = +/- 1 mg of prednisone equivalence. 
Finally, the cumulative oral/IV steroid dose (prednisone equivalent dose) per patient will be 
calculated as the sum of all prednisone equivalent doses taken by the patient each day during the 
duration of current COPD exacerbation. 
7.1.4.17 BODE index 
BMI 
The BMI is to be calculated from the weight and height obtained at scheduled visits where the 
BODE index is required. BODE uses the binary classification for BMI > 21 kg/m2 (scored as 0) or 
≤ 21 kg/m2 (scored as 1). 
Obstruction 
The level of obstruction for the BODE index will be collected from the spirometry done at the 


 
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timepoints where the BODE index is specified. The index to be used is the FEV1 (% predicted 
value). BODE uses the following classification for FEV1 (% predicted): ≥ 65% (scored as 0), 50-
64% (scored as 1), 36-49 % (scored as 2) or ≤ 35% (scored as 3). 
Dyspnoea (mMRC score) 
The mMRC dyspnoea scale is a questionnaire that consists of five statements about perceived 
breathlessness: grade 0 (scored as 0), “I only get breathless with strenuous exercise”; grade 1 
(scored as 0), “I get short of breath when hurrying on the level or up a slight hill”; grade 2 (scored 
as 1), “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 (scored as 2), “I stop for breath 
after walking 100 yards or after a few minutes on the level”; grade 4 (scored as 3), “I am too 
breathless to leave the house”. 
Exercise (6MWT) 
The 6-Minute Walk Test (6MWT) to achieve the BODE index will be performed at scheduled 
visits 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.  
The distance covered over 6 minutes will be recorded as well as the speed (if available) and the 
oxygen saturation. BODE uses the following classification for 6MWT (meters): ≥ 350 meters 
(scored as 0), 250-349 meters (scored as 1), 150-249 meters (scored as 2), ≤ 149 meters (scored as 
3) or Not Done (scored as 3). 
BODE Index 
The BODE index is used to evaluate the functional status of subjects with COPD. Each parameter 
of the index (airflow obstruction, dyspnoea score per mMRC and exercise tolerance using the 
6MWT) is graded from 0 to 3 with the exception of BMI which is graded as 0 or 1. The overall 
BODE score is the sum of all 4 individual scores and may vary from 0 to 10. (Refer Appendix E) 
7.1.5 Definitions relative to safety parameters 
7.1.5.1 Adverse Event (AE) 
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. 


 
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7.1.5.2 Serious Adverse Event (SAE) 
A Serious Adverse Event (SAE) is defined as an AE that results in one of the following outcomes: 
 
Results in death 
 
Is life-threatening 
 
Requires in-patient hospitalisation or prolongs existing hospitalisation (this does not 
include prolonged hospitalisation for study purposes) 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly/birth defect 
 
Is an important medical event. 
7.1.5.3 Duration of AEs 
The duration of an AE will be calculated as the resolution date minus the date at which it first 
appeared plus 1. 
In the case of an AE still continuing at the end of the study, the duration will be considered as 
unknown. 
7.1.5.4 Relationship of AEs 
The relationship between an AE and the study treatment (BCT197 or placebo) will be determined 
by the Investigator on the basis of his or her clinical judgment and the definitions in Table 7. 
Table 7: Assessment of Relationship 
Reasonable possibility of 
relatedness 
If there is enough evidence or argument to suggest the causal 
relationship. The investigator should consider, but not limited to, 
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 
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. 
No reasonable possibility of 
relatedness 
o there are NOT enough evidence or argument to suggest the causal 
relationship 
Adverse events will be considered causally related to the use of the IMP when the relationship is 


 
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not recorded. For pre-treatment adverse events, a causality assessment is not relevant. 
7.1.5.5 Intensity of AEs 
The Investigator will assess the intensity of AEs using the following definitions:  
 
Mild (awareness of sign or symptom, but easily tolerated) 
 
Moderate (discomfort sufficient to cause interference with normal activities) 
 
Severe (incapacitating, with inability to perform normal activities). 
7.1.5.6 Adverse Event of Special Interest (AESI) 
Following Adverse Events are of Special Interest: 
 
Pneumonia 
 
Liver injury (liver enzymes: ALT, AST, bilirubin total and fractions) 
 
Dermatologic events (Rash/Acneiform dermatitis/Pruritus) 
 
Headache 
 
Inflammation of cervix and vagina. 
7.2 
Handling of missing data and outliers 
7.2.1 Missing data analysis methods 
No strategy for imputation of missing values from subjects who dropped out will be applied 
because the mixed model for repeated measurements analysis done for the primary endpoint is 
known to produce a valid analysis if the drop-out mechanism is missing at random5.  
The analysis (and clinical database) will only include those FEV1 results assessed as being of 
acceptable quality for each time point. 
7.2.2 Handling of missing or incomplete dates 
7.2.2.1 Partial dates of first COPD diagnosis 
In order to calculate the COPD disease duration (i.e. time since first COPD diagnosis), the 
following rules will be applied for partial dates for first diagnosis of COPD: 
 
if the day of the month is missing it is imputed to be the 15th 
 
if both the day and month are missing, they are imputed to be June 30 
 
missing years will be left as missing. 
The above will be flagged and described as a footnote in the appropriate listings. 
7.2.2.2 Partial dates of current COPD exacerbation symptoms start/stop 
In order to calculate the current COPD exacerbation duration (i.e. from the date when symptoms 
started until the date when symptoms stopped) and the times from start/stop of current COPD 
exacerbation to first dosing, the following rules will be applied for partial dates for current COPD 
exacerbation symptoms start and stop: 


 
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 
if the day of the month is missing it is imputed to be the 15th 
 
missing months will be left as missing 
 
missing years will be left as missing. 
The above will be flagged and described as a footnote in the appropriate listings. 
7.2.2.3 Concomitant medications definitions and handling of missing or 
incomplete dates 
Medications will be assigned as being prior to study treatment, concomitant with study treatment, 
or occurring in the Stabilisation Phase, based on the start and stop dates of the medication and the 
IMP dosing. 
If the medication stop date is before the date of the first IMP dose, the medication will be assigned 
as being discontinued prior to study treatment. Otherwise, the medication will be assigned as being 
concomitant with study treatment unless the start date of the medication is after Visit 9 date, when 
it will then be classified as occurring in the post-treatment period. 
Should the stop date for a medication be missing (not ongoing) or incomplete to the extent that it 
could be before, on or after the time of start of study treatment, then it will be assumed that the 
medication was stopped on or after the start of study treatment (i.e. reported as concomitant 
medication). Similarly, if it is not clear whether the medication start date was on or before, or after 
the Visit 9 date, then it will be assumed the medication was begun on or before the Visit 9 date (i.e. 
reported as a concomitant medication) (worst case approach). 
For listings of medications, dates will be presented as they have been recorded (missing and partial 
dates will not be replaced). 
7.2.2.4 Definition of treatment-emergent AEs and handling of missing or 
incomplete dates 
A Treatment-Emergent AE (TEAE) is defined as an AE occurring or worsening on or after the first 
IMP dose. Events with an onset date at or after the patient has signed the ICF and prior to the first 
IMP dose will be classified as pre-treatment AEs.  
In the event of an incomplete onset date, the event will be considered to be treatment-emergent 
unless the partial onset date information or complete or partial end date confirms onset or end prior 
to the first IMP dose date (worst case approach). 
Analysis of TEAEs/SAEs will be performed separately for Acute Exacerbation Phase (from Study 
Day 1 until Day 14 included) and Stabilisation Phase (after Day 14 until Week 26), as well as 
overall (both study phases combined together). Events with an onset date after the date of Visit 9 
(Day 14) will be classified as occurring during the Stabilisation Phase.  
Should any onset date for a TEAE be incomplete then it will be assumed that the TEAE occurred 
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the Visit 9 date (worst case approach). 
In case of partial onset date of COPD exacerbation reported in the ‘Acute Exacerbation COPD’ 
form of the eCRF, the onset of the event will be assumed as the first day of the month in the 
analysis of time to next COPD exacerbation. 
For AEs listings, dates will be presented as they have been recorded (missing and partial dates will 
not be replaced). 
7.2.2.5 Time since last documented COPD exacerbation 
In order to calculate the time since last documented COPD exacerbation, the following rule will be 
applied for partial dates for last documented COPD exacerbation: 
 
if the day of the month is missing it is imputed to be the last day of the month. 
The above will be flagged and described as a footnote in the appropriate listings. 
7.2.3 Missing items in a questionnaire (CRQ) within a patient/visit 
The method of data imputation to be used for CRQ is to substitute a person-specific estimate for 
any missing item, when the respondent answered at least 50% of the items in a scale or subscale. 
The estimate is the average score, across completed items in the same scale or subscale, for that 
respondent. Otherwise the average score will be set to missing for that patient/visit. 
7.2.4 Handling of changes in study endpoints due to protocol amendments 
The Appendix A summarises the key changes to each protocol amendment and which study 
endpoints are impacted by the protocol amendments. 
Sensitivity and subgroup analyses will be performed on the study endpoints impacted by the 
protocol amendments, and are detailed throughout this SAP when applicable. 


 
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8 
STATISTICAL METHODS 
8.1 
General statistical conventions 
All statistical procedures will be completed using SAS version 9.4 or higher. 
8.1.1 Populations for analysis 
Demographic and baseline characteristics will be summarised in the Safety, ITT and PP 
populations, unless otherwise stated. 
Analyses of the primary efficacy endpoint will be performed on the ITT population, and also on the 
PP population as a sensitivity analysis. 
The secondary and exploratory efficacy endpoints will be analysed using the ITT and PP 
populations for this PoC and hypothesis-generating study. 
The safety and tolerability variables will be analysed using the Safety population. 
PK data will be analysed using the PK population. 
For the populations to be considered in the subgroup analyses, see section 8.8.3 below.  
8.1.2 Treatment groups 
Statistics will be displayed for the following treatment groups: 
8.1.3 Descriptive statistics 
Continuous variables will be summarised using descriptive statistics including number of non-
missing observations (n), arithmetic mean (Mean), median (Median), standard deviation (SD), 
minimum value (Min) and maximum value (Max). One additional decimal point for mean and 
median and 2 additional decimal points for SD will be used.  
For categorical variables, summaries will include the number of non-missing observations (n) or 
the number of patients in the population (N) as applicable, the counts of subjects and percentages. 
Percentages will be rounded to one decimal place. The number of missing values will be presented 
as a separate category with no percentage, but only if any missing value is recorded in the data for 
that summary. 
 
 


 
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For efficacy and safety data, summary statistics will be presented at each visit when relevant. 
Changes from baseline will be summarised in a similar manner. 
Data in summary tables will generally be presented on an Observed Cases (OC) basis. 
8.1.4 Statistical significance 
Unless otherwise stated, all statistical testing will be two-sided and conducted at the significance 
(alpha) level of 0.05. Two-sided 95% confidence intervals (CIs) will be provided when relevant. 
All three treatment regimens will be assessed by pairwise comparisons for efficacy data, and no 
adjustment for multiplicity will be made. 
8.1.5 Definitions of Baseline 
The efficacy/exploratory endpoints to be analysed separately during the Acute Exacerbation Phase 
and the Stabilisation Phase are the EXACT-PRO total score and subscores (and exacerbation 
parameters derived from EXACT-PRO), the change from baseline in CRQ over time and the 
change from baseline in mMRC dyspnoea scale over time. 
For summary purposes, the baseline value for Acute Exacerbation Phase will be defined as the last 
non-missing value collected prior to the first dose of study medication, unless other specified. 
Moreover, for the efficacy/exploratory endpoints to be analysed separately during the Acute 
Exacerbation Phase (from Study Day 1 until Day 14) and the Stabilisation Phase (from Day 14 
until Week 26), the baseline value for Stabilisation Phase will be defined as the value collected on 
Visit 9 (Day 14), unless other specified. For Stabilisation Phase, no value available prior to Visit 9 
(Day 14) will be used for definition of baseline, as the patient might not yet be under stable 
condition for COPD prior to Day 14.  
For EXACT-PRO, as there is no stable period during which EXACT-PRO scores are collected 
prior to administrating the study drug, the definition of the Baseline EXACT-PRO from the user 
manual6 will not be used for Acute Exacerbation Phase. The score and subscores obtained on Day 1 
of the EXACT-PRO observation period, which corresponds to Study Day 1, will be used as the 
baseline for Acute Exacerbation Phase. Moreover, the Baseline EXACT-PRO score (or subscores) 
for Stabilisation Phase will be defined as the mean EXACT score during the first 7 days of the 
Stabilisation Phase (Week 3; Days 15-21), with a minimum of 4 days of available data required to 
compute the baseline value. If 4 or more of the first 7 days of data are not available, the baseline 
EXACT-PRO score for Stabilisation Phase will not be calculated. 
8.1.6 Visit dates 
For each visit, the date recorded by the Investigator in the eCRF (variable SVSTDTC in the SDTM 
SV dataset) will be considered as the visit date in all the algorithms and the listings. 
 
 


 
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8.1.7 Data re-allocation 
The following general rules to handle repeated assessments will be considered: 
 
PFT (spirometry): 
o If the spirometry was repeated before the first study medication intake, the last 
assessment performed will be considered as the Visit 1 assessment in all the 
analyses. 
o If the spirometry was repeated at a visit after the first study medication intake, the 
assessment performed ‘post-bronchodilator’ will be considered as the visit 
assessment in all the analyses. 
 
12-lead ECG: 
o in case of multiple measurements associated to the same timepoint (e.g. triplicate 
ECGs), the average value will be considered for HR, RR interval, PR interval, 
QRS duration, QT interval, QTcB interval and QTcF interval. 
o The last 12-lead ECG performed before the first study medication intake will be 
considered in the analysis as the Visit 1 ECG. 
 
