E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
severe chronic obstructive pulmonary disease (COPD) |
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E.1.1.1 | Medical condition in easily understood language |
In all patient information material COPD is used. There is no term in trivial language available. |
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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 | 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 investigate the effect of roflumilast 500 μg tablets once daily versus placebo on exacerbation rate, pulmonary function and major adverse cardiovascular events (MACE) in COPD patients who are concomitantly treated with a fixed combination of long-acting β2-agonists (LABA) and inhaled glucocorticosteroids (ICS). |
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E.2.2 | Secondary objectives of the trial |
To obtain data on safety and tolerability of roflumilast in COPD patients concomitantly treated with a fixed combination of LABA and ICS.
To further characterise the population pharmacokinetic profile of roflumilast and roflumilast N-oxide.
To further characterise the pharmacokinetics/pharmacodynamics (PK/PD) relationship of roflumilast, roflumilast N-oxide and ‘total phosphodiesterase 4 inhibitory’ activity (tPDE4i) in terms of efficacy and relevant safety aspects. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
According to Protocol Amendment 1, dated 02 May 2012.
1. Giving written informed consent 2. History of COPD (according to GOLD 2009) for at least 12 months prior to baseline Visit V0 associated with chronic productive cough for 3 months in each of the 2 years prior to baseline Visit V0 (with other causes of productive cough excluded) 3. Age ≥ 40 years 4. Forced expiratory volume after one second (FEV1)/forced vital capacity (FVC) ratio (post-bronchodilator) < 70% 5. FEV1 (post-bronchodilator) ≤ 50% of predicted 6. At least two documented moderate or severe COPD exacerbations, separated by at least 10 days, within one year prior to baseline Visit V0. 7. Patients must be pre-treated with LABA and ICS for at least 12 months before baseline Visit V0. Up to 3 months before baseline Visit V0 free or fixed combinations of LABA and ICS are allowed, including changes in dose, active substances, and brands. In the last 3 months before baseline Visit V0 patients must be pre-treated with fixed combinations of LABA and ICS at a constant dose (maximum approved dosage strength of the combination). 8. Former smoker (defined as smoking cessation at least one year ago) or current smoker both with a smoking history of at least 20 pack years |
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E.4 | Principal exclusion criteria |
According to Protocol Amendment 1, dated 02 May 2012.
Criteria affecting the read-out parameters of the trial: 1. Moderate or severe COPD exacerbation and/or COPD exacerbations treated with antibiotics ongoing at the baseline Visit V0 2. Lower respiratory tract infection not resolved 4 weeks prior to the baseline Visit V0 3. Diagnosis of asthma and/or other relevant lung disease (e.g. history of primary bronchiectases, cystic fibrosis, bronchiolitis, lung resection, lung cancer, interstitial lung disease [e.g. fibrosis, silicosis, sarcoidosis], or active tuberculosis) 4. Current participation in a pulmonary rehabilitation program or completion of a pulmonary rehabilitation program within 3 months preceding the baseline Visit V0. However, physical exercise maintenance following the completion of the initial pulmonary rehabilitation program and which is continuously performed within 3 months preceding baseline Visit V0 and during the complete trial is allowed 5. Known alpha-1-antitrypsin deficiency
Criteria within ethical considerations in terms of general health: 6. Clinically relevant abnormal laboratory values suggesting an undiagnosed disease requiring further clinical evaluation (as assessed by the Investigator) 7. Severe psychiatric or neurological disorders 8. History of depression associated with suicidal ideation or behaviour 9. Congestive heart failure severity grade IV according to NYHA (New York Heart Association Functional Classification) 10. Haemodynamically significant cardiac arrhythmias or heart valve deformations 11. Computed tomography (CT) or chest x-ray findings indicating an acute pulmonary disease other than COPD (e.g. tuberculosis, severe bronchiectasis, tumours) 12. Severe immunological diseases (e.g. known HIV infection, multiple sclerosis, lupus erythematosus, progressive multifocal leukoencephalopathy) 13. Liver impairment Child-Pugh B or C and/or active viral hepatitis 14. Severe acute infectious diseases (e.g. tuberculosis, or acute hepatitis) 15. Any diagnosis of a malignant disease (except basal cell carcinoma) within 5 years before trial start 16. Alcohol or drug abuse within the past year 17. Suspected hypersensitivity to roflumilast or rescue medication or ingredients thereof, or any other contraindication for the use thereof 18. Female patients of childbearing potential, not using and not willing to continue using a medically reliable method of contraception for the entire trial duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, unless they are surgically sterilized/hysterectomised or post-menopausal > 1 year or who are not using any other method of contraception considered sufficiently reliable by the Investigator in individual cases 19. Pregnancy, breast feeding, planned oocyte donation or oocyte implantation 20. Planned donation of germ cells, blood, organs or bone marrow during the course of the trial 21. Participation in another trial (use of investigational product) within 30 days preceding the baseline Visit V0 or re-entry of patients previously enrolled in this trial 22. Suspected inability or unwillingness to comply with trial procedures (e.g. language problems, psychological disorders, number and timing of visits at the site) 23. Suffering from any concomitant disease that might interfere with trial procedures or evaluations 24. Use of disallowed drugs (see below) 25. Employee at the investigational site, relative or spouse of the Investigator
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E.5 End points |
E.5.1 | Primary end point(s) |
Rate of moderate or severe COPD exacerbations per patient per year. Moderate exacerbations are defined as requiring oral or parenteral glucocorticosteroids, severe as requiring hospitalisation and/or leading to death |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The 1-year treatment period is considered appropriate to investigate the primary endpoint, reduction of exacerbation rate, taking into account the seasonal variation of COPD exacerbations during the year. |
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E.5.2 | Secondary end point(s) |
Key secondary Endpoints 1. Change from randomisation (V2) over 52 weeks of treatment in postbronchodilator FEV1 [L] 2. Rate of severe COPD exacerbations per patient per year. Other secondary endpoints: 1. Spirometry - Lung Function 2. Diary endpoints: Use of rescue medication, COPD symptoms score. 3. Quality of Life (COPD Assessment Test (CAT) 4. Time to mortality and time to trial withdrawal 5. Major adverse cardiovascular events 6. Pharmacokinetic profiles and parameters 7. Safety |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At the 52-week treatment period for end points COPD exacerbations, Lung Function, Symptoms and Quality of Life, and use of rescue medication. Other end points are evaluated at timing of occurence.
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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 | Yes |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | 2 |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 120 |
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 |
Australia |
Austria |
Belgium |
Brazil |
Canada |
Denmark |
France |
Germany |
Greece |
Hungary |
Israel |
Italy |
Korea, Democratic People's Republic of |
Netherlands |
Poland |
Russian Federation |
Slovakia |
South Africa |
Spain |
Turkey |
United Kingdom |
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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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For all randomised patients who completed the trial treatment period as scheduled, one follow-up visit with further protocol-specified assessments is implemented 12 weeks after end of the treatment period. All parties involved in the trial will remain blinded between the end of the treatment period and the follow-up visit (VFU). The end-of-trial is defined as database hard-lock, which will be subsequently to the follow-up visit of the last patient |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |