A study to compare the efficacy and safety of BCT197 when it is used together with current treatments for acute respiratory exacerbations of chronic obstructive pulmonary disease (COPD) that result in hospitalisation in adults

• Register: EUCTR
• Last refreshed on: 22 January 2018
• Main ID: EUCTR2015-004631-13-LV
• Date of registration: 03/02/2016
• Prospective Registration: Yes
• Primary sponsor: Mereo BioPharma 1 Ltd
• Public title: A study to compare the efficacy and safety of BCT197 when it is used together with current treatments for acute respiratory exacerbations of chronic obstructive pulmonary disease (COPD) that result in hospitalisation in adults
• Scientific 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.
• Date of first enrolment: 14/04/2016
• Target sample size: 270
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-004631-13
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Bulgaria, Czech Republic, Germany, Hungary, Italy, Latvia, Poland, Romania, Russian Federation, United Kingdom, United States

Contacts

• Name: Project Management
• Affiliation: ICON Clinical Research

• Name: Project Management
• Affiliation: ICON Clinical Research

Key inclusion & exclusion criteria

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 ß2-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
• Inhaled corticosteroids/long-acting ß2-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 ß2-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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 108
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 162

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 ß-blockers in the 10days preceding Screening Visit. Those subjects may enter the study after non-selective ß-blockers withdrawal and/or cardioselective ß-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. Subjects requiring long term (at least 12hrs daily) oxygen therapy for chronic hypoxemia
8. 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 a-1 antitrypsin deficiency, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension and interstitial
lung disease
9. Subjects who have had pulmonary lobectomy or lung volume reduction surgery or lung transplantation
10. Subjects who have had a vaccination in the 14days (or 30days for live vaccines) prior to study start
11. 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
12. 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
13. 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
14. Current diagnosis of pneumonia, pulmonary embolus or pneumothorax.
15. History of hypersensitivity to anti-cholinergics, ß2-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
16. 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
17. Subjects with liver enzyme alterations (serum alanine aminotransferase and/or aspartate aminotransferase > 2 x upper limit of normal [ULN], bilirubin > 1.5 ULN)
18. Impairment of renal function (defined as creatinine clearance < 60 mL/min (estimated by Cockcroft-Gault)
19. Concomitant/recent use of the CYP3A inhibitors or P-gp inhibitors including, but not limited to macrolide antibiotics and the calcium channel blockers verapamil

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Acute exacerbations of chronic obstructive pulmonary disease
MedDRA version: 19.0 Level: LLT Classification code 10010953 Term: COPD exacerbation System Organ Class: 100000004855

Therapeutic area: Diseases [C] - Respiratory Tract Diseases [C08]

Intervention(s)

Product Name: BCT197 20mg hard gelatine capsules
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Acumapimod
CAS Number: 836683-15-9
Current Sponsor code: BCT197
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Product Name: BCT197 25mg hard gelatine capsules
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Acumapimod
CAS Number: 836683-15-9
Current Sponsor code: BCT197
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Product Name: BCT197 50mg hard gelatine capsules
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Acumapimod
CAS Number: 836683-15-9
Current Sponsor code: BCT197
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: - 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

Main Objective: 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.

Timepoint(s) of evaluation of this end point: Please refer to protocol (Table 9-1 Schedule of Assessments).

Primary end point(s): Change in FEV1 from Baseline (pre-dose) at Day 7.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Please refer to protocol (Table 9-1 Schedule of Assessments).

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 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 (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
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-a, 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

Secondary ID(s)

MBCT206

Source(s) of Monetary Support

Mereo BioPharma 1 Ltd