Vital signs, physical examination, clinical laboratory tests: 
o The last assessment performed before the first study medication intake of each 
parameter will be considered in the analysis as the Visit 1 assessment. 
8.1.8 Exclusion of data from the statistical analysis 
Spirometries assessed as being of unacceptable quality will be removed upstream from the clinical 
database, thus excluded from the statistical analysis. 
8.1.9 Data listings 
All the relevant subject data, including those derived, will be presented in individual subject data 
listings. All listings will be sorted by treatment regimen, investigational site, patient number, 
date/time and visit. The patient’s sex and age will be stated on each listing. Unless otherwise stated, 
data listings will be based on all patients randomised. 
Unscheduled visit results will be included in date/time chronological order within patient listings, 
but will not be tabulated. 
8.2 
Subject disposition 
All patients who provided informed consent will be included in a summary of patient 
accountability. The number of subjects screened, the number of screen failures, the frequency of 
patients randomised (by treatment regimen and overall), the frequency and percentage of patients in 
the Safety population, in the ITT population, in the PP population and in the PK population (by 
treatment regimen and overall) will be summarised.  
Subject disposition information will be summarised by treatment regimen and overall. The number 


 
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of subjects completing and withdrawing study drug intake, completing Acute Exacerbation Phase, 
completing and withdrawing from the study will be tabulated in the study disposition table which 
will also include the reasons for treatment discontinuation and early withdrawal of the patient as 
reported on the eCRF. The summary will also be presented by country. 
Finally, the reasons for screen failure as reported on the eCRF will be tabulated. 
The follow-up time (number of days from first study treatment to last contact) will be summarised 
descriptively.  
A listing will include the randomisation/kit numbers, randomisation date/time and study disposition 
data (on all subjects screened). 
8.3 
Protocol deviations 
The number of patients excluded from ITT, Safety, PP and PK populations and reasons for 
exclusion will be summarised by treatment regimen and overall.  
Population membership details will be listed, including reason for exclusion from each population 
(on randomised patients). 
All protocol deviations identified will be summarised by treatment regimen and overall. 
All protocol deviations identified will be listed based on data recorded on the eCRF and/or protocol 
deviation Logs (from CTMS). 
8.4 
Demographics and baseline characteristics 
Statistical comparisons will be performed whenever possible in order to examine the relationship 
between each demographics and baseline characteristic and treatment regimen. The associated two-
sided p-values representing the comparison across the treatment regimens [one-way ANOVA test, 
Kruskal-Wallis test (or Wilcoxon Rank-Sum test for pairwise treatment regimens), Pearson’s Chi-
square test or Fisher’s exact test, as appropriate] will be reported in the summary tables and 
regarded as descriptive. 
See Appendix F for SAS code used to implement these standard univariate tests. 
For the final analysis, if the Safety and ITT populations are equal, the tables on the ITT population 
will not be presented if available also on the Safety population. 
8.4.1 Demographics 
Demographic variables will be listed and summarised by treatment regimen and overall. This will 
include age, sex, race, country of origin, weight, height and BMI. Separate summaries will be 
produced using the Safety, ITT and PP populations. 
8.4.2 Smoking status 
Smoking status at Screening (ex-smoker or current smoker), duration of smoking (years) and 


 
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number of pack-years will be presented by treatment regimen and overall. Separate summaries will 
be produced using the ITT and PP populations. 
8.4.3 COPD history 
Duration of COPD disease (years), current (last year) severity of the disease, number of moderate 
or severe COPD exacerbations in the last 12 months before screening [as a continuous and 
categorical variable (0, 1, 2, 3, >3)], time since last documented COPD exacerbation (months), 
treatment with systemic corticosteroids or antibiotics (or both) or hospitalisation for the last 
documented COPD exacerbation, pre-study spirometry results (pre- and post-bronchodilator) from 
most recent PFT performed outside an exacerbation in the last 12 months will be presented by 
treatment regimen and overall. Separate summaries will be produced using the ITT and PP 
populations. 
8.4.4 Baseline treatment for COPD 
COPD treatment category at study entry (Monotherapy: Long-Acting 2-Agonist [LABA] alone, 
Long-Acting Muscarinic Antagonist [LAMA] alone, Inhaled Corticosteroids [ICS]; Dual therapy: 
LABA+LAMA, LABA+ICS, LAMA+ICS; Triple therapy: LABA+LAMA+ICS; Other) will be 
presented by treatment regimen and overall. Separate summaries will be produced using the ITT 
and PP populations. 
8.4.5 Current COPD exacerbation data 
Duration of current COPD exacerbation symptoms (days) and worsening of respiratory symptoms 
(breathlessness, wheeze, cough, reduction in exercise tolerance, fever, change in sputum production 
[change in quantity; aspect purulent vs. non purulent], unusual increase of use of “rescue” 
medication, other worsened symptoms) will be presented by treatment regimen and overall. 
Separate summaries will be produced using the ITT and PP populations. 
Other exacerbation characteristics data not tabulated above will be listed. 
8.4.6 Spirometry at Screening and Visit 1 Pre-dose 
The following spirometry parameters will be summarised by treatment regimen and overall: 
 
Screening: FEV1 pre- and post-bronchodilator, FEV1 % of predicted normal value pre- 
and post-bronchodilator, FVC pre- and post-bronchodilator, FVC % of predicted normal 
value pre- and post-bronchodilator, FEV1/FVC pre- and post-bronchodilator, FEV1/FVC 
% of predicted normal value pre- and post-bronchodilator 
 
Visit 1: FEV1 post-bronchodilator, FEV1 % of predicted normal value post-bronchodilator, 
FVC post-bronchodilator, FVC % of predicted normal value post-bronchodilator, 
FEV1/FVC post-bronchodilator, FEV1/FVC % of predicted normal value post-
bronchodilator. 
Separate summaries will be produced using the Safety, ITT and PP populations. 


 
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8.4.7 EXACT-PRO at Visit 1 Pre-dose 
The EXACT-PRO total score and domain scores at Visit 1 (pre-dose) will be summarised by 
treatment regimen and overall using the ITT and PP populations.  
8.4.8 CRQ at Visit 1 Pre-dose 
The CRQ total score and domain scores at Visit 1 (pre-dose) will be summarised by treatment 
regimen and overall using the ITT and PP populations. 
8.4.9 BODE index at Visit 1 Pre-dose 
For the subgroup of patients enrolled in the study under protocols V2.0 and V3.0, the BODE index 
and subscores at Visit 1 (pre-dose) will be summarised by treatment regimen and overall using the 
ITT and PP populations. 
8.4.10 Other Baseline and disease characteristics 
Gynaecological history data will be summarised by treatment regimen and overall using the ITT 
population and listed. Additional investigations performed for COPD exacerbation data 
(microbiology culture, arterial blood gases, chest X-ray, chest CT scan, other) will be summarised 
by treatment regimen and overall using the ITT and PP populations and listed. Other Baseline and 
disease characteristics data will be listed. 
8.4.11 Medical history and concomitant diseases 
A summary of medical history and concomitant diseases will be presented by system organ class 
(SOC) and preferred term (PT), by treatment regimen and overall using Medical Dictionary for 
Regulatory Affairs® (MedDRA) Version 20.0 or higher. Separate summaries will be produced 
using the Safety and ITT populations. A listing of medical history and concomitant diseases will be 
provided. 
Note: 
 
Medical histories are defined as records in the medical history and concomitant diseases 
eCRF form which are not ongoing at Screening Visit 
 
Concomitant diseases are defined as records in the medical history and concomitant 
diseases eCRF form which are ongoing at Screening Visit. 
8.4.12 Prior and concomitant medications 
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary (March 2017 or later). 
Prior and concomitant medications will be summarised by ATC classification and Preferred Name 
by treatment regimen for the ITT population through frequency distributions and percentages and 
presented in separate tables for the following groups: 
 
 


 
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 
Previous medication (discontinued prior to study treatment): 
o COPD medications. 
 
Medication concomitant to study treatment: 
o COPD medications not including medications for COPD exacerbation 
o Medications for COPD exacerbation 
o Non-COPD medications. 
 
Medications occurring in the Stabilisation Phase (post-treatment medication): 
o Medications for COPD exacerbation. 
The following rules to identify COPD medications (administered for COPD exacerbations and for 
other reasons) are proposed for selecting medications: 
COPD medications: 
Any medications with an indication = ‘COPD exacerbation: current/during the study‘ or ‘COPD 
(non-exacerbation related)‘ or ‘Rescue medication‘, or which contains ‘COPD’ or ‘CHRONIC 
OBSTRUCTIVE PULMONARY DISEASE’ or ‘RESCUE MEDICATION’ for ‘Indication, 
specify’ field will be considered as COPD medications. 
Medications for COPD exacerbations: 
Any medications with an indication = ‘COPD exacerbation: current/during the study’ will be 
considered as medications for COPD exacerbations. 
Details for imputing missing or partial start and/or stop dates of medication are described in 
Section 7.2.2.3. 
8.4.13 Vital signs at Screening and Visit 1 Pre-dose 
Body temperature, systolic (SBP) and diastolic (DBP) blood pressure, pulse rate (PR), respiratory 
rate (RR), blood oxygen (% HbO2 saturation) assessed pre-salbutamol at Screening and pre-dose at 
Visit 1 will be summarised by treatment regimen and overall using the Safety population. 
8.4.14 12-lead ECG at Screening and Visit 1 Pre-dose 
The HR, RR, PR, QRS, QT, QTcB and QTcF values obtained from the 12-lead ECG pre-
salbutamol at Screening and pre-dose at Visit 1 will be summarised by treatment regimen and 
overall using the Safety population. 
8.4.15 Eosinophils at Screening and Visit 1 Pre-dose 
Descriptive summaries of eosinophils relative count (%) collected at Screening and pre-dose at 
Visit 1 will be presented. A summary for eosinophils (%) (<2% or ≥2%) will also be presented. All 
summaries will be by treatment regimen and overall using the ITT and PP populations. 


 
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8.5 
Extent of exposure 
8.5.1 Treatment duration 
Exposure to randomised IMP (number of days) will be defined as: 
(date of last dose of randomised IMP – date of first dose of randomised IMP) + 1 
and 
8.5.2 Treatment compliance 
IMP administration details, including the number of capsules administered and the complete/partial 
administration of study drug dose (and reason, if partial) 
by 
treatment regimen on the ITT population using descriptive statistics. 
The total number of doses taken as well as the overall treatment compliance (%) will also be 
presented by treatment regimen using the ITT population. 
The formula for overall compliance (%) calculation is:  
Compliance (%) = (total number of capsules administered / 6)*100 
8.6 
Efficacy analyses 
This section addresses separately the analyses to be conducted on the primary, secondary and 
exploratory efficacy variables. 
All definitions relative to efficacy and exploratory endpoints are detailed in Section 7.1.4. 
8.6.1 Analysis methods 
Descriptive statistics will be presented for all endpoints. All statistical tests of the efficacy and 
exploratory endpoints will be two-sided tests and compared to a 5% significance level and all 
estimates will be presented with two-sided 95% CIs, unless otherwise specified. 
Unless otherwise stated, all ANCOVA models and repeated measures models will include the 
baseline value (last non-missing value collected prior to the first dose of study medication) of the 
variable as covariate and treatment regimen, severity of airflow limitation at baseline (post-
bronchodilator FEV1 at baseline (pre-dose) <30% or ≥30% of predicted normal value), blood 
eosinophils (%) value at baseline (<2% or ≥2%), time from start of current COPD exacerbation to 
first IMP dosing (≤2 days, 3-4 days or ≥5 days), presence of cardiovascular comorbidities at 
screening (yes, no) and COPD exacerbation treatment at screening (systemic corticosteroids only, 
antibiotics only or both systemic corticosteroids and antibiotics) as fixed effects. Repeated 
measures models will also include visit/inter-visit period, the treatment by visit/inter-visit period 
interaction and the baseline by visit/inter-visit period interaction. The adjusted mean difference 
between treatment regimens will be presented along with a two-sided 95% CI for the time-points of 
interest. 


 
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The calculation of the adjusted means (least squares means) will be based on: 
 
coefficients for classification effects (i.e., the effects of categorical covariates) proportional 
to the margins observed in the group of patients analysed; 
 
effects of quantitative covariates set equal to their mean values in the group of patients 
analysed. 
See Appendix F for details on the calculation of adjusted means (least squares means). 
8.6.1.1 Multiplicity 
All three treatment regimens will be assessed by pairwise comparisons. No adjustment will be 
made for multiple comparisons. 
8.6.1.2 Treatment by center interaction analysis (multi-center study) 
No analysis will be made to assess the treatment-by-center interaction. 
8.6.2 Analysis of primary efficacy endpoint(s) 
The primary efficacy endpoint for this study is the change in FEV1 from baseline (pre-dose) to Day 
7, defined as: FEV1 value at Day 7 – FEV1 value at baseline (pre-dose). 
8.6.2.1 Primary analysis 
The primary analysis of efficacy will be based on the ITT population and observed cases. 
The primary analysis will compare each of the treatment regimens together using pairwise 
comparison tests based on a mixed model for repeated measurements (MMRM) using an 
unstructured covariance matrix and the Kenward-Roger adjustment for the denominator degrees of 
freedom. The model will use FEV1 absolute changes at Days 2, 3, 4, 5, 6 and 7, and will include 
treatment 
severity of airflow limitation at 
baseline (post-bronchodilator FEV1 at baseline (pre-dose) <30% or ≥30% of predicted normal 
value), blood eosinophils (%) value at baseline (<2% or ≥2%), time from start of current COPD 
exacerbation to first IMP dosing (≤2 days, 3-4 days or ≥5 days), presence of cardiovascular 
comorbidities at screening (yes, no) and COPD exacerbation treatment at screening (systemic 
corticosteroids only, antibiotics only or both systemic corticosteroids and antibiotics) as fixed 
effects and baseline FEV1 value as covariate. In addition the baseline FEV1 value-by-visit and the 
treatment-by-visit interactions will be included in the model.  
LSMEAN and standard error (SE) of each treatment regimen as well as the adjusted mean 
difference between treatment regimens and associated two-sided 95% CIs will be obtained from the 
MMRM model at Days 2, 3, 4, 5, 6 and 7. Each pairwise treatment regimen comparison will be 
tested at an alpha level of 5%. Difference will be considered and confirmed between pairwise 
treatments if the two-sided P-value for the test for difference is below 0.05. P-values of the effects 
will also be presented.  


 
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Hypotheses: 
The ‘superiority’ null hypothesis will be: 
 
H0: T2-T1 = 0 (T2 is equivalent to T1) vs the alternative 
 
Ha: T2-T1 ≠ 0 (T2 is different to T1) 
MMRM model and SAS code: 
The SAS code used to implement linear mixed model for repeated measures for FEV1 and 95% CIs 
of differences between treatments will be similar to that shown below: 
 
PROC MIXED data = dataset; 
       CLASS ID trt visit severity eosino time_symp cv_comorb COPD_trt; 
       MODEL change = trt visit trt*visit severity eosino time_symp cv_comorb COPD_trt baseline 
       baseline*visit / ddfm=KenwardRoger; 
       REPEATED visit / subject=ID type=UN; 
       LSMEANS trt*visit /  cl;  
       LSMEANS trt / cl;  
 
       LSMESTIMATE trt*visit 
                'A vs B: Visit 2' 1 0 0 0 0 0 -1 0 0 0 0 0 0 0 0 0 0 0, 
                'A vs B: Visit 3'  0 1 0 0 0 0 0 -1 0 0 0 0 0 0 0 0 0 0, 
                'A vs B: Visit 4'  0 0 1 0 0 0 0 0 -1 0 0 0 0 0 0 0 0 0, 
                'A vs B: Visit 5'  0 0 0 1 0 0 0 0 0 -1 0 0 0 0 0 0 0 0, 
                'A vs B: Visit 6'  0 0 0 0 1 0 0 0 0 0 -1 0 0 0 0 0 0 0, 
                'A vs B: Visit 7'  0 0 0 0 0 1 0 0 0 0 0 -1 0 0 0 0 0 0, 
                'A vs C: Visit 2' 1 0 0 0 0 0 0 0 0 0 0 0 -1 0 0 0 0 0, 
                'A vs C: Visit 3'  0 1 0 0 0 0 0 0 0 0 0 0 0 -1 0 0 0 0, 
                'A vs C: Visit 4'  0 0 1 0 0 0 0 0 0 0 0 0 0 0 -1 0 0 0, 
                'A vs C: Visit 5'  0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 -1 0 0, 
                'A vs C: Visit 6'  0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 -1 0, 
                'A vs C: Visit 7'  0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 -1, 
                'B vs C: Visit 2' 0 0 0 0 0 0 1 0 0 0 0 0 -1 0 0 0 0 0, 
 
                'B vs C: Visit 3'  0 0 0 0 0 0 0 1 0 0 0 0 0 -1 0 0 0 0, 
                'B vs C: Visit 4'  0 0 0 0 0 0 0 0 1 0 0 0 0 0 -1 0 0 0, 
                'B vs C: Visit 5'  0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 -1 0 0, 
                'B vs C: Visit 6'  0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 -1 0, 
                'B vs C: Visit 7'  0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 -1 / cl; 
 
       LSMESTIMATE trt; 
                'A vs B: Overall' 1 -1 0, 
                'A vs C: Overall' 1 0 -1, 
                'B vs C: Overall' 0 1 -1 / cl; 
RUN; 
 
 


 
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Notes:  
– 
Change represents the change from baseline to each visit of the variable; 
– 
Trt represents the treatment group; 
– 
Visit represents the clinic visit; 
– 
Severity represents the severity of airflow limitation (post-bronchodilator FEV1 at 
baseline (pre-dose) classified into 2 groups: < 30% or ≥ 30% of predicted normal 
value); 
– 
Eosino represents the blood eosinophils (%) value at baseline (classified into 2 groups: 
< 2% or ≥ 2%); 
– 
Time_symp represents the time from start of current COPD exacerbation symptoms to 
first IMP dosing (≤2 days, 3-4 days or ≥5 days); 
– 
Cv_comorb represents the cardiovascular comorbidities at screening (presence or 
absence); 
– 
COPD_trt represents the COPD exacerbation treatment at screening (systemic 
corticosteroids only, antibiotics only or both systemic corticosteroids and antibiotics); 
– 
Baseline represents the baseline value of the variable; 
– 
ID represents the Patient Number; 
– 
Treatment order: 1 = High dose BCT197, 2 = Low dose BCT197; 3 = Placebo 
– 
the ‘Overall’ least squares means and contrasts will be estimated only for the change 
from baseline in FEV1. 
 
