| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic obstructive pulmonary disease (COPD) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic obstructive pulmonary disease (COPD) |
|
| 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 | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010952 |
| E.1.2 | Term | COPD |
| E.1.2 | System Organ Class | 100000004855 |
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| 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 demonstrate the superiority of CHF 5993 pMDI over Tiotropium in terms of moderate and severe COPD exacerbation rate over 52 weeks of treatment. |
|
| E.2.2 | Secondary objectives of the trial |
Key secondary objectives:
To demonstrate the superiority of CHF 5993 pMDI over Tiotropium in terms of pulmonary function (change from baseline in pre-dose morning FEV1 at Week 52).
To demonstrate the non-inferiority of CHF 5993 pMDI relative to CHF 1535 pMDI+Tiotropium in terms of pulmonary function (change from baseline in pre-dose morning FEV1 at Week 52).
Secondary objectives:
To evaluate the effect of CHF 5993 pMDI on other lung function parameters, patient’s health status and clinical outcome measures.
To perform a population PK analysis (in a subset of patients treated with CHF 5993 pMDI) investigating the inter-subject variability in the drug exposure and the effects of selected covariates on PK parameters of B17MP, FF and GB.
To collect data in order to assess the impact of study treatments on health economic outcomes.
To assess the safety and the tolerability of the study treatments.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female adults aged ≥ 40 years with written informed consent obtained prior to any study-related procedure.
2. Patients with a diagnosis of COPD (according to GOLD guidelines, updated February 2013) at least 12 months before the screening visit.
3. Current smokers or ex-smokers who quit smoking at least 6 months prior to screening visit, with a smoking history of at least 10 pack years [pack-years = (number of cigarettes per day x number of years)/20]
4. A post-bronchodilator FEV1 < 50% of the predicted normal value and a post-bronchodilator FEV1/FVC ratio < 0.7 within 30 min after 4 puffs (4 x 100 mcg) of salbutamol pMDI
5. A documented history of at least one exacerbation in the 12 months preceding the screening visit.
6. Patients under double therapy for at least 2 months prior to screening with either:
- Inhaled corticosteroids/long-acting β-agonist or
- Inhaled corticosteroids/long-acting muscarinic antagonist or
- Inhaled long-acting β-agonist and inhaled long-acting muscarinic antagonist or
Patients under monotherapy with long-acting muscarinic antagonist for at least 2 months prior to screening.
7. Symptomatic patient at screening with a CAT score ≥ 10.
|
|
| E.4 | Principal exclusion criteria |
1. Pregnant or lactating women and all women physiologically capable of becoming pregnant (i.e. women of childbearing potential) Pregnancy testing will be carried out during the course of the study in all women of childbearing potential.
Any postmenopausal women or women permanently sterilized can be enrolled in the study.
2. Diagnosis of asthma, history of allergic rhinitis or atopy (atopy which may raise contra-indications or impact the efficacy of the study according to investigator’s judgment).
3. Patients requiring use of the following medications:
a. Systemic steroids for COPD exacerbation in the 4 weeks prior to screening.
b. A course of antibiotics for COPD exacerbation longer than 7 days in the 4 weeks prior to screening.
c. PDE4 inhibitors in the 4 weeks prior to screening.
d. Use of antibiotics for a lower respiratory tract infection (e.g pneumonia) in the 4 weeks prior to screening.
4. COPD exacerbation requiring prescriptions of systemic corticosteroids and/or antibiotics or hospitalization during the run-in period.
5. Patients treated with non-cardioselective β-blockers in the month preceding the screening visit or during the run-in period.
6. Patients treated with long-acting antihistamines 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. Patients requiring long term (at least 12 hours daily) oxygen therapy for chronic hypoxemia.
8. Known respiratory disorders other than COPD which may impact the efficacy of the study drug according the investigator’s judgment.
9. Patients who have clinically significant cardiovascular condition.
10. Patients with atrial fibrillation (AF).
11. An abnormal and clinically significant 12-lead ECG that results in active medical problem which may impact the safety of the patient according to investigator’s judgement in consultation with the Corporate Cardiac Leader’s opinion.
Patients whose electrocardiogram (ECG) (12 lead) shows QTcF >450 ms for males or QTcF >470 ms for females at screening visit are not eligible.
12. Medical diagnosis of narrow-angle glaucoma, clinically relevant prostatic hypertrophy or bladder neck obstruction that in the opinion of the investigator would prevent use of anticholinergic agents.
13. History of hypersensitivity to M3 Antagonists, β2-agonist, corticosteroids or any of the excipients contained in any of the formulations used in the trial which may raise contra-indications or impact the efficacy of the study drug according to the investigator’s judgement.
14. 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 investigator’s judgement.
15. Patients with serum potassium levels < 3.5 mEq/L (or 3.5 mmol/L).
16. Unstable concurrent disease, or other which may impact the feasibility of the results of the study according to investigator’s judgment.
17. History of alcohol abuse and/or substance/drug abuse within 12 months prior to screening visit
18. Participation in another clinical trial where investigational drug was received less than 8 weeks prior to screening visit.
Patients included in the subset for PK assessment
19. Patients with unsuitable veins for repeated venipuncture.
20. Blood donation (equal or more than 450 mL) or blood loss in the 4 weeks before randomization.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Moderate and severe COPD exacerbation rate |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Change from baseline in pre-dose morning FEV1
- COPD exacerbation (moderate or severe, rate and time to first)
- FEV1 response (change from baseline in pre-dose morning FEV1 ≥ 100 ml)
- SGRQ score (change from baseline of total/domain scores)
- Use of rescue medication
- PK analysis |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
assessment in week 26 and/or week 52
Plasma levels measured in week 4 |
|
| 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 | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 123 |
| 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 |
| Italy |
| Croatia |
| Romania |
| Slovakia |
| Argentina |
| Belarus |
| Czech Republic |
| Germany |
| Hungary |
| Mexico |
| Poland |
| Russian Federation |
| Turkey |
| Ukraine |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 14 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 14 |
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