| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute exacerbations of chronic obstructive pulmonary disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Worsening of respiratory function in patients with chronic obstructive pulmonary disease |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010953 |
| E.1.2 | Term | COPD exacerbation |
| E.1.2 | System Organ Class | 100000004855 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
- 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.
- Safety and tolerability of BCT197
- Please see protocol for exploratory objectives |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 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:
• Inhaled corticosteroids/long-acting β2-agonist combination, longacting
muscarinic antagonist without regular use of any short-acting
bronchodilator (any short-acting bronchodilator allowed if used as
needed [PRN]) or
• Inhaled corticosteroids/long-acting β2-agonist combination, without
regular use of any short-acting bronchodilator (any short-acting
bronchodilator allowed if used PRN) or
• Inhaled corticosteroids/long-acting muscarinic antagonist
combination, without regular use of any short-acting bronchodilator (any
short-acting bronchodilator allowed if PRN) or
• Inhaled long-acting β2-agonist and inhaled long-acting muscarinic
antagonist (with any PRN short acting bronchodilator) or
• 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. |
|
| E.4 | Principal exclusion criteria |
1. Current diagnosis of asthma
2. Subjects who have already completed treatment for current
exacerbation of COPD
3. Subjects who have been treated with or require the following
medications:
• Systemic steroids for longer than 3days for COPD exacerbation in the
4weeks prior to the current exacerbation
• Antibiotics for COPD exacerbation for longer than 7days in the 4weeks
prior to the current exacerbation
• Phosphodiesterase type 3/4 inhibitors
• Any p38 mitogen-activated protein kinase inhibitor treatment
• Antibiotics for lower respiratory tract infection in the 4weeks prior to
the current exacerbation (except for treatment of the current
exacerbation, but not longer than 2days)
4. Subjects currently requiring intensive care unit and/or mechanical
ventilation
5. Subjects treated with non-cardioselective β-blockers in the 10days
preceding Screening Visit. Those subjects may enter the study after nonselective
β-blockers withdrawal and/or cardioselective β-blockers intake
for at least 10days before Randomisation
6. Subjects treated with long-acting anti-histamines unless taken at
stable regimen at least 2months 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
efficacy of 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, NYHA
Class III/IV, left ventricular failure, acute myocardial infarction); or
current exacerbation is due to a cardiovascular condition
11. An abnormal and clinically significant 12-lead ECG which may impact
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, pulmonary embolus or
pneumothorax.
14. History of hypersensitivity to anti-cholinergics, β2-agonist,
corticosteroids or any excipients contained in 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 < 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.
19. Unstable concurrent disease: e.g. uncontrolled hyperthyroidism,
uncontrolled diabetes mellitus or other endocrine disease; significant
hepatic impairment; significant renal impairment; uncontrolled
gastrointestinal disease; uncontrolled neurological disease; uncontrolled
haematological disease; uncontrolled auto-immune disorders, or other
which may impact the e.fficacy or the safety of the study drug according
to the investigator's judgement
20. History of alcohol abuse and/or substance/drug abuse within
12months 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
8weeks (whichever is longer) (6months in the case of a monoclonal
antibody) prior to Screening Visit. Participation in observational/noninterventional
studies is allowed.
22. Pregnant or nursing women
23. Sexually active men unless they are using double barrier method for
the period of dosing and for the 5 half-lives (8days) 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 8daysafter treatment with investigational medication |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change in FEV1 from Baseline (pre-dose) at Day 7. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Please refer to protocol (Table 9-1 Schedule of Assessments). |
|
| E.5.2 | Secondary end point(s) |
Efficacy:
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
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 (salbutamol or fenoterol) during the study
14. Time from hospitalisation until the subject is medically ready 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 (oral body temperature, RR, heart rate (HR), 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, 10, 14, and at Weeks 8, 12 and 26
6. Laboratory data including sputum cultures and 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 antibioticso 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 in BODE index scores on Days 7 and 14 (relative to Baseline) comparing among groups
7. Change in BODE index scores when compared with Baseline on Days 7 and 14, and Weeks 8, 12 and 26.
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 (oral 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.
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 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to protocol (Table 9-1 Schedule of Assessments). |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 16 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 61 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Bulgaria |
| Czech Republic |
| Germany |
| Hungary |
| Italy |
| Latvia |
| Poland |
| Romania |
| Russian Federation |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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