In case of non-convergence of the above model using an unstructured covariance matrix, the 
following variance structures will be tested, and based on Akaike’s information criteria the best 
fitting model will be chosen. The variance models that will be considered for the within patient 
variation in case of non-convergence are in this order: Ante-dependence, Toeplitz, Heterogeneous 
AR(1), Heterogeneous Compound Symmetry, and Compound Symmetry.  
8.6.2.2 Descriptive analysis 
FEV1 results (absolute values and changes from baseline) will be summarised by treatment 
regimen and visit on the ITT population. This descriptive analysis will also be performed based on 
the PP population. 
A figure with adjusted mean change from baseline in FEV1 at each visit by treatment regimen 
derived from the linear mixed model will be provided on the ITT population. The three treatment 
regimens will be plotted on the same graph. This graph will also be performed based on the PP 
population. 
Moreover, a bar chart per treatment regimen on the ITT population for the change from baseline in 
best FEV1 until Day 7 showing the percentage of subjects with changes within the following 
change from baseline categories: < -200 mL, [-200 mL, -100 mL[, [-100 mL, 0[, …[200 mL, 300 
mL[, ≥ 300 mL The increment may be updated if not judged suitable for the range of the data 
obtained. 
 
 


 
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8.6.2.3 Sensitivity analyses 
MMRM on PP Population: 
Additionally to assess the robustness of the ITT results, a supportive MMRM analysis using the PP 
population will be carried out. 
ANCOVA (OC): 
The primary endpoint will be analysed using an ANCOVA model estimating the effect at Day 7, 
using OC, including treatment, severity of airflow limitation at baseline, blood eosinophils (%) 
value at baseline, time from start of current COPD exacerbation to first IMP dosing, presence of 
cardiovascular comorbidities at screening and COPD exacerbation treatment at screening as fixed 
effects and baseline FEV1 value as a covariate. 
The ANCOVA model results will be presented with LSMEAN and standard error (SE) of each 
treatment regimen as well as the adjusted mean difference between treatment regimens at Day 7 
and associated two-sided 95% CIs. Each pairwise treatment regimen comparison will be tested at 
an alpha level of 5%. Difference will be considered and confirmed between pairwise treatments if 
the two-sided P-value for the test for difference is below 0.05. P-values of the effects will also be 
presented.  
ANCOVA Model and SAS code: 
The SAS code used to implement ANCOVA model for FEV1 at Day 7 and 95% CIs of differences 
between treatments will be similar to that shown below: 
 
PROC MIXED data = dataset; 
       CLASS trt severity eosino time_symp cv_comorb COPD_trt; 
       MODEL change_d7 = trt severity eosino time_symp cv_comorb COPD_trt baseline /  
       ddfm=KenwardRoger; 
       LSMEANS trt / cl;  
       LSMESTIMATE trt; 
                'A vs B: Overall' 1 -1 0, 
                'A vs C: Overall' 1 0 -1, 
                'B vs C: Overall' 0 1 -1 / cl; 
RUN; 
 
Notes:  
– 
Change_d7 represents the change from baseline to Day 7 of the variable; 
– 
Trt represents the treatment group; 
– 
Severity represents the severity of airflow limitation (post-bronchodilator FEV1 at 
baseline (pre-dose) classified into 2 groups: < 30% or ≥ 30% of predicted normal 
value); 
– 
Eosino represents the blood eosinophils (%) value at baseline (classified into 2 groups: 
< 2% or ≥ 2%); 
– 
Time_symp represents the time from start of current COPD exacerbation symptoms to 
first IMP dosin
; 


 
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– 
Cv_comorb represents the cardiovascular comorbidities at screening (presence or 
absence); 
– 
COPD_trt represents the COPD exacerbation treatment at screening (systemic 
corticosteroids only, antibiotics only or both systemic corticosteroids and antibiotics); 
– 
Baseline represents the baseline value of the variable; 
– 
Treatment order
 
– 
the ‘Overall’ least squares means and contrasts will be estimated only for the change 
from baseline in FEV1. 
MMRM on subgroup of patients enrolled in the study under protocols V4.0 and V5.0: 
For patients enrolled in the study under protocols V4.0 and V5.0, the inclusion criterion 7 regarding 
post-bronchodilator spirometry was removed, as it was challenging in the acute exacerbation 
setting to conduct pre- and post- bronchodilator spirometry. Thus, all spirometry measurements 
were performed ‘on bronchodilator’ for patients enrolled in the study under protocols V4.0 and 
V5.0 (i.e. the way of measuring the primary efficacy endpoint has been changed). 
Therefore, a MMRM analysis using the ITT population will be performed as a sensitivity analysis 
on the subgroup of patients enrolled in the study under protocols V4.0 and V5.0. 
8.6.3 Analysis of secondary efficacy endpoint(s) 
The analysis of secondary efficacy endpoints will be performed on the ITT and PP populations. 
8.6.3.1 Comparison of FEV1 on Days 3, 10, and 14 
A descriptive summary table will be presented for FEV1 absolute values and change for baseline 
on Days 3, 10, and 14 by treatment regimen and visit. 
Change in FEV1 from baseline (pre-dose) to Day 3 will be analysed using an ANCOVA model 
estimating the effect at Day 3, using OC, including treatment, severity of airflow limitation at 
baseline, blood eosinophils (%) value at baseline, time from start of current COPD exacerbation to 
first IMP dosing, presence of cardiovascular comorbidities at screening and COPD exacerbation 
treatment at screening as fixed effects and baseline FEV1 value as a covariate. 
The ANCOVA model results will be presented with LSMEAN and standard error (SE) of each 
treatment regimen as well as the adjusted mean difference between treatment regimens at Day 3 
and associated two-sided 95% CIs. Each pairwise treatment regimen comparison will be tested at 
an alpha level of 5%. P-values of the effects will also be presented.  
A similar ANCOVA model will be used for analysis of: 
 
Change in FEV1 from baseline to Day 10 
 
Change in FEV1 from baseline to Day 14. 
Additionally, similar analyses as detailed above (descriptive summary table and ANCOVA model) 
will be performed for: 


 
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 
Comparison of FVC on Days 3, 7, 10, and 14 (Note: ANCOVA model includes baseline 
FVC value as a covariate) 
 
Comparison of FEV1/FVC on Days 3, 7, 10, and 14 (Note: ANCOVA model includes 
baseline FEV1/FVC value as a covariate). 
Furthermore, descriptive summary tables will be presented for the following spirometry parameters 
(i.e. absolute values and change for baseline on Days 3, 7, 10, and 14 by treatment regimen and 
visit): 
 
FEV1 % of predicted normal value 
 
FVC % of predicted normal value 
 
FEV1/FVC % of predicted normal value. 
8.6.3.2 Normalisation of spirometry parameters over time compared with 
the most recent test performed within the last 12 months outside an 
exacerbation 
The number and proportion of patients normalised for FEV1 (i.e. FEV1 returns to a value ≥ 89% of 
the most recent FEV1 value measured within the last 12 months outside an exacerbation) at each 
visit will be reported by treatment regimen and Pearson’s Chi-square test (or Fisher’s exact test as 
appropriate) will be applied to compare normalisation rates at each visit between treatment 
regimens (two-sided test at 5% alpha level). 
Moreover, a bar chart will be presented per treatment regimen for the normalisation of FEV1 at 
each visit showing the percentage of subjects normalised compared with the most recent test 
performed within the last 12 months outside an exacerbation. 
A similar analysis will be used for: 
 
Normalisation of FEV1/FVC (i.e. FEV1/FVC returns to a value ≥ 89% of the most recent 
FEV1/FVC value measured within the last 12 months outside an exacerbation) at each 
visit. 
The timepoints to consider for these analyses are Days 1 to 7, Days 10 and 14, and Weeks 8, 12 
and 26. 
8.6.3.3 Time to improvement in FEV1 value over time 
8.6.3.3.1 Time to improvement of 100 mL in FEV1 over time 
Time to improvement of 100 mL in FEV1 from baseline will be analysed using the Kaplan-Meier 
method. Patients without an improvement of 100 mL in FEV1 from baseline or who are 
discontinued before reaching it will be considered as “censored” patients. 
For the study periods Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Days 8-10, Days 11-14, 
Weeks 3-8, Weeks 9-12 and Weeks 13-26, the number of patients without an improvement of 100 
mL in FEV1 from baseline at the beginning of the period, the cumulative number of patients with 


 
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an improvement of 100 mL in FEV1 at the end of the period and the probability of improvement of 
100 mL in FEV1 at the end of the period with the associate two-sided 95% CIs will be presented by 
treatment regimen. The point estimates and the relative two-sided 95% CIs will be presented by 
treatment regimen for the 75th, 50th and 25th percentiles. A Kaplan-Meier plot will also be 
presented. Comparisons between treatment regimens will be performed by means of the log-rank 
test. The p-values of the pairwise log-rank test comparisons will be displayed on the figure. 
See Appendix F for SAS code used to implement Kaplan-Meier method. 
8.6.3.3.2 Time to improvement of 80 mL in FEV1 over time 
A similar analysis as in Section 8.6.3.3.1 will be performed for the time to improvement of 80 mL 
in FEV1 from baseline over time. 
8.6.3.4 Standardised AUC of FEV1 over time 
The standardised AUCs of FEV1 (Day 1 to Day 3, Day 1 to Day 7, Day 1 to Day 10 and Day 1 to 
Day 14) will be derived and summarised with standard descriptive statistics by treatment regimen.  
The standardised AUC from Day 1 to Day 14 will be analysed using an ANCOVA model 
estimating the effect up to Day 14, using OC, including treatment, severity of airflow limitation at 
baseline, blood eosinophils (%) value at baseline, time from start of current COPD exacerbation to 
first IMP dosing, presence of cardiovascular comorbidities at screening and COPD exacerbation 
treatment at screening as fixed effects and baseline FEV1 value as a covariate. 
The ANCOVA model results will be presented with LSMEAN and standard error (SE) of each 
treatment regimen as well as the adjusted mean difference between treatment regimens at Day 14 
and associated two-sided 95% CIs. Each pairwise treatment regimen comparison will be tested at 
an alpha level of 5%. P-values of the effects will also be presented.  
A similar ANCOVA model will be used for analysis of: 
 
Standardised AUC of FEV1 from Day 1 to Day 7 
 
Standardised AUC of FEV1 from Day 1 to Day 10. 
8.6.3.5 Normalisation of RR over time (daily from Days 1 to 7, 10 and 14) 
The number and proportion of patients normalised for RR (i.e. RR returns to a plateau level, as 
defined in Section 7.1.4.6) at each visit during the Acute Exacerbation Phase will be reported by 
treatment regimen and Pearson’s Chi-square test (or Fisher’s exact test as appropriate) will be 
applied to compare normalisation rates at each visit between treatment regimens (two-sided test at 
5% alpha level). 
The timepoints to consider for these analyses are Days 1 to 7, Day 10 and Day 14. 
 
 


 
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8.6.3.6 Change in RR on Days 3, 7, 10 and 14 
A descriptive summary table will be presented for RR absolute values and change from baseline on 
Days 3, 7, 10, and 14 by treatment regimen and visit. 
A graphical representation of the RR distribution using mean plots (mean and SD) will be provided 
over time per treatment regimen. The three treatment regimens will be plotted on the same graph. 
8.6.3.7 Time to improvement based on EXACT-PRO total score 
All EXACT-PRO rolling average results available at Day 3, 5, 7, 10, 14 and 29 will be summarised 
at each visit by treatment regimen using descriptive statistics. The improvements (changes) in 
EXACT-PRO rolling average from baseline (Day 1 pre-dose) will also be summarised at Day 3, 5, 
7, 10, 14 and 29 by treatment regimen.  
MMRM analysis using an unstructured covariance matrix and the Kenward-Roger adjustment for 
the denominator degrees of freedom will be performed for statistical comparison of treatment 
regimens with improvement in EXACT-PRO rolling average as an outcome. Model will consider 
treatment, severity of airflow limitation at baseline, blood eosinophils (%) value at baseline, time 
from start of current COPD exacerbation to first IMP dosing, presence of cardiovascular 
comorbidities at screening and COPD exacerbation treatment at screening as fixed effects and 
baseline EXACT-PRO Rolling Average score as covariate. In addition the baseline score-by-visit 
and the treatment-by-visit interactions will be included in the model. 
LSMEAN and standard error (SE) of each treatment regimen, difference of LSMEANS between 
treatment regimens and their associated  two-sided 95% CIs and corresponding two-sided P-values 
for Day 3, Day 5, Day 7, Day 10, Day 14 and Day 29 will be estimated by the model. P-values of 
the effects will also be presented. 
The unstructured covariance matrix (which does not presume a particular correlation structure for 
repeated measurements within patients over time) will be used to adjust for the within-patient error 
variance covariance. In case model fails to converge, other covariance matrix structures will be 
considered in the sequence of Ante-dependence, Toeplitz, Heterogeneous AR(1), Heterogeneous 
Compound Symmetry, and Compound Symmetry.  
Similar descriptive analysis and MMRM analysis as above will be performed for each of the 3 
EXACT-PRO subscores. 
The following figure will be produced for the EXACT-PRO total score and each of the 3 EXACT-
PRO subscores: 
 
Mean EXACT-PRO Rolling Average over time for Day 1 to Day 29 by treatment regimen 
Improvement based on EXACT-PRO total score is defined as a decrease in the Rolling Average 
EXACT score ≥ 9 points from the previous day’s Maximum Observed Value during an event. 


