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    Summary
    EudraCT Number:2011-002905-31
    Sponsor's Protocol Code Number:RO-2455-405-RD
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2011-10-19
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2011-002905-31
    A.3Full title of the trial
    Effect of roflumilast 500 μg tablets once daily at acute COPD exacerbations treated with standard therapy of oral steroids and antibiotics.
    A randomised, double-blind, placebo-controlled, parallel-group trial.
    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 roflumiliast tablets once daily on acute worsening of symptoms (exacerbations) treated with standard therapy in patiens with chronic obstructive pulmonary disease (COPD)
    A.3.2Name or abbreviated title of the trial where available
    TREAT
    A.4.1Sponsor's protocol code numberRO-2455-405-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.1.3.4CountryGermany
    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.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNycomed GmbH
    B.5.2Functional name of contact pointClinical Trial Management Daxas
    B.5.3 Address:
    B.5.3.1Street AddressByk-Gulden-Str. 2
    B.5.3.2Town/ cityKonstanz
    B.5.3.3Post code78467
    B.5.3.4CountryGermany
    B.5.4Telephone number +49-(0)7531-84-2370
    B.5.5Fax number +49-(0)7531-84-92370
    B.5.6E-mailhildegard.boss@nycomed.com
    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.2.1.1.1Trade name Daxas
    D.2.1.1.2Name 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 500µg 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 162401-32-3
    D.3.9.2Current sponsor codeBY217
    D.3.9.4EV Substance CodeAS1
    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.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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
    Acute exacerbations of chronic obstructive pulmonary disease (COPD)
    E.1.1.1Medical condition in easily understood language
    Acute worsening of symptoms (exacerbations) of chronic obstructive pulmonary disease (COPD)
    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 16.0
    E.1.2Level LLT
    E.1.2Classification code 10010952
    E.1.2Term COPD
    E.1.2System Organ Class 100000004855
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level LLT
    E.1.2Classification code 10010953
    E.1.2Term COPD exacerbation
    E.1.2System Organ Class 100000004855
    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 (od) versus placebo on sputum neutrophilic inflammation at acute exacerbations of chronic obstructive pulmonary disease (COPD).
    E.2.2Secondary objectives of the trial
    • To investigate the effect of roflumilast on other secondary sputum and blood biomarkers, and on lung function.
    • To investigate the effect of roflumilast on length, severity and recovery periods of acute COPD exacerbations (based on diary reports), and on other daily diary outcomes with respect to the exacerbation.
    • To investigate the effect of roflumilast on patient-reported outcomes with respect to the exacerbation.
    • To provide data on safety and tolerability of roflumilast intake during exacerbation episodes and following weeks.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    I1. Written informed consent (IC);
    I2. Age ≥40 years;
    I3. History of COPD for at least 12 months prior to enrolment (Visit V0);
    I4. Chronic productive cough for 3 months in each of the 2 years prior to enrolment (if other causes of productive cough have been excluded) and/or an exacerbation with predominantly bronchitic symptoms at enrolment;
    I5. Presentation of an acute exacerbation of COPD that will be associated with increased sputum volume or change in sputum colour;
    I6. Documented fixed airway obstruction determined by an FEV1/FVC ratio (post-bronchodilator) <70% (if a pulmonary function test is not possible at Visit V0 a previous measurement can be taken which must not be older than 6 months);
    I7. Former smoker (defined as: smoking cessation at least 1 year ago) or current smoker both with a smoking history of at least 10 pack years
    E.4Principal exclusion criteria
    E1. Diagnosis of asthma and/or other relevant lung disease (e.g. history of bronchiectasis, cystic fibrosis, bronchiolitis, lung resection, lung cancer, interstitial lung disease [e.g. fibrosis, silicosis, sarcoidosis] or active tuberculosis);
    E2. Known α-1-antitrypsin deficiency;
    E3. Recurrent exacerbations (within 8 weeks of a preceding exacerbation);
    E4. Treatment of current exacerbation with oral corticosteroids and/or antibiotics already started at enrolment;
    E5. Treatment with PDE4 inhibitors within 3 months prior to Visit V0;

    Criteria within ethical considerations in terms of general health:

    E6. Oxygen therapy (more than 8 hours daily);
    E7. Formal contraindications to sputum collection or impossibility to obtain a sample of sputum valid for analysis;
    E8. Respiratory failure when presenting at Visit V0;
    E9. Severe psychiatric or neurological disorders;
    E10. History of depression associated with suicidal ideation or behaviour;
    E11. Congestive heart failure severity grade IV according to the New York Heart Association Functional Classification;
    E12. Haemodynamically significant cardiac arrhythmias or heart valve deformations;
    E13. Immunological diseases or known infection with human immunodeficiency virus;
    E14. Liver impairment Child-Pugh B and C and/or active viral hepatitis;
    E15. Severe acute infectious diseases;
    E16. Any diagnosis of a malignant disease (other than basal or squamous cell carcinoma) within 5 years before trial start;
    E17. Alcohol or drug abuse within the past year;
    E18. Suspected hypersensitivity to the IMP or ingredients thereof, or any other contraindication for the use thereof;
    E19. 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 sterilised/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;
    E20. Pregnancy, breast feeding, planned oocyte donation or oocyte implantation;
    E21. Planned donation of germ cells, blood, organs or bone marrow during the course of the trial;
    E22. Participation in another trial (use of investigational product) within 30 days of Visit V0 or re-entry of patients previously enroled in this trial;
    E23. Suspected inability or unwillingness to comply with trial procedures (e.g. language problems, psychological disorders);
    E24. Suffering from any concomitant disease that might interfere with trial procedures or evaluations;
    E25. Use of disallowed drugs (see Section 6.8);
    E26. Employee at the trial site, relative or spouse of the investigator.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is change in sputum neutrophil counts from V0 to V2 (Day 14). Missing values will be imputed by the last available measurement after V0 up to V2.
    E.5.1.1Timepoint(s) of evaluation of this end point
    V0 (Day 1), V1 (Day 7), V2 (Day 14).
    E.5.2Secondary end point(s)
    1) Proportion of patients whose sputum neutrophil counts have returned to stable state levels at Day 14

    2) Induced sputum markers, serum biomarkers and lung function

    3) Continuous endpoints and scores, which are derived from patient reported outcomes (CAT, EXACT-PRO) and diaries (PEF, symptom score, hours out of house)

    4) Diary endpoints exacerbation length, time to next exacerbation and length of stay in hospital

    5) Hospitalisation rate
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) Will be compared between treatments with a continuity corrected Chi-squared test. For stable state levels, the value from a visit where the patient is free of exacerbations will be used; specifications will be provided in the SAP.

    2) Will be analysed by repeated measures with change from Visit V0 (to Visit V1, to Visit V2, to Visit V3) as the dependent variable.
    A second model will include the changes from V0 to the last available measurement up to VFU.

    3) /4) /5) Will be presented descriptively (including graphical displays) on a day by day basis and additionally on a weekly basis, stratified by treatment. The time period covered by the displays will be Day -14 up to Day 56 (VFU).
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Patient Reported Outcome with CAT and EXACT-PRO questionnaires
    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.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    Defined as data base hard lock (see protocol section 14.1)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned 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.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 70
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 70
    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 state140
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 140
    F.4.2.2In the whole clinical trial 140
    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)
    When patients conclude the IMP after randomisation, either regularly or prematurely, they should be treated at the discretion of the investigator.
    As roflumilast is registered as DAXAS® and is marketed in UK, patients may receive the medication after trial completion. It is at the discretion of the investigator to prescribe DAXAS®.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2011-12-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-11-24
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2014-04-14
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