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    The EU Clinical Trials Register currently displays   37564   clinical trials with a EudraCT protocol, of which   6160   are clinical trials conducted with subjects less than 18 years old.
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    EudraCT Number:2010-019685-87
    Sponsor's Protocol Code Number:RO-2455-404-RD
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-02-22
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2010-019685-87
    A.3Full title of the trial
    Effect of roflumilast on exacerbation rate in patients with COPD treated with fixed combinations of LABA and ICS. A 52-week, randomised double-blind trial with roflumilast 500 μg versus placebo
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The trial investigates the effect of 500 μg roflumilast tablets once daily
    versus placebo on exacerbation rate and pulmonary function in patients
    with Chronic Obstructive Pulmonary Disease (COPD) who are treated
    with a fixed combination of long-acting β2-agonists (LABA) and inhaled
    glucocorticosteroids (ICS). Additionally it provides data on safety and
    tolerability in COPD patients treated with a fixed combination of LABA
    and ICS.
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberRO-2455-404-RD
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNycomed GmbH
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNycomed GmbH
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNycomed Danmark
    B.5.2Functional name of contact pointAsk Aabenhus
    B.5.3 Address:
    B.5.3.1Street AddressLangebjerg 1
    B.5.3.2Town/ cityRoskilde 46754269
    B.5.3.3Post code4000
    B.5.4Telephone number+4546771 691
    B.5.5Fax number+4546754 269
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D. name Daxas
    D. of the Marketing Authorisation holderNycomed GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRoflumilast 500 µg film-coated tablet
    D.3.2Product code BY217
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNROFLUMILAST
    D.3.9.1CAS number 162401323
    D.3.9.2Current sponsor codeBY217
    D.3.9.3Other descriptive nameN/A
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    severe chronic obstructive pulmonary disease (COPD)
    E.1.1.1Medical condition in easily understood language
    In all patient information material COPD is used. There is no term in trivial language available.
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10010952
    E.1.2Term COPD
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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).
    E.2.2Secondary 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.
    E.2.3Trial contains a sub-study No
    E.3Principal 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
    E.4Principal 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

    E.5 End points
    E.5.1Primary 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
    E.5.1.1Timepoint(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.
    E.5.2Secondary end point(s)
    Key secondary Endpoints
    1. Change from randomisation (V2) over 52 weeks of treatment in post-bronchodilator 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
    E.5.2.1Timepoint(s) of evaluation of this end point
    Over 52 weeks of treatment for end-points COPD exacerbations, Lung Function, COPD Symptoms , Use of rescue medication, Quality of Life (COPD Assessment Test), Major Adverse Cardiovascular Events.
    Other end-points are evaluated at timing of occurence.

    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA120
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Korea, Democratic People's Republic of
    Russian Federation
    South Africa
    United Kingdom
    E.8.7Trial 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
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months8
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F. of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F. of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F. of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F. of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F. of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F. of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 2002
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1000
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state52
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1308
    F.4.2.2In the whole clinical trial 3002
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Standard of care.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2011-03-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-04-11
    P. End of Trial
    P.End of Trial StatusCompleted
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