 
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Time to EXACT-PRO improvement will be analysed using the Kaplan-Meier method. Patients 
without any EXACT-PRO improvement from baseline over the observed period (Day 1 to Day 29) 
or who are discontinued before reaching it will be considered as “censored” patients. 
For the following study periods: Day 1, Days 2-3, Days 4-5, Days 6-7, Days 8-10, Days 11-14 and 
Days 15-29, the number of patients without an improvement of EXACT-PRO total score from 
baseline at the beginning of the period, the cumulative number of patients with an EXACT-PRO 
improvement at the end of the period and the probability of improvement at the end of the period 
with the associate two-sided 95% CIs will be presented by treatment regimen. The point estimates 
and the relative two-sided 95% CIs will be presented by treatment regimen for the 75th, 50th and 
25th percentiles. A Kaplan-Meier plot will also be presented. Comparisons between treatment 
regimens will be performed by means of the log-rank test. The p-values of the pairwise log-rank 
test comparisons will be displayed on the figure. 
8.6.3.8 Time to recovery based on EXACT-PRO total score 
Recovery based on EXACT-PRO total score is defined as the first day in which a patient 
experiences a persistent, sustained improvement in their condition over the observed period (Day 1 
to Day 29). Improvement (as defined above) must be present for 7 consecutive days. The first day 
of the 7-day period is designated as the first day of Recovery.  
Time to EXACT-PRO recovery will be analysed using the Kaplan-Meier method. Patients without 
any EXACT-PRO recovery from baseline over the observed period (Day 1 to Day 29) or who are 
discontinued before reaching it will be considered as “censored” patients. 
For the following study periods: Day 1, Days 2-3, Days 4-5, Days 6-7, Days 8-10, Days 11-14 and 
Days 15-29, the number of patients without a recovery of EXACT-PRO total score from baseline at 
the beginning of the period, the cumulative number of patients with an EXACT-PRO recovery at 
the end of the period and the probability of recovery at the end of the period with the associate two-
sided 95% CIs will be presented by treatment regimen. The point estimates and the relative two-
sided 95% CIs will be presented by treatment regimen for the 75th, 50th and 25th percentiles. A 
Kaplan-Meier plot will also be presented. Comparisons between treatment regimens will be 
performed by means of the log-rank test. The p-values of the pairwise log-rank test comparisons 
will be displayed on the figure. 
8.6.3.9 Standardised AUC of EXACT-PRO over time 
The standardised AUCs of EXACT-PRO (Day 1 to Day 3, Day 1 to Day 5, Day 1 to Day 7, Day 1 
to Day 10, Day 1 to Day 14, Day 1 to Day 29) will be derived and summarised with standard 
descriptive statistics by treatment regimen.  
The standardised AUC from Day 1 to Day 14 will be analysed using an ANCOVA model 
estimating the effect up to Day 14, using OC, including treatment, severity of airflow limitation at 
baseline, blood eosinophils (%) value at baseline, time from start of current COPD exacerbation to 


 
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first IMP dosing, presence of cardiovascular comorbidities at screening and COPD exacerbation 
treatment at screening as fixed effects and baseline EXACT-PRO Rolling Average score as a 
covariate. 
The ANCOVA model results will be presented with LSMEAN and standard error (SE) of each 
treatment regimen as well as the adjusted mean difference between treatment regimens at Day 14 
and associated two-sided 95% CIs. Each pairwise treatment regimen comparison will be tested at 
an alpha level of 5%. P-values of the effects will also be presented.  
A similar ANCOVA model will be used to analyse the standardised AUC of EXACT-PRO from 
Day 1 to Day 7 and from Day 1 to Day 10. 
All the analyses above will be repeated for each of the 3 EXACT-PRO subscores AUCs. 
8.6.3.10 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 
All EXACT-PRO rolling average scores available will be summarised at baseline (Day 1 pre-dose) 
and at specific timepoints during the Acute Exacerbation Phase (Day 3, Day 5, Day 7, Day 10, Day 
14) by treatment regimen using descriptive statistics. The improvements (changes) in EXACT-PRO 
rolling average score from baseline (Day 1 pre-dose) will also be summarised at these timepoints 
by treatment regimen (See SAP Section 8.6.3.7). Considering Stabilisation Phase, All EXACT-
PRO rolling average scores available will be summarised at baseline (Stabilisation Phase), Day 29 
(end of Week 4), Day 57 (end of Week 8), Day 85 (end of Week 12), Day 113 (end of Week 16), 
Day 141 (end of Week 20), Day 169 (end of Week 24) and Week 26 Visit during the Stabilisation 
Phase by treatment regimen using descriptive statistics. The changes in EXACT-PRO rolling 
average score from baseline (Stabilisation Phase) will also be summarised at these timepoints by 
treatment regimen. 
The following figures will be produced for the EXACT-PRO rolling average score: 
 
Mean EXACT-PRO rolling average score over time by treatment regimen (Acute 
Exacerbation Phase and Stabilisation Phase separately). 
 
Mean EXACT-PRO rolling average score change from baseline over time by treatment 
regimen (Acute Exacerbation Phase and Stabilisation Phase separately). 
The same analysis as above will be performed for each of the 3 EXACT-PRO subscores. 
8.6.3.11 Number of COPD-related exacerbations during the study derived 
from ‘Acute Exacerbation COPD’ form of the eCRF 
COPD-related exacerbations during the study derived from the ‘Acute Exacerbation COPD’ form 
of the eCRF will be considered for this analysis.  


 
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Only COPD exacerbations with symptoms start date ≥ first study treatment intake on the form will 
be included in the analysis. The ‘date when symptoms started’ recorded on the form will be defined 
as the start date of the COPD exacerbation. 
The number and the percentage of patients with COPD exacerbations, the number of COPD 
exacerbations and the total follow-up time in years will be summarised by treatment regimen. 
The rate of COPD exacerbations per patient per year will be calculated for each treatment regimen 
using a weighted approach (which consists of pooling all patients of a treatment regimen and 
dividing the total number of COPD exacerbations by the total follow-up time). 
The number and the percentage of patients with COPD exacerbations, the number of COPD 
exacerbations and the COPD exacerbation rate per patient per year as above will also be presented 
by treatment regimen for each of the following types of COPD exacerbation: 
 
Mild COPD exacerbations (intensity recorded as ‘Mild’ on the form) 
 
Moderate COPD exacerbations (intensity recorded as ‘Moderate’ on the form) 
 
Severe COPD exacerbations (intensity recorded as ‘Severe’ on the form) 
 
Moderate/Severe COPD exacerbations (intensity recorded as ‘Moderate’ or ‘Severe’ on the 
form) 
 
COPD exacerbations resulting in death (i.e. COPD-related deaths; serious criteria ‘Results 
in death’ ticked on the form) 
 
COPD exacerbations requiring hospitalisation (i.e. serious criteria ‘Requires in-patient 
hospitalisation or prolongs existing hospitalisation’ ticked on the form). 
Additionally (and more generally), the number (%) of patients with COPD exacerbations and the 
number of COPD exacerbations will be presented by treatment regimen for each of the following 
category: 
 
COPD exacerbations treated with systemic corticosteroids only (box ticked on the form) 
 
COPD exacerbations treated with antibiotics only (box ticked) 
 
COPD exacerbations treated with systemic corticosteroids and antibiotics (both boxes 
ticked) 
 
COPD exacerbations requiring invasive ventilation support (box ticked) 
 
COPD exacerbations requiring non-invasive ventilation support (box ticked) 
 
COPD exacerbations requiring Intensive Care Unit (ICU) admission (box ticked) 
 
COPD exacerbations with each of the following aetiologies: Infection, Environmental 
pollutants, 
Extrapulmonary 
co-morbidities, 
Concomitant 
pulmonary 
co-morbidities, 
Allergic, Other, Missing (if no aetiology was recorded). A multiple aetiology is possible: in 
this case the exacerbation will be counted in all the relevant categories. 
The proportion of patients with COPD-related exacerbations during the study will be compared 
between treatment regimens using Pearson’s Chi-square test (or Fisher’s exact test as appropriate) 


 
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(two-sided test at 5% alpha level). This comparison will also be made for mild COPD-related 
exacerbations, for moderate COPD-related exacerbations, for severe COPD-related exacerbations 
and for moderate/severe COPD-related exacerbations separately. 
Finally, the following acute COPD exacerbation characteristics data (from ‘Acute Exacerbation 
COPD’ form of the eCRF) will be summarised by treatment regimen and overall for ITT and PP 
populations: duration of acute COPD exacerbation symptoms (days), time until complete recovery 
from the acute COPD exacerbation (days) (if completely recovered), COPD medication category 
(systemic corticosteroids/antibiotics) for treating the acute exacerbation, hospitalisation data, 
oxygen therapy and ventilation support data, worsening of respiratory symptoms (breathlessness, 
wheeze, cough, reduction in exercise tolerance, fever, change in sputum production [change in 
quantity; aspect purulent vs. non purulent], unusual increase of use of “rescue” medication, other 
worsened symptoms) and COPD exacerbation aetiology (primary and secondary reasons). 
Likewise, additional investigations performed for acute COPD exacerbation data (microbiology 
culture, arterial blood gases, chest X-ray, chest CT scan, other) will be summarised by treatment 
regimen and overall using the ITT and PP populations. For patients who experienced more than one 
further COPD exacerbation after the initial COPD exacerbation, the most recent COPD 
exacerbation will be considered for tabulations. 
8.6.3.12 Number of COPD-related deaths during the study 
See section 8.6.3.11 for the derivation of COPD-related deaths. 
The proportion of patients with a COPD-related death during the study will be compared between 
treatment regimens using Fisher’s exact test (two-sided test at 5% alpha level). 
8.6.3.13 Time to next COPD exacerbation 
8.6.3.13.1 Time to next COPD exacerbation derived from ‘Acute Exacerbation 
COPD’ form of the eCRF 
See section 8.6.3.11 for the derivation of COPD-related exacerbations. 
Time to next COPD exacerbation will be analysed using the Kaplan-Meier method. Patients 
without a COPD exacerbation or who are discontinued before having it will be considered as 
“censored” patients. 
For the following study periods: [0-4) weeks, [4-8) weeks, [8-12) weeks, [12-16) weeks, [16-20) 
weeks and [20-26) weeks, the number of COPD exacerbation-free patients at the beginning of the 
period, the cumulative number of patients with COPD exacerbation at the end of the period and the 
probability of having experienced a COPD exacerbation at the end of the period with the associate 
two-sided 95% CIs will be presented by treatment regimen. The point estimates and the relative 
two-sided 95% CIs will be presented by treatment regimen for the 75th, 50th and 25th percentiles. A 
Kaplan-Meier plot will also be presented. Comparisons between treatment regimens will be 


 
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performed by means of the log-rank test. The p-values of the pairwise log-rank test comparisons 
will be displayed on the figure. 
A similar analysis using the Kaplan-Meier method will be performed for: 
 
Time to next mild COPD exacerbation (intensity recorded as ‘Mild’ on the form) 
 
Time to next moderate COPD exacerbation (intensity recorded as ‘Moderate’ on the form) 
 
Time to next severe COPD exacerbation (intensity recorded as ‘Severe’ on the form) 
 
Time to next moderate/severe COPD exacerbation (intensity recorded as ‘Moderate’ or 
‘Severe’ on the form). 
8.6.3.13.2 Time to next COPD exacerbation based on EXACT-PRO total score 
COPD-related exacerbations during the Stabilisation Phase based on EXACT-PRO total score will 
be considered for this analysis. 
Appendix C describes the EXACT raw scores and EXACT scoring instructions to compute the 
EXACT daily scores and event frequency, duration and severity. 
Time to next COPD exacerbation during the Stabilisation Phase will be analysed using the Kaplan-
Meier method. Patients without a COPD exacerbation or who are discontinued before having it will 
be considered as “censored” patients. 
For the following study periods in the Stabilisation phase: [2-6) weeks, [6-10) weeks, [10-14) 
weeks, [14-18) weeks, [18-22) weeks and [22-26) weeks, the number of COPD exacerbation-free 
patients at the beginning of the period, the cumulative number of patients with COPD exacerbation 
at the end of the period and the probability of having experienced a COPD exacerbation at the end 
of the period with the associate two-sided 95% CIs will be presented by treatment regimen. The 
point estimates and the relative two-sided 95% CIs will be presented by treatment regimen for the 
75th, 50th and 25th percentiles. A Kaplan-Meier plot will also be presented. Comparisons between 
treatment regimens will be performed by means of the log-rank test. The p-values of the pairwise 
log-rank test comparisons will be displayed on the figure. 
8.6.3.14 Time from hospitalisation admission until the subject is medically 
ready for discharge (current COPD) 
Time from hospitalisation admission until the subject is medically ready for discharge (current 
COPD) will be analysed using the Kaplan-Meier method. Only patients with initial hospitalisation 
for COPD date on or prior to Study Day 1 (i.e. in hospital on Day 1) are included in this analysis. 
Patients who are discontinued before being medically ready for discharge will be considered as 
“censored” patients. 
For the following study periods: [0-1) days, [1-2) days, [2-3) days, [3-4) days, [4-5) days, [5-6) 
days, [6-7) days, [7-8) days, [8-9) days, [9-10) days, [10-11) days, [11-12) days, [12-13) days, [13-
14) days and [14 days-End of Study], the number of patients not medically ready for discharge at 
the beginning of the period, the cumulative number of patients medically ready for discharge at the 


 
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end of the period and the probability of being medically ready for discharge at the end of the period 
with the associate two-sided 95% CIs will be presented by treatment regimen. The point estimates 
and the relative two-sided 95% CIs will be presented by treatment regimen for the 75th, 50th and 
25th percentiles. A Kaplan-Meier plot will also be presented. Comparisons between treatment 
regimens will be performed by means of the log-rank test. The p-values of the pairwise log-rank 
test comparisons will be displayed on the figure. 
8.6.3.15 Percentage of days with intake of COPD rescue therapy  
Based on ‘Rescue Medication’ form of the eCRF, a descriptive summary of the number and 
proportion of subjects requiring COPD rescue therapy will be provided for each visit per treatment 
regimen. Moreover, the COPD rescue medication category (Monotherapy: Short-Acting 2-
Agonist [SABA] alone, Short-Acting Muscarinic Antagonist [SAMA] alone, Long-Acting β2-
Agonist [LABA] alone; Dual therapy: SABA+SAMA, SABA+Inhaled Corticosteroids [ICS], 
LABA+ICS, LABA+SAMA, LABA+SABA; Other) will be presented for each visit per treatment 
regimen. 
Additionally, the percentage of days with intake of COPD rescue therapy (see Section 7.1.4.12 for 
further details on calculation) will be summarised for each inter-visit period, for the Acute 
Exacerbation Phase and for the Stabilisation Phase separately, using descriptive statistics by 
treatment regimen. 
8.6.4 Analysis of exploratory endpoint(s) 
The analysis of exploratory endpoints will be performed on the ITT and PP populations. 
8.6.4.1 Exploratory composite scale endpoints at Weeks 8, 12 and 26 
The cumulative proportion of patients presenting each of the criteria below during the study will be 
summarised per treatment regimen at Days 30, 60, 90, 120, 150 and 180 and compared between 
treatment regimens at each timepoint using Pearson’s Chi-square test (or Fisher’s exact test as 
appropriate) (two-sided test at 5% alpha level): 
 
Worsening of symptoms warranting the addition of another antibiotic or initiation of a new 
antibiotic 
 
Worsening of symptoms warranting an increase in dose of oral corticosteroids or initiation 
of new oral corticosteroids 
 
Worsening of symptoms requiring additional treatment regimen of oral corticosteroids 
and/or antibiotics after completion of the initial regimen 
 
Re-hospitalisation due to worsening of COPD and requiring additional treatment during the 
duration of the study due to an exacerbation of respiratory symptoms (emergency room 
admission for longer than 24 hours will qualify as a hospitalisation) 
 
COPD-related death. 
 
 


 
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Moreover, the cumulative incidence of CTF (i.e. any one of the individual criteria above is met) 
will be evaluated at Days 30, 60, 90, 120, 150 and 180 and compared between treatment regimens 
at each timepoint using Pearson’s Chi-square test (or Fisher’s exact test as appropriate) (two-sided 
test at 5% alpha level). 
A bar chart will be presented per treatment regimen showing the cumulative incidence of CTF at 
Days 30, 60, 90, 120, 150 and 180. 
In addition, time to CTF will be analysed using the Kaplan-Meier method. Patients who don’t meet 
any one of the individual criteria above or who are discontinued before having it will be considered 
as “censored” patients. 
For the following study periods: [0-4) weeks, [4-8) weeks, [8-12) weeks, [12-16) weeks, [16-20) 
weeks and [20-26) weeks, the number of clinical treatment failure-free patients at the beginning of 
the period, the cumulative number of patients with CTF at the end of the period and the probability 
of having experienced a CTF at the end of the period with the associate two-sided 95% CIs will be 
presented by treatment regimen. The point estimates and the relative two-sided 95% CIs will be 
presented by treatment regimen for the 75th, 50th and 25th percentiles. A Kaplan-Meier plot will also 
be presented. Comparisons between treatment regimens will be performed by means of the log-
rank test. The p-values of the pairwise log-rank test comparisons will be displayed on the figure. 
8.6.4.2 Change in CRQ from Baseline at Day 14 and Weeks 8, 12 and 26 
This exploratory endpoint will be analysed separately during the Acute Exacerbation Phase (from 
Study Day 1 until Day 14 included) and the Stabilisation Phase (from Day 14 until Week 26). 
The CRQ total score and domain scores will be summarised at each visit by treatment group using 
descriptive statistics. Changes in CRQ from baseline (Visit 1 pre-dose) will be summarised at Day 
14 during the Acute Exacerbation Phase by treatment regimen. Changes in CRQ from baseline 
(Visit 9, Day 14) will also be summarised at each post-baseline visit (Weeks 8, 12 and 26) during 
the Stabilisation Phase by treatment regimen. 
Change in CRQ total score from baseline (Visit 1 pre-dose) to Day 14 (Acute Exacerbation Phase) 
will be analysed using an ANCOVA model estimating the effect at Day 14, using OC, including 
treatment, severity of airflow limitation at baseline (pre-dose), blood eosinophils (%) value at 
baseline (pre-dose), time from start of current COPD exacerbation to first IMP dosing, presence of 
cardiovascular comorbidities at screening and COPD exacerbation treatment at screening as fixed 
effects and baseline CRQ total score (Visit 1 pre-dose) as a covariate. 
The ANCOVA model results will be presented with LSMEAN and standard error (SE) of each 
treatment regimen as well as the adjusted mean difference between treatment regimens at Day 14 
and associated two-sided 95% CIs. Each pairwise treatment regimen comparison will be tested at 
an alpha level of 5%. P-values of the effects will also be presented.  


 
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A similar ANCOVA analysis as above will be performed for each of the 3 CRQ domain scores 
during the Acute Exacerbation Phase. 
MMRM analysis using an unstructured covariance matrix and the Kenward-Roger adjustment for 
the denominator degrees of freedom will be performed for statistical comparison of treatment 
regimens during the Stabilisation Phase with change in CRQ total score as an outcome. Model will 
consider treatment, severity of airflow limitation at baseline (pre-dose), blood eosinophils (%) 
value at baseline (pre-dose), time from start of current COPD exacerbation to first IMP dosing, 
presence of cardiovascular comorbidities at screening and COPD exacerbation treatment at 
screening as fixed effects and baseline CRQ total score (Visit 9/Day 14) as covariate. In addition 
the baseline CRQ total score-by-visit and the treatment-by-visit interactions will be included in the 
model. 
LSMEAN and standard error (SE) of each treatment regimen, difference of LSMEANS between 
treatment regimens and their associated  two-sided 95% CIs and corresponding two-sided P-values 
for Weeks 8, 12 and 26 (Stabilisation Phase) will be estimated by the model. P-values of the effects 
will also be presented. 
The unstructured covariance matrix (which does not presume a particular correlation structure for 
repeated measurements within patients over time) will be used to adjust for the within-patient error 
variance covariance. In case model fails to converge, other covariance matrix structures will be 
considered in the sequence of Ante-dependence, Toeplitz, Heterogeneous AR(1), Heterogeneous 
Compound Symmetry, and Compound Symmetry. 
A similar MMRM analysis as above will be performed for each of the 3 CRQ domain scores during 
the Stabilisation Phase. 
A figure with adjusted mean change from baseline (Visit 9/Day 14) in CRQ total score and domain 
scores at each visit during the Stabilisation Phase by treatment regimen derived from the linear 
mixed model will also be provided for each score. 
8.6.4.3 Cumulative oral/IV steroid dose during the duration of current COPD 
exacerbation 
A descriptive summary table will be presented by treatment regimen for the cumulative oral/IV 
steroid dose (prednisone equivalent dose) during the duration of current COPD exacerbation. The 
cumulative prednisone dose will be compared between treatment regimens using a one-way 
ANOVA test, and the associated two-sided p-value will be reported in the summary table. 
Should the normality assumptions for cumulative prednisone dose not be met (the skewness and 
kurtosis measurements will be considered as supportive indicators), the relationship between 
cumulative prednisone dose and treatment regimen will be tested using the non-parametric 
approach of Kruskal-Wallis test (or Wilcoxon Rank-Sum test for pairwise treatment regimens).  


 
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8.6.4.4 Change in inflammatory blood biomarkers 
Blood biomarkers parameters (IL-6, TNF-α, Fibrinogen, Hs-CRP, MPO) will be measured on days 
1 to 7, days 10 and 14, and at Week 8, 12 and 26. 
Biomarker data are reported as concentration results, measured using a specific assay with a 
working range defined by the two limits: Lower limit of quantification (LLOQ) and Upper limit of 
quantification (ULOQ). Values which fall below the LLOQ or above the ULOQ are reported as < 
LLOQ * dilution factor (dilution factor: if sample diluted and concentration measured still below 
LLOQ) and > ULOQ * dilution factor, respectively. 
All results for the above biomarker parameters, if collected, will be summarised on the ITT and PP 
populations by descriptive statistics stratified by treatment regimen and time-point, and including 
the geometric mean and coefficient of variation. Changes in the biomarker concentrations from 
baseline (Study Day 1 pre-dose) will be also summarised at each post-baseline time-point. 
In the summary table, the frequency (n, %) of values below the LLOQ and above the ULOQ, 
respectively, will be included. 
In case of censored values (values below the LLOQ and/or values above the ULOQ), the values 
reported as <LLOQ will be imputed as 0.5*LLOQ and values reported as >ULOQ will be imputed 
as 1.5*ULOQ. 
8.6.4.5 Change from Baseline in mMRC dyspnoea scale over time 
This exploratory endpoint will be analysed separately during the Acute Exacerbation Phase (from 
Study Day 1 until Day 14 included) and the Stabilisation Phase (from Day 14 until Week 26). 
The mMRC dyspnoea scale (graded from 0 to 4) will be summarised at each visit by treatment 
regimen using descriptive statistics. Changes in mMRC dyspnoea scale from baseline (Visit 1 pre-
dose) will be summarised at each post-baseline visit (Day 7 and Day 14) during the Acute 
Exacerbation Phase by treatment regimen. Changes in mMRC dyspnoea scale from baseline (Visit 
9, Day 14) will also be summarised at each post-baseline visit (Weeks 8, 12 and 26) during the 
Stabilisation Phase by treatment regimen. 
MMRM analysis using an unstructured covariance matrix and the Kenward-Roger adjustment for 
the denominator degrees of freedom will be performed for statistical comparison of treatment 
regimens with change in mMRC as an outcome. MMRM analyses will be done separately for the 
Acute Exacerbation Phase and for the Stabilisation Phase. Both models will consider treatment, 
severity of airflow limitation at baseline (pre-dose), blood eosinophils (%) value at baseline (pre-
dose), time from start of current COPD exacerbation to first IMP dosing, presence of 
cardiovascular comorbidities at screening and COPD exacerbation treatment at screening as fixed 
effects and baseline mMRC (Visit 1 pre-dose for the Acute Exacerbation Phase, Visit 9/Day 14 for 
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visit interactions will be included in the model. 
LSMEAN and standard error (SE) of each treatment regimen, difference of LSMEANS between 
treatment regimens and their associated two-sided 95% CIs and corresponding two-sided P-values 
for Day 7, Day 14 (Acute Exacerbation Phase) and Weeks 8, 12 and 26 (Stabilisation Phase) will 
be estimated by the model. P-values of the effects will also be presented. 
The unstructured covariance matrix (which does not presume a particular correlation structure for 
repeated measurements within patients over time) will be used to adjust for the within-patient error 
variance covariance. In case model fails to converge, other covariance matrix structures will be 
considered in the sequence of Ante-dependence, Toeplitz, Heterogeneous AR(1), Heterogeneous 
Compound Symmetry, and Compound Symmetry. 
A figure with adjusted mean change from baseline (Visit 1 pre-dose) in mMRC dyspnoea scale at 
each visit during the Acute Exacerbation Phase by treatment regimen derived from the linear mixed 
model will be provided. A similar figure with adjusted mean change from baseline (Visit 9/Day 14) 
in mMRC dyspnoea scale will also be provided for the Stabilisation Phase separately. 
8.6.4.6 BODE index at Day 14 
A descriptive summary table will be presented for BODE index at Day 14 by treatment regimen. 
BODE index at Day 14 will be compared between treatment regimens using a one-way ANOVA 
test, and the associated two-sided p-value will be reported in the summary table. 
Should the normality assumptions for BODE index at Day 14 not be met (the skewness and 
kurtosis measurements will be considered as supportive indicators), the relationship between 
BODE index at Day 14 and treatment regimen will be tested using the non-parametric approach of 
Kruskal-Wallis test (or Wilcoxon Rank-Sum test for pairwise treatment regimens).  
For the subgroup of patients enrolled in the study under protocols V2.0 and V3.0, a separate 
descriptive summary table will be presented for BODE index at baseline (Visit 1 pre-dose), Day 7, 
Day 14, Week 8, Week 12 and Week 26 by treatment regimen. Due to the small number of patients 
involved, no statistical comparison between treatment regimens will be performed. 
8.7 
Safety analyses 
All definitions relative to safety endpoints are detailed in Section 7.1.5. 
All the safety analyses will be based on the Safety population (treated subject) and will be 
performed for all safety variables specified below. 
In order to assess the safety and tolerability of two different dosing regimens of BCT197 added to 
SoC versus placebo added to SoC in patients with severe acute exacerbations of COPD, all subjects 
will have routine safety monitoring throughout the study, including TEAEs/SAEs, TEAEs of 
special interest (pneumonia, rash/acneiform dermatitis/pruritus, cervical/vaginal inflammation, 


 
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headache and liver enzymes), 12-Lead ECGs, vital signs, clinical laboratory assessments 
(haematology, blood chemistry, urinalysis, pregnancy tests) and quantitative sputum cultures. 
The safety parameters collected and changes in these parameters from baseline will be summarised 
for the treatment regimens separately using standard tabulations and listings. The patients who did 
not receive the treatment planned by the randomisation will be analysed per the treatment received. 
No statistical test will be performed. 
8.7.1 Adverse events 
All AEs will be classified by SOC and PT according to the MedDRA Version 20.0 or higher.  
AEs will be classified as pre-treatment AEs or TEAEs. Additionally, TEAES will be classified as 
occurring during the Acute Exacerbation Phase (from Study Day 1 until Day 14 included) or 
occurring during the Stabilisation Phase (after Day 14 until Week 26). 
Details for imputing missing or partial start dates of adverse events are described in Section 7.2.2.4. 
Acute exacerbations of COPD reported in the ‘Acute Exacerbation COPD’ form of the eCRF will 
also be included in the analysis of AEs (tables and listings). 
Notes: 
 
Two AEs with the same PT and classified in the same category (pre-treatment AE or 
TEAE) will be considered as two different events when calculating the “number of 
events” in the tables.  
 
Where a subject has the same AE, based on preferred terminology, reported multiple 
times in the same category (pre-treatment AE or TEAE), the subject will only be 
counted once at the preferred terminology level in AE frequency tables. 
 
Where a subject has multiple AEs within the same SOC in the same category (pre-
treatment AE or TEAE), the subject will only be counted once at the SOC level in AE 
frequency tables. 
Pre-treatment AEs and TEAEs will be presented separately. Pre-treatment AEs will be presented in 
the listings only. 
An overall summary of AEs will be provided. The total number of events and number and 
proportion of subjects experiencing any AEs, TEAEs, TEAEs of special interest, AEs related to 
study medication, SAEs, SAEs related to study medication, severe AEs, AEs leading to permanent 
discontinuation of study treatment and AEs leading to death will be tabulated for each treatment 
regimen and overall. This overall summary of AEs will also be provided for TEAEs occurred 
during the Acute Exacerbation Phase and for TEAEs occurred during the Stabilisation Phase 
separately. 
Additionally, TEAEs, TEAEs of special interest, related TEAEs, serious TEAEs, related SAEs, 
severe TEAEs, AEs leading to permanent discontinuation of study treatment and AEs leading to 


 
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death will be summarised by SOC and PT for each treatment regimen and overall (number and 
percentage of subjects experiencing at least one AE per PT as well as the number of observed 
events per PT). All TEAEs will also be summarised separately by maximum severity grade for 
each SOC and PT and by relationship to study medication for each SOC and PT. These 
summarisations of TEAEs will also be provided for TEAEs occurred during the Acute 
Exacerbation Phase and for TEAEs occurred during the Stabilisation Phase separately. 
A table presenting the number and percentage of subjects with at least one AE and the number of 
AEs for the most common treatment-emergent AEs (reported in ≥ 1% of patients in any treatment 
regimen) will be provided. PTs will be used for tabulation, sorted by decreasing overall frequency. 
This table will also be presented for TEAEs occurred during the Acute Exacerbation Phase and for 
TEAEs occurred during the Stabilisation Phase separately. 
The number and percentage of subjects with any treatment-emergent pneumonias, pneumonias 
related to study medication, serious pneumonias, serious pneumonias related to study medication, 
severe pneumonias, pneumonias leading to permanent discontinuation of study treatment, 
pneumonias leading to death will be presented by treatment regimen and overall. The number of 
events will also be displayed. This table will also be presented for treatment-emergent pneumonias 
occurred during the Acute Exacerbation Phase and for treatment-emergent pneumonias occurred 
during the Stabilisation Phase separately. 
Treatment-emergent pneumonias will be analysed in terms of rate per 1’000 patient per year. The 
follow-up time (in years) will be calculated using the following formula:  
(date of last contact - date of first study treatment + 1) / 365.25 
The rate of treatment-emergent pneumonia per 1’000 patient per year will be calculated for each 
treatment using a weighted approach (which consists of pooling all patients of a treatment regimen 
and dividing the total number of events by the total follow-up time, multiplying the result by 1000). 
All AEs will be presented in full in a comprehensive listing including subject number, treatment 
regimen, severity, seriousness, actions taken, outcome, relationship to treatment, onset/stop and 
duration. Details of all AEs (pre-treatment AEs, TEAEs during the Acute Exacerbation Phase and 
TEAEs during the Stabilisation Phase separately), TEAEs of special interest, SAEs, AEs leading to 
permanent discontinuation of study treatment and AEs leading to death will be listed separately.  
8.7.2 Clinical laboratory evaluations 
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 


 
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laboratory for analysis, with the exception of urine dipstick pregnancy test that should be done at 
the local laboratory. The following laboratory parameters will be assessed: 
 
Blood chemistry: 
o Creatinine 
o Blood urea nitrogen [BUN] 
o Fasting serum glucose  
o Aspartate aminotransferase [AST] 
o Alanine aminotransferase [ALT] 
o Gamma-glutamyl transpeptidase 
o Total bilirubin 
o Albumin 
o Chloride 
o Calcium 
o Phosphorous 
o Uric acid 
o Total protein 
o Sodium 
o Potassium. 
 
Haematology: 
o Red Blood Cell Count [RBC] 
o White Blood Cell Count [WBC] 
o Neutrophils 
o Lymphocytes 
o Monocytes 
o Eosinophils 
o Basophils 
o Haemoglobin 
o Haematocrit 
o Platelets 
o INR (not required during the Stabilisation Phase) 
o Prothrombin time (not required during the Stabilisation Phase). 
 
Urinalysis: 
o Specific gravity 
o pH 
o Protein 
o Glucose 
o Blood. 
 
 


 
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 
Pregnancy test: 
o Serum β-HCG 
o Urinary pregnancy test. 
For the purposes of summarisation in both the tables and listings, all clinical laboratory data will be 
reported in Standard International (SI) units.  
If a lab value is reported using a nonnumeric qualifier e.g., less than (<) a certain value, or greater 
than (>) a certain value, the given numeric value will be used in the summary statistics, ignoring 
the nonnumeric qualifier. 
Descriptive statistics will be presented for quantitative clinical 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 individual data 
listings along with the Investigator’s assessment. 
In addition, the number and percentages of subjects with laboratory values for liver function and 
enzymes of clinical concern7 as follows will be presented descriptively per treatment regimen 
during the Acute Exacerbation Phase. 
Parameter 
Level for clinical concern 
ALT 
> 1.5 times the upper limit of the 
normal range (ULN) 
> 2xULN 
> 3xULN 
> 5xULN 
> 10xULN 
AST 
> 1.5xULN 
> 2xULN  
> 3xULN 
> 5xULN 
> 10xULN 
Bilirubin Total 
> 2xULN 
> 3xULN 
ALT/AST and Bilirubin Total 
ALT/AST> 3xULN and Bilirubin 
Total> 2xULN 
Haematology, blood chemistry, pregnancy test results and qualitative urinalysis parameters 
(protein, glucose and blood) will be listed, including data from scheduled and unscheduled 
timepoints. 


 
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8.7.3 Vital signs 
Vital signs will be performed at each visit in the Acute Exacerbation Phase and in the Stabilisation 
Phase. 
Descriptive statistics (absolute values and changes from baseline) will be presented for each 
treatment regimen and time-point for vital sign measurements (body temperature, RR, PR, SBP, 
DBP, blood oxygen [measured using a pulse oximeter]).  
A data listing of vital signs will also be provided. 
8.7.4 Physical examinations 
Physical examination will be performed at each visit in the Acute Exacerbation Phase and in the 
Stabilisation Phase. 
The number and percentage of patients experiencing an abnormal physical examination finding will 
be presented per body system for each treatment regimen and time-point. 
All physical examination data and abnormalities will be listed by subject and body system. 
8.7.5 Electrocardiograms 
A central ECG laboratory will be used. ECG assessments will be performed at each visit in the 
Acute Exacerbation Phase (Days 1, 3, and 5 pre-dose). For patients enrolled in the study under 
protocols V4.0 and V5.0, additional ECGs will be performed at any 2 of the 3 IMP dosings (Days 
1, 3, or 5) and at PK sample times (pre-dose, 0-2 h post-dose, 4-8 h post-dose, > 12h post-dose). 
Descriptive statistics (absolute values and changes from baseline) will be presented for the 12-lead 
ECG measurements for each treatment regimen and time-point (per visit, and separately for 
multiple assessments within a visit) for ECG parameters (HR, RR interval, PR interval, QRS 
interval, QT interval, QTcB interval and QTcF interval). Within a visit change from pre-dose 
summaries to each post-dose (0-2 h, 4-8 h, > 12h) PK ECG assessment will also be produced. In 
addition, the overall ECG interpretation will be summarised by presenting the number and 
percentage of subjects with “Normal”, “Abnormal, NCS” and “Abnormal, CS” for each treatment 
regimen and time-point (per visit, and separately for multiple assessments within a visit).  
A separate descriptive summary of ECG assessments will be performed for the subgroup of 
patients enrolled in the study under protocols V4.0 and V5.0. 
A data listing of ECG measurements will be provided. 
8.7.6 Sputum for microbiology culture 
If sputum for microbiology culture is collected for clinical purposes, the results from sputum 
culture (qualitative and quantitative) will be listed. 


 
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8.7.7 Other safety assessments 
Gynaecological assessment (including assessment of inflammation of cervix and vagina), acute 
COPD exacerbation assessment, additional investigations for COPD exacerbation, additional 
investigations for pneumonia and dermatologic assessment data will be listed. 
8.8 
Other analysis 
8.8.1 Efficacy analyses based on acute exacerbations of COPD adjudication 
An independent, external IAC has been set-up to carry out responsibilities as detailed in the 
Independent Adjudication Committee Charter, Final Version 1.0, dated 07 February 2017.  
Specific details regarding procedures for clinical adjudication of the components of the endpoint as 
well as the adjudication data collection/transfer process are fully described in the following 
documents: 
 
IAC Charter 
 
Systems Requirements Specifications, Final Version 2.0, dated 28 February 2017 
 
Data Delivery Specification, Final Version 1.0, dated 10 May 2017. 
Once subjects have completed study treatment, the events to be adjudicated by the IAC are all new 
reports of acute exacerbation of COPD and events of hospitalisation due to new exacerbations of 
COPD (dataset AECOPD – AECOPD Adjudication Assessment). Each Adjudication case will be 
reviewed independently by each of the three adjudicators. If the adjudicators agree on all non-text 
fields the case will be complete and final. If they do not agree, they will meet and complete in 
Consensus.  
The data derivations and statistical analyses to be performed based on acute exacerbations of 
COPD adjudication are described below: 
 
Number and percentage of patients with positively adjudicated moderate/severe COPD 
exacerbations will be provided by treatment regimen 
 
Number of positively adjudicated moderate/severe COPD exacerbations during the study 
will be provided by treatment regimen 
 
Rate of positively adjudicated moderate/severe COPD exacerbations per patient per year 
will be provided for each treatment regimen (same approach as for the non-adjudicated 
data) 
 
The proportion of patients with positively adjudicated moderate/severe COPD 
exacerbations during the study will be compared between treatment regimens using 
Pearson’s Chi-square test (or Fisher’s exact test as appropriate) (two-sided test at 5% alpha 
level) 
 
The time to next positively adjudicated moderate/severe COPD exacerbation will be 
analysed using the Kaplan-Meier method. Patients without a positively adjudicated 
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considered as “censored” patients. The same approach as for the non-adjudicated data will 
be used. 
 
Similar analyses as above will be performed for positively adjudicated moderate COPD 
exacerbations and for positively adjudicated severe COPD exacerbations separately. 
8.8.2 PK/PD analyses 
Subjects 
 sample to be take
taken 4-8 hours post-dose, and one sample no earlier than 12 hours post-dose.  
This plan does not address the PK/PD analyses of BCT197 (nonlinear mixed effects PK/PD 
modelling evaluating the relationship between BCT197 exposure and efficacy/safety endpoints) for 
this study. These analyses will be performed by ICON Pharmacokinetics, Pharmacodynamics, 
Modelling and Simulation Department and will be detailed in a separate analysis plan. Results from 
the PK/PD modelling will be reported separately from the CSR. An overview of the PK/PD 
analyses of BCT197 is provided here: “A population PK model for BCT197 will be developed 
using nonlinear mixed effects and the sparsely sampled PK concentration, from which measures of 
BCT197 exposure will be derived. If necessary, additional PK data from more intensively sampled 
studies will be included to support the development of the structural model. The population PK 
model will also evaluate the potential influence of demographic factors and covariates on the PK of 
BCT197. A graphical exploration will be undertaken to identify potential relationships between 
BCT197 exposure and selected efficacy/safety endpoints to be formally evaluated using nonlinear 
mixed effects modelling (including BCT197 exposure/QTc modelling)”. 
BCT197 concentrations will be summarised on the PK population by descriptive statistics stratified 
by BCT197 dose-level and time-point, and including the geometric mean and coefficient of 
variation. 
A graphical representation of the BCT197 concentrations distribution using mean plots (mean and 
SD) will be provided over time per BCT197 dose-level on the PK population. Both dose-levels will 
be plotted on the same graph. 
8.8.3 Subgroup analysis 
To verify the internal consistency of the trial data and results, statistical analyses of the primary 
efficacy endpoint, i.e. summarisation of FEV1 results (absolute values and changes from baseline) 
by treatment regimen and visit (until Day 7) on the ITT population, will be repeated for the 
following subgroups of patients: 
 
Severity of COPD disease at screening (Gold C, Gold D) 
 
Sex (Males, Females) 
 
Geographic region (Europe, Rest of World) 
 
Blood eosinophils relative count (%) at baseline (< 2%, ≥ 2%) 


 
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 
FEV1 % of predicted normal value post-bronchodilator at baseline (based on tertiles) 
 
FEV1 absolute value post-bronchodilator at baseline (based on tertiles) 
 
FEV1/FVC % of predicted normal value post-bronchodilator at baseline (based on tertiles) 
 
FEV1/FVC absolute value post-bronchodilator at baseline (based on tertiles) 
 
COPD exacerbation aetiology (primary reason) at screening (Infection, Environmental 
Pollutants, Extrapulmonary Co-morbidities, Concomitant Pulmonary Co-morbidities, 
Allergic, Other) 
 
Change in sputum production at screening (No Change, Yes: Purulent; Yes: Non Purulent) 
 
Cardiovascular comorbidities at screening (Presence, Absence) 
 
Time from start of current COPD exacerbation to first IMP dosing (≤2 days, 3-4 days or ≥5 
days) 
 
Protocol Version under which the patient was enrolled to (Protocols V2.0 and V3.0, 
Protocols V4.0 and V5.0). 
For each subgroup of patients, the mean change in FEV1 from baseline (pre-dose) to Day 7 will be 
compared between treatment regimens using a one-way ANOVA test, and the associated two-sided 
p-value will be reported in the summary table and regarded as descriptive. 
Should the normality assumptions for change in FEV1 from baseline (pre-dose) to Day 7 not be 
met (the skewness and kurtosis measurements will be considered as supportive indicators), the 
relationship between change in FEV1 from baseline (pre-dose) to Day 7 and treatment regimen will 
be tested using the non-parametric approach of Kruskal-Wallis test (or Wilcoxon Rank-Sum test 
for pairwise treatment regimens). 
8.9 
Interim analysis 
No formal interim analysis is planned for this study. 
However, an independent, external DMC has been set-up to carry out responsibilities as detailed in 
the Data Monitoring Committee Charter, Final Version 1.0, dated 01 February 2016. 
Accumulating unblinded safety data of BCT197 were reviewed periodically (approximately 
quarterly) by the DMC. Should safety concerns be identified, a decision might be taken to halt the 
trial.  
A separate DMC SAP, Final Version 2.0, dated 13 December 2016, has been developed to describe 
the data derivations and data summaries to be presented for the DMC analysis of Clinical Protocol 
MBCT206, for comparing the safety of two different dosing regimens of BCT197 when added to 
SoC versus placebo added to SoC for the treatment of acute respiratory exacerbations of COPD 
requiring hospitalisation in adults. 
 
 


 
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9 
CHANGES TO PLANNED ANALYSIS FROM STUDY PROTOCOL 
 
Definition of PP population: 
The PP definition stated in the protocol was clarified, in that only key inclusion/exclusion 
criteria with respect to factors likely to affect the assessment of efficacy need to be 
satisfied to include a subject in the PP population. 
 
 
PP analyses: 
A PP analysis was added for the secondary and exploratory efficacy endpoints for this PoC 
and hypothesis-generating study. This PP analysis was initially planned in the study 
protocol on the primary efficacy endpoint only. 
 
 
Cumulative oral/IV steroid dose analysis: 
The exploratory endpoint specified in the study protocol is “Cumulative oral/IV steroid 
dose from Day 1 to Day 14 and from Day 14 to Week 26”. This analysis was finally 
performed during the duration of current COPD exacerbation (i.e. from the date when 
symptoms started until the date when symptoms stopped) upon Mereo’s request. Sponsor 
was more interested in the amount of systemic steroids needed to control the current COPD 
exacerbation. 
 
 


 
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10 REFERENCES 
1. 
ICH Topic E9: Statistical Principles for Clinical Trials (CPMP/ICH/363/96 – adopted 
March 1998). 
2. 
Lee Goldman, Andrew I. Schafer. Goldman-Cecil Medicine, 2-Volume Set, 25th Edition 
(June 2015). p. 29. 
3. 
Pellegrino R, Viegi G, Brusasco V, et al. Interpretative strategies for lung function tests. 
Eur Respir J. 2005;26:948-68. 
4. 
Mackay AJ, Donaldson GC, Patel ARC, et al. Detection and severity grading of COPD 
exacerbations using the exacerbations of chronic pulmonary tool (EXACT). Eur Respir J. 
2014;43:735-44. 
5. 
Siddiqui O, et al. MMRM vs. LOCF: a comprehensive comparison based on simulation 
study and 25 NDA datasets. J Biopharm Stat. 2009;19(2):227-46. 
6. 
EXACT-PRO User Manual Version 8.0 dated March 2016 
7. 
Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, 
FDA. Guidance for Industry. Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation. Final, July 2009. 
 
 


 
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11 APPENDICES 
 
 


 
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Appendix A – Summary of Protocol Amendments - Key Changes 
Amendment 
Change 
Rationale 
Protocol Version 2.0, 
Amendment 1 (revisions 
to Protocol Version 1.0) 
Added pulse oximeter measurements as 
part of vital sign measurements to be 
carried out 
At the request of the FDA 
Protocol Version 3.0, 
Amendment 2 (revisions 
to Protocol Version 2.0) 
Laboratory test change: requirement 
for INR and prothrombin time 
sampling and testing after Day 14 
removed  
As the last dose is taken on Day 5, analysis 
of INR and prothrombin time is only 
deemed necessary during the Acute 
Exacerbation Phase  
Protocol Version 3.0, 
Amendment 2 (revisions 
to Protocol Version 2.0) 
Reduction of ECG testing from 
triplicate to a single test  
ECG are no longer required in triplicate by 
the Central Reader  
Protocol Version 3.0, 
Amendment 2 (revisions 
to Protocol Version 2.0) 
Addition of inflammation of cervix and 
vagina as an adverse event of special 
interest  
Align with Investigator’s Brochure at the 
request of the UK Regulatory Agency  
Protocol Version 4.0, 
Amendment 3 (revisions 
to Protocol Version 3.0) 
Modification of inclusion criterion 4 to 
reflect that spirometry in the past 12 
months is required but the result does 
not need to be available before dosing. 
Spirometry is being done at screening and 
this will be used to determine eligibility 
for the study. Historical data is required for 
data analysis demography only. If 
historical values are not available, pre and 
post bronchodilator spirometry will be 
conducted during the stabilization phase, 
for demographic purposes. 
Protocol Version 4.0, 
Amendment 3 (revisions 
to Protocol Version 3.0) 
Modification of inclusion criterion 5 to 
allow subjects who have given up 
smoking in the last 6 months into the 
study. 
The impact of smoking cessation within 6 
months is not significant to the patient 
assessment, within the trial. 
Protocol Version 4.0, 
Amendment 3 (revisions 
to Protocol Version 3.0) 
Increase of FEV1 to <65 % of the 
predicted normal value for inclusion 
criterion 6. 
This will facilitate recruitment of the 
appropriate population and is not 
anticipated to adversely impact safety of 
subjects or efficacy outcomes.  


 
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Protocol Version 4.0, 
Amendment 3 (revisions 
to Protocol Version 3.0) 
Removal of inclusion criterion 7 
regarding post-bronchodilator 
spirometry. 
In the acute exacerbation setting it is 
challenging to conduct pre and post 
bronchodilator spirometry. Therefore, all 
spirometry measurements will be 
performed 'on bronchodilator'.  
Protocol Version 4.0, 
Amendment 3 (revisions 
to Protocol Version 3.0) 
Update of regular medication 
requirements for inclusion criterion 9. 
Restriction changed to allow the use of any 
short acting rescue medication to match 
with standard clinical practice. 
Protocol Version 4.0, 
Amendment 3 (revisions 
to Protocol Version 3.0) 
Removed exclusion criterion of history 
of allergic rhinitis and atopic disease. 
Exclusion only for allergic asthma needed 
to ensure COPD is expected diagnosis.  
Rhinitis and atopic disease exclusion not 
required. 
Protocol Version 4.0, 
Amendment 3 (revisions 
to Protocol Version 3.0) 
Removal of macrolide and calcium 
channels blockers from exclusion 
criterion 3. 
Removed to avoid replication as they are 
covered by exclusion criterion 9. 
Protocol Version 4.0, 
Amendment 3 (revisions 
to Protocol Version 3.0) 
Update of exclusion criterion 10 to 
reflect that only live vaccines should be 
withheld for 30 days before screening. 
Non-live vaccines are required to be 
withheld for only 14 days, the period of 
the immune response to the vaccines. 
Protocol Version 4.0, 
Amendment 3 (revisions 
to Protocol Version 3.0) 
Removal of criterion 14 excluding 
those in whom anti-muscarinic agents 
are contraindicated. 
Antimuscarinic use is not a requirement 
for study participation so this exclusion 
criterion is not required. 
Protocol Version 4.0, 
Amendment 3 (revisions 
to Protocol Version 3.0) 
Removal of exclusion criterion 20 for 
concomitant use of agents that prolong 
the QTc interval.  
Recent PK/PD modelling of available 
clinical data indicates there is no 
concentration – QTc relationship with 
BCT197.  The recent data, in addition to 
the available preclinical data, indicate that 
BCT197 at the concentrations predicted to 
be achieved would not prolong the QTc 
interval. 
Protocol Version 4.0, 
Amendment 3 (revisions 
to Protocol Version 3.0) 
Addition of excluded concomitant 
medication of P-gp inhibitors to 
exclusion criterion 19. 
P-gp inhibitors were previously included 
in the list of excluded medications but not 
included as an exclusion criterion. 


 
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Protocol Version 4.0, 
Amendment 3 (revisions 
to Protocol Version 3.0) 
Addition of exclusion criteria for 
subjects with pneumonia, 
pneumothorax or pulmonary embolus. 
Subjects with these conditions should not 
be enrolled in the study, for subject safety. 
Protocol Version 4.0, 
Amendment 3 (revisions 
to Protocol Version 3.0) 
Modification of spirometry assessment 
and timings to reflect that all 
spirometry will be taken at least 1 hour 
after regular long acting bronchodilator 
administration and 30 minutes after a 
short acting bronchodilator rescue 
medication has been taken.  For 
patients with acute exacerbation it is 
not practical to have FEV1 after 
bronchodilator wash out. 
It is necessary to standardize baseline and 
post study drug assessment of spirometry 
as much as practically possible.  
Protocol Version 4.0, 
Amendment 3 (revisions 
to Protocol Version 3.0) 
Modification to timing of ECG 
assessments. 
BCT197 would not be expected to be 
present in the body at 8, 12 and 26 weeks 
post dose and so ECGs at these time points 
have been removed. Additional ECGs have 
been added at dosing and PK sample times 
to increase safety monitoring and to allow 
for PK/PD analysis of QTc data around the 
time of maximum concentration BCT197 
are included. 
Protocol Version 4.0, 
Amendment 3 (revisions 
to Protocol Version 3.0) 
Collection of baseline information on 
presence of specific symptoms of acute 
exacerbation (increased sputum 
production, increased cough and/or 
increased dyspnea). 
Data required to better characterize the 
patient population. 
Protocol Version 4.0, 
Amendment 3 (revisions 
to Protocol Version 3.0) 
Addition of theophylline to permitted 
concomitant medications. 
May form part of standard care. 
Protocol Version 4.0, 
Amendment 3 (revisions 
to Protocol Version 3.0) 
Six minute walk test has been reduced 
to single measurement at end of acute 
exacerbation. 
The expectation is that subjects will be 
unable to perform this test due to their 
clinical condition in the early part of the 
exacerbation.  A single measurement at 


 
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day 14 gives adequate data. 
Protocol Version 4.0, 
Amendment 3 (revisions 
to Protocol Version 3.0) 
The composite score has been removed 
from Baseline Visit. 
The composite score detects treatment 
failure so should not be included at 
Baseline. 
Protocol Version 4.0, 
Amendment 3 (revisions 
to Protocol Version 3.0) 
Inclusion of vaginal inflammation 
evaluation (history and if indicated by 
symptoms, examination). 
Included following regulatory agency 
feedback. 
Protocol Version 5.0, 
Amendment 4 (revisions 
to Protocol Version 4.0) 
Azithromycin is no longer a prohibited 
medicine as an exclusion criteria 
Results of a drug interaction study with 
BCT197 and azithromycin showed no 
clinically meaningful impact of 
concomitant dosing on BCT197 levels 
Protocol Version 5.0, 
Amendment 4 (revisions 
to Protocol Version 4.0) 
Clarification in prohibited meds that 
the P-gp inhibitor Azithromycin is not 
prohibited  
Results of a drug interaction study with 
BCT197 and azithromycin showed no 
clinically meaningful impact of 
concomitant dosing on BCT197 levels  
Protocol Version 5.0, 
Amendment 4 (revisions 
to Protocol Version 4.0) 
Removal of exclusion of killed vaccine 
in last 14 days as exclusion criterion 
No safety risk in administering killed 
vaccine.  
Protocol Version 5.0, 
Amendment 4 (revisions 
to Protocol Version 4.0) 
Removal of killed vaccine as a 
prohibited medication  
No safety risk in administering killed 
vaccine.  
Protocol Version 5.0, 
Amendment 4 (revisions 
to Protocol Version 4.0) 
Removal of oral requirement for body 
temperature 
There is no requirement for oral body 
temperature and any body site (oral, rectal, 
axillar, etc.) is suitable. 
Protocol Version 5.0, 
Amendment 4 (revisions 
to Protocol Version 4.0) 
Removal of exclusion criteria 7 - 
Subjects requiring long term (at least 
12 hours daily) oxygen therapy for 
chronic hypoxemia  
Reduction of respiratory testing procedures 
in the previous protocol amendment (v4) 
enables patients on long term oxygen 
therapy to undertake the required 
assessments during the study. Therefore, 
there is no longer any need to exclude 
patients on long term oxygen therapy. 
 
 


 
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Appendix B – Protocol Deviations Criteria List 
The list of protocol deviations to be identified and to be included in the body of the CSR is defined 
as: 
 
Failure to obtain written informed consent prior to a patient’s participation in the study 
(Randomised/ITT/PP/Safety/PK) 
 
Patient does not meet one or more of the inclusion criteria (PP) 
 
Patient meets one or more of the exclusion criteria (PP) 
 
Disallowed medications, as per Section 10.6 - Concomitant Therapy of the protocol (PP) 
 
Patient/Investigator unblinded to treatment 
 
Serious Breach of GCP 
 
Incorrect treatment allocation/taken wrong study medication (PP) 
 
Same medication number given to more than one patient 
 
Non-compliance with IMP administration 
 
(ITT/PP/Safety/PK) 
 
Failure to complete spirometry assessments at visits 1-12; in particular failure to complete 
adequate measurement of the primary variable (i.e. Baseline and/or Day 7 FEV1 values not 
provided) (ITT/PP) 
 
Failure to complete BODE at Visit 9 
 
Failure to complete mMRC at visits 1, 7, 9, 10, 11 and 12 
 
Failure to obtain PK samples on 2 of the 3 dosing days (PK) 
 
Failure to complete CRQ at visits 1, 9, 10, 11 and 12 
 
Failure to report a SAE within timelines required by GCP, the protocol and applicable 
regulations 
 
Failure to report AEs of special interest as required by protocol 
 
Temperature excursion where IMP is stored (IMP dispensed to patient) (PP) 
 
Expired IMP administered to a patient (PP) 
 
Drug accountability incomplete to the extent that an IMP kit cannot be 100% traced from 
sponsor/warehouse to site and back (PP) 
 
Patient non-compliance with e-diary 
 
Lack of source data in the patient source – direct entry into the eCRF 
 
IRB/EC was not constituted in accordance with the establishment requirements 
 
IRB/EC review was conducted in an inappropriate procedure such as circulation etc. other 
than normal Meeting 
 
Study visit out-of-window as defined in the current protocol (PP) 
 
Missed study visit (PP) 
 
Missing Central Laboratory assessments 
 
Missing Respiratory Rate results 
 
Missing QTc Interval results. 
 


 
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Appendix C – EXACT Scoring Instructions 
1. Computing EXACT Daily Scores 
Raw Scores 
Raw scores are assigned to each item response option, as shown in Table 1 of this Appendix. Note 
that items 3, 8, 9, 10, 11, and 14 have unique scoring instructions. Item responses should be 
converted to item-level scores as the first step in scoring.  
The recommended programming for the electronic EXACT diary does not allow a study patient to 
skip individual items. If a patient tries to skip a question, a message should appear to prompt the 
patient to complete the question. Thus, no missing data are expected for individual items in the 
electronic data capture setting. If missing values do occur for individual items, the scores for that 
day cannot be calculated and should be set to missing. 
EXACT Total Score 
An EXACT Total score should be computed for each day of diary collection. The EXACT Total 
score is based on a logit scoring system with conversion to a 0 to 100 scale for ease of 
interpretation and use. The scores are computed using a simple conversion table, by hand or 
electronically (e.g., software data interface for ePRO devices or statistical software, such as 
SAS®). To compute the EXACT Total score:  
Convert each original item response code to an item-level raw score, by matching the responses to 
Table 1 below. For example, for question 1, if the data-collection form or system encodes the 
response of “Not at all” as code 1, recode it to a zero (0) to match Table 1, question 1. Note that 
some questions group certain original item response codes into a single item-level raw score; for 
example, question 3 groups original responses of “A little” and “Some” into the item-level raw 
score of 1.  
Sum the item-level raw scores of the 14 EXACT items to form the raw summed score.  
Note: do not sum the original item responses; sum the recoded values obtained in the step described 
above.  
For each raw summed score, look up the corresponding EXACT Total score from Table 2 of this 
appendix. The EXACT Total score ranges from 0 to 100. Sample SAS program code for converting 
raw summed scores to the EXACT Total score is provided in Table 4 of this appendix.  
If the EXACT Total score is 0, change it to missing. This scoring rule is based on previous 
validation work demonstrating that moderate-to-severe COPD patients will experience symptom(s) 
each day, and a score of zero on all 14 EXACT items is likely to represent a situation where in 
order to complete the diary quickly, the respondent did not accurately report their daily 
symptom(s).  
 
 


 
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Where no diary entry exists for a given day, create a record in the data file for that day and enter a 
missing value for the EXACT Total score. Each day a patient is followed in the study must have a 
record for the day, even if there is no data and the EXACT Total score is missing. 
Domain Scores 
Three respiratory symptom domains are also embedded within the EXACT measure: 
Breathlessness, Cough & Sputum, and Chest Symptoms.  
To compute domain scores:  
Item assignments to domains are as follows. Please note that items 4, 12, 13, and 14 do not 
correspond to a domain score and are not used in domain-specific analyses.  
 
Breathlessness – Items 7, 8, 9, 10, and 11  
 
Cough & Sputum – Items 2 and 3  
 
Chest Symptoms – Items 1, 5, and 6. 
For each day, sum the item-level raw scores of the items comprising the domain to form the 
domain raw summed score. If no diary entry exists for a given day, leave the domain raw summed 
score missing. 
Each domain raw summed score has its corresponding “EXACT Domain” score. For each domain 
raw summed score, look up the corresponding EXACT domain score from Table 3 below. If no 
diary entry exists for a given day, leave the EXACT domain score missing. 
If the daily EXACT domain score is 0, change it to missing. This scoring rule is based on previous 
validation work demonstrating that moderate to severe COPD patients will experience symptom(s) 
each day, and a score of zero on all 14 EXACT items is likely to represent a situation where in 
order to complete the diary quickly, the respondent did not accurately report their daily 
symptom(s). 
2. Computing Event Frequency, Duration, and Severity 
All exacerbation parameters are based on the EXACT Total score. 
Baseline EXACT Total Score 
For studies enrolling patients during a stable baseline period, baseline EXACT values are computed 
and used to identify the onset of EXACT events.  
For MBCT206 study, as there is no stable period during which EXACT-PRO scores are collected 
prior to administrating the study drug, the definition of the Baseline EXACT-PRO from the user 
manual will not be used for Acute Exacerbation Phase.  
The score and subscores obtained on Day 1 of the EXACT-PRO observation period, which 
corresponds to Study Day 1, will be used as the baseline for Acute Exacerbation Phase. 
Nevertheless, the definition of the Baseline EXACT-PRO from the user manual will be used for 
Stabilisation Phase. Baseline is defined as a period during which the patient is considered within 


 
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his/her condition as stable or their usual state. The Baseline EXACT-PRO score (or subscores) for 
Stabilisation Phase will therefore be defined as the mean of EXACT-PRO scores from the first 7 
days of the Stabilisation Phase (Week 3; Days 15-21), with a minimum of 4 days of available data 
required to compute the baseline value. If 4 or more of the first 7 days of data are not available, the 
baseline EXACT-PRO score for Stabilisation Phase will not be calculated.  
Resetting Baseline EXACT Total Score (Stabilisation Phase) 
Over the course of the trial, Baseline should be reset every 4 weeks (28 days) in the absence of an 
EXACT-based event to allow for improvements or deterioration in disease state over time, as 
follows: 
Event-free Periods (Stable Reset Baseline – Baseline SR#) 
For patients who do not experience an EXACT-based event during Weeks 4 to 7 of the study, 
Baseline is reset beginning Day 1, Week 8. Data from the last 7 days of the 4 week period (Week 7; 
Days 43–49) are used for this purpose, with a minimum of 4 days of data required to compute the 
reset value (BaselineSR1; mean within patient-score over 7 days). If fewer than 4 days of data are 
available, the Baseline will not be reset; the previous Baseline value (i.e. mean of EXACT-PRO 
scores from the first 7 days of the Stabilisation Phase (Week 3; Days 15-21)) will be used until the 
next reset period.  
Using this reset Baseline (BaselineSR1), the data are examined moving forward from Week 8, Day 1 
for evidence of an EXACT-based event during the subsequent 4 weeks (Week 8, Day 1 to Week 
11, Day 7). In the absence of such an event, the Baseline is reset again (BaselineSR2) beginning Day 
1, Week 12. Data from the last 7 days of the 4 week period (Week 11; Days 1–7) are used for this 
purpose, with a minimum of 4 days of data required to compute the reset value (BaselineSR2). If 
fewer than 4 days of data are available, the Baseline will not be reset; the previous Baseline value 
will be used until the next reset period.  
The resetting process continues every 28 days throughout the duration of the study or until an 
EXACT event occurs (see instructions below). 
Re-Setting Following an EXACT Event (Event Reset Baseline – Baseline ER#) 
If or when an EXACT event occurs during the Stabilisation Phase, the patient’s Baseline value is 
re-established following recovery. To reset Baseline values following an exacerbation, the patient’s 
mean EXACT score during the fourth week following Recovery (Days 22–28 post-Recovery) is 
used. If the patient experiences a new EXACT event during this 4 week period (Days 1 to 28 post-
Recovery), the Baseline is not reset until the fourth week following Recovery from that subsequent 
event. A minimum of 4 days of data are required to reset Baseline. If fewer than 4 days of data are 
available, the Baseline will not be reset; the previous Baseline value (i.e. mean of EXACT-PRO 
scores from the first 7 days of the Stabilisation Phase (Week 3; Days 15-21)) will be used until the 
next reset period. 
 
 


 
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The reset Baseline following Recovery from the first exacerbation (BaselineER1) is used to identify 
subsequent events during the next 4 week period. In the absence of an event during this 4 week 
period, the Baseline value is reset again (BaselineER2), beginning Recovery Week 9, Day 1, using 
data from the final 7 days of the 4-week event-free period (Recovery Week 8; Days 1–7 post-
Recovery). If fewer than 4 days of data are available, the Baseline will not be reset; the previous 
Baseline value will be used until the next reset period.  
This process of resetting Baseline in the absence of an EXACT event continues through the 
duration of the study. 
Event Frequency (Stabilisation Phase) 
Two parameters are required to identify event frequency: (1) Baseline and (2) Onset. Baseline has 
been previously described for Acute Exacerbation Phase and for Stabilisation Phase. Due to the 
design of the study, the EXACT-PRO user manual definition of “Onset” will not be used for Acute 
Exacerbation Phase, and the EXACT-PRO value on Study Day 1 will replace the “Onset” in the 
definitions. Therefore, event frequency will not be identified for Acute exacerbation Phase. 
Nevertheless, the EXACT-PRO user manual definition of “Onset” will be used for Stabilisation 
Phase. Onset is defined as the first day in which the patient experiences an acute, sustained 
worsening of their baseline condition. Therefore, event frequency will be identified for 
Stabilisation Phase. 
Onset 
Onset is identified in 1 of 2 ways: Either (1) an increase in EXACT score ≥12 points above the 
patient’s mean Baseline for 2 consecutive days, with Day 1 of the 2 days serving as Day1 (Onset) 
of the event OR (2) an increase ≥9 points above the patient’s mean Baseline for 3 consecutive 
days, with Day 1 of the 3 days serving as Day1 (Onset) of the event. The presence of either 
constitutes Onset of an event during the Stabilisation Phase. Note that the requirement of 
consecutive days is the reason the data file must have a record for every day for a patient, even if 
the EXACT score is missing. 
Event Duration (Stabilisation Phase) 
Event Duration requires identification of the following parameters: (1) Onset; (2) 3-day Rolling 
Average; (3) Maximum Observed Value; (4) Threshold for Improvement; and (5) Recovery. It is 
possible that Improvement may occur at multiple timepoints during an event and that this 
Improvement may or may not reflect full Recovery. As the EXACT-PRO user manual definition of 
“Onset” will not be used for Acute Exacerbation Phase, event duration will not be identified for 
Acute Exacerbation Phase. Nevertheless, the 4 other parameters will be identified for Acute 
Exacerbation Phase as below. 
On the other hand, the EXACT-PRO user manual definition of “Onset” will be used and event 
duration will be identified for Stabilisation Phase. Therefore, the 5 parameters will be identified for 


 
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Stabilisation Phase as below. 
Three-day Rolling Average 
A 3-day Rolling Average is used to account for day-to-day variability in EXACT scores. This is 
operationalized as a 3-day Rolling of the mean EXACT score [Dayx-1, Dayx, Dayx+1] initiated on 
Study Day 1 (Onset) and ends on Day 1 of recovery. 
The 3-day Rolling Average will be calculated from Study Day 1 to Day 1 of recovery: 
- 
At Day 1, the Rolling Average will be the total score of Study Day 1 (Onset), and will be 
missing if the total score of Study Day 1 is missing 
- 
At Day 2 the Rolling Average will be the total score of Study Day 2, and will be missing if 
the total score of Study Day 2 is missing 
- 
The Rolling Average at any other Day x (including Day 1 of recovery) will be computed as 
the mean of Study Dayx-1, Dayx, Dayx+1, if at least one of Dayx-1, Dayx, Dayx+1 is available. 
Only 1 of the 3 data points needs to be present for this computation.  
Improvement from Day 1 in EXACT-PRO Rolling Average will be calculated as:  
Improvement from Day 1 = Rolling Average at Day 1 - Rolling Average at Day x 
The improvement from Day 1 in EXACT-PRO Rolling Average will be left missing if the Rolling 
Average at Day 1 cannot be computed or if it is missing at Day x. 
Maximum Observed Value between Day 1 and Day 14 
The Maximum Observed Value (MOV) is the highest Rolling Average EXACT score observed in 
the context of an EXACT exacerbation within the first 14 days of the exacerbation (i.e. between 
Day 1 and Day 14). The MOV is allowed to increase over the first 14 days of an exacerbation. 
Starting on Day 15 of an exacerbation, the MOV stays at the level on the 14th day for the remainder 
of the exacerbation. 
Threshold for Improvement 
Improvement is defined as a decrease in the Rolling Average EXACT score ≥ 9 points from the 
previous day’s MOV during an event.  
Recovery 
Recovery is defined as the first day in which a patient experiences a persistent, sustained 
improvement in their condition over the observed period. Improvement must be present for 7 
consecutive days. The first day of the 7-day period is designated as the first day of Recovery 
(DayR).  
Based on the scoring algorithm for Recovery, EXACT exacerbations can be categorized as 
Recovered, Censored, or Persistent Worsening. Recovered is defined as an EXACT exacerbation 
meeting the Recovery definition outline above. Censored is defined as an EXACT exacerbation 
that began within 28 days of study termination and did not meet the Recovery definition during that 


 
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time period. Persistent Worsening is defined as an EXACT exacerbation that never meets the 
Recovery criteria, i.e., the patient’s EXACT scores never meet the Recovery definition. All 
analyses including Recovery should be based on resolved events only, unless otherwise specified. 
New Event (Stabilisation Phase) 
Score increases consistent with Onset and occurring any time after the 7th day of the Recovery 
period are counted as a new event. To identify a new exacerbation, use the last available Baseline 
value. The reset Baseline value (BaselineRX) is used if a patient’s Baseline was re-established prior 
to the EXACT exacerbation; otherwise the original Baseline value from Stabilisation Phase (i.e. 
mean EXACT score during the first 7 days of the Stabilisation Phase (Week 3; Days 15-21)) is 
used. If no new event is experienced during the 4 week period post-Recovery, Baseline is reset in 
the manner described previously. There may be a new event beginning on the day after the day of 
recovery, but not on the day of recovery. 
Duration (Stabilisation Phase) 
Duration is the length of time in days from Onset to Recovery. Duration is calculated as the 
difference, in days, between the day of Onset (Day1) and the day of Recovery (DayR). The day of 
Recovery (DayR) is not included in calculating Duration days. 
Event Severity (Stabilisation Phase) 
Severity is the highest EXACT Total score of the observation period from Onset (Day1) to 
Recovery (DayR), not using the 3-day Rolling Average. For patients who do not recover severity is 
the highest EXACT Total score of the observation period. 
 
 


 
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Table 1: Annotated EXACT for Raw Score Assignment 
The following annotates the raw item-level score values associated with each text response for the 
EXACT items. 
 
 
 


 
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Table 2: Raw Summed Score to Scale Score Conversion Table for EXACT Total Score 
 
 
 


 
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Table 3: Raw Summed Score to Scale Score Conversion Table for EXACT Domains  
 
 
 


 
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Table 4: SAS Coding Instructions for Computing Daily Scores 
The following example assumes all original item responses are coded as 0, 1, 2, 3, 4, etc. on the 
data collection forms or electronic data capture system, ordered from least severe to most severe. In 
this case, only items 3, 8, 9, 10, 11, and 14 need to be recoded to form item-level scores. If the 
original codes begin with 1 for least severe (e.g., 1, 2, 3, 4, 5 for question 1), then the codes must 
be shifted to a 0 starting point for all items before these SAS statements can be used. 
 
 
 


 
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Appendix D – Chronic Respiratory Questionnaire (CRQ) 
 
 
 
 
 
 


 
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Appendix E – Body mass index, airflow Obstruction, Dyspnoea and Exercise index (BODE) 
 
 
 
BODE Index for COPD 
 
 
 
 


 
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Appendix F – Algorithms/SAS Reference Codes 
 
Calculation of adjusted means (least squares means): 
The approach described below will ensure that the least squares means calculated by SAS will 
be based on: 
– 
coefficients for classification effects (i.e., the effects of categorical covariates) 
proportional to the margins observed in the group of patients analysed; 
– 
effects of quantitative covariates set equal to their mean values in the group of patients 
analysed. 
The analysis is based on the following steps: 
1. generate a dataset by selecting: 
– 
in case of repeated post-randomisation measurements (e.g. FEV1 at each visit, 
analysed using a linear mixed model for repeated measures): all the post-
randomisation records for patients with at least one available and valid post-
randomisation measurement and no missing covariates; 
– 
in case of single post-randomisation measurement (e.g. number of COPD 
exacerbations during the Stabilisation Phase based on EXACT-PRO, analysed 
using a negative binomial model): all the patients with available and valid 
response and no missing covariates; 
2. in case of repeated post-randomisation measurements, add to the dataset generated in 
step 1 the records for missing post-randomisation visits of the patients included in the 
dataset. In the added records the value of the response variable will be missing, but the 
full information on covariates has to be included; 
3. use the dataset obtained as the input dataset for the MIXED or the GENMOD 
procedure, specifying the following options in the LSMEANS statement: 
– 
in case of repeated post-randomisation measurements: OM AT MEANS; 
– 
in case of single post-randomisation measurement: OM. 
Example: analysis of change from baseline (Visit 1) at all visits (Visits 2 to 7) based on a mixed 
model for repeated measures including the effects of treatment, visit (categorical variable), 
treatment by visit interaction, baseline and another covariate.  
 
 


 
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Original dataset (X = available value; . = missing or invalid value): 
Patient 
Treatment 
Covariate 
Baseline 
Visit 
Change from baseline 
1 
A 
X 
X 
1 
. 
1 
A 
X 
X 
2 
. 
1 
A 
X 
X 
3 
X 
1 
A 
X 
X 
4 
X 
1 
A 
X 
X 
5 
X 
1 
A 
X 
X 
6 
X 
1 
A 
X 
X 
7 
. 
2 
B 
X 
X 
1 
. 
2 
B 
X 
X 
2 
. 
2 
B 
X 
X 
3 
X 
3 
C 
X 
X 
1 
. 
3 
C 
X 
X 
2 
. 
3 
C 
X 
X 
3 
X 
3 
C 
X 
X 
4 
. 
3 
C 
X 
X 
5 
X 
3 
C 
X 
X 
6 
. 
3 
C 
X 
X 
7 
X 
4 
B 
X 
X 
1 
. 
4 
B 
X 
X 
2 
. 
5 
A 
. 
X 
1 
. 
5 
A 
. 
X 
2 
. 
5 
A 
. 
X 
3 
X 
 
Step 1 (visit 1 not selected since pre-treatment, patient 4 not selected due to missing post-
randomisation measurements, patient 5 not selected due to missing covariate): 
Patient 
Treatment 
Covariate 
Baseline 
Visit 
Change from baseline 
1 
A 
X 
X 
2 
. 
1 
A 
X 
X 
3 
X 
1 
A 
X 
X 
4 
X 
1 
A 
X 
X 
5 
X 
1 
A 
X 
X 
6 
X 
1 
A 
X 
X 
7 
. 
2 
B 
X 
X 
2 
. 
2 
B 
X 
X 
3 
X 
3 
C 
X 
X 
2 
. 
3 
C 
X 
X 
3 
X 
3 
C 
X 
X 
4 
. 
3 
C 
X 
X 
5 
X 
3 
C 
X 
X 
6 
. 
3 
C 
X 
X 
7 
X 
 
 
 


 
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Step 2 (added records in italic and bold): 
Patient 
Treatment 
Covariate 
Baseline 
Visit 
Change from baseline 
1 
A 
X 
X 
2 
. 
1 
A 
X 
X 
3 
X 
1 
A 
X 
X 
4 
X 
1 
A 
X 
X 
5 
X 
1 
A 
X 
X 
6 
X 
1 
A 
X 
X 
7 
. 
2 
B 
X 
X 
2 
. 
2 
B 
X 
X 
3 
X 
2 
B 
X 
X 
4 
. 
2 
B 
X 
X 
5 
. 
2 
B 
X 
X 
6 
. 
2 
B 
X 
X 
7 
. 
3 
C 
X 
X 
2 
. 
3 
C 
X 
X 
3 
X 
3 
C 
X 
X 
4 
. 
3 
C 
X 
X 
5 
X 
3 
C 
X 
X 
6 
. 
3 
C 
X 
X 
7 
X 
 
 
Tables that require Chi-Square test with continuity correction: 
 
 
 
PROC FREQ DATA = <dataset name>; 
 TABLES <outcome variable>*<predictor variable> / CHISQ OUT=<output dataset 
name> 
 
 
 
OUTPUT OUT=stats; 
 
 
RUN; 
 
 
Notes:  
- 
In case the assumption of Chi-square test is not met (e.g. expected cell frequencies < 
5), a Fisher’s exact test will be carried out. The SAS code is similar as above but with 
“FISHER” option in the “TABLES” statement above. 
 
 
Tables that require One-way ANOVA test: 
 
 
 
PROC ANOVA DATA = <dataset name>; 
 
 
 
CLASS <predictor variable>; 
 
 
 
MODEL <outcome variable> = <predictor variable>; 
 
 
RUN; 
 
 
Notes:  
- 
Should the normality assumptions for the outcome variable not be met (the skewness 
and kurtosis measurements will be considered as supportive indicators), the 
relationship between the outcome variable and the predictor variable will be tested 
using the non-parametric approach of Kruskal-Wallis test (or Wilcoxon Rank-Sum test 
for two groups). The SAS code used to implement this test will be: 


 
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PROC NPAR1WAY DATA = <dataset name> WILCOXON; 
 
 
 
CLASS <predictor variable>; 
 
 
 
VAR <outcome variable>; 
 
 
RUN; 
 
 
Tables that require Kaplan-Meier estimates and log-rank test: 
 
 
 
PROC LIFETEST data=dataset timelist=(0 t1 t2 t3 t4 t5 … EoS) alpha=.05 outsurv=estim  
                                               reduceout; 
 
 
TIME time*event(0); 
 
 
STRATA trt; 
 
 
RUN; 
 
 
Notes:  
- 
Time represents the time to event or time to censoring; 
- 
Event represents the censoring indicator (0 = censored); 
- 
Trt represents the treatment group; 
- 
EoS should be replaced by the last time to event >26 weeks (if any).