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    The EU Clinical Trials Register currently displays   36820   clinical trials with a EudraCT protocol, of which   6079   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2013-001788-21
    Sponsor's Protocol Code Number:RO-2455-302-RD
    National Competent Authority:Bulgarian Drug Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-07-10
    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 ConcernedBulgarian Drug Agency
    A.2EudraCT number2013-001788-21
    A.3Full title of the trial
    A multicenter, randomized, double-blind phase 3 study to evaluate tolerability and
    pharmacokinetics of 500μg roflumilast once daily with an up-titration regimen in COPD, including an open-label down-titration period evaluating tolerability and pharmacokinetics of 250μg roflumilast once daily in subjects not tolerating 500μg roflumilast once-daily.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to evaluate how to optimise the use of roflumilast in subjects who
    have a lung disease called chronic obstructive pulmonary disease (COPD).
    A.3.2Name or abbreviated title of the trial where available
    Evaluation of tolerability and pharmacokinetics of roflumilast (250μg and 500μg)
    A.4.1Sponsor's protocol code numberRO-2455-302-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 SponsorTAKEDA DEVELOPMENT CENTRE EUROPE LTD
    B.1.3.4CountryUnited Kingdom
    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 supportTAKEDA DEVELOPMENT CENTRE EUROPE LTD
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTAKEDA DEVELOPMENT CENTRE EUROPE LTD
    B.5.2Functional name of contact pointCLINICAL STUDY MANAGER
    B.5.3 Address:
    B.5.3.1Street Address61 ALDWYCH
    B.5.3.2Town/ cityLONDON
    B.5.3.3Post codeWC2B 4AE
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+442031168483
    B.5.6E-mailnyree.williamson@takeda.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 No
    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 250 μg
    D.3.4Pharmaceutical form 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.3.9.4EV Substance CodeSUB10358MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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.IMP: 2
    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 Daliresp™
    D.2.1.1.2Name of the Marketing Authorisation holderForest Pharmaceuticals inc
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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
    D.3.4Pharmaceutical form 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.3.9.4EV Substance CodeSUB10358MIG
    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 placeboTablet
    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
    chronic obstructive pulmonary disease (COPD)
    E.1.1.1Medical condition in easily understood language
    lung disease in which the lungs are damaged, making it hard to breathe.
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate discontinuation rates of roflumilast 500μg OD using an up-titration regimen with either 250μg OD or 500μg EOD for the first 4 weeks of treatment followed by 500μg OD for 8 weeks compared with continuous treatment of 500μg OD during the entire 12-week main period.

    To evaluate if subjects who do not tolerate roflumilast 500μg OD have a drug exposure with 250μg roflumilast OD similar to that observed in other subjects with the 500μg OD dose.
    E.2.2Secondary objectives of the trial
    To evaluate the gastro-intestinal tolerability of roflumilast 500μg OD with an up-titration regimen compared with continuous treatment of 500μg OD.
    To evaluate the safety, discontinuations and tolerability especially the gastro-intestinal tolerability of roflumilast 250μg OD in subjects not tolerating the 500μg OD dose.
    To evaluate the safety of roflumilast 500μg OD with an up-titration regimen compared with continuous treatment of 500μg OD.
    To evaluate the efficacy of roflumilast 500μg OD with an up-titration regimen on lung function compared with continuous treatment of 500μg OD.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. In the opinion of the investigator, the subject is capable of understanding and complying with protocol requirements.
    2. The subject or, when applicable, the subject’s legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.
    3. The subject has a history of COPD (according to GOLD 2013[1]) for at least 12 months prior to Screening (Visit V0) associated with chronic productive cough for 3 months in each of the 2 years prior to Screening (Visit V0, with other causes of productive cough excluded).
    4. The subject shows a post-bronchodilator FEV1 of ≤50% of predicted.
    5. The subject shows an FEV1/forced vital capacity (FVC) ratio (post-bronchodilator) <70%.
    6. The subject has at least one documented COPD exacerbation within one year prior to Screening (Visit V0).
    7. The subject is on standard of care COPD maintenance treatment including LABAs, long acting anticholinergics, or any combination thereof taken on a constant daily dose within 12 weeks prior to Screening (Visit V0)
    8. The subject must be a former smoker (defined as smoking cessation at least one year ago) or current smoker both with a smoking history of at least 10 pack years.
    9. The subject is male or female and aged 40 or older.
    10. A female subject of childbearing potential* who is sexually active with a nonsterilized* male partner agrees to use routinely adequate contraception* from signing of informed consent throughout the duration of the study and for 30 days after the last dose of study medication..
    E.4Principal exclusion criteria
    1. The subject has a COPD exacerbation ongoing at the Screening (Visit V0), or has a COPD exacerbation between V0 and V1.
    2. The subject has a lower respiratory tract infection not resolved 4 weeks prior to Screening (Visit V0).
    3. The subject has a diagnosis of asthma and/or other relevant lung disease (eg, history of primary bronchiectases, cystic fibrosis, bronchiolitis, lung resection, lung cancer, interstitial lung disease [eg, fibrosis, silicosis, sarcoidosis], or active tuberculosis).
    4. The subject has a known α1-antitrypsin deficiency.
    5. The subject has taken roflumilast within 6 months of Screening (Visit V0).
    Criteria within ethical considerations in terms of general health
    6. The subject has clinically relevant abnormal laboratory values suggesting an undiagnosed disease requiring further clinical evaluation (as assessed by the investigator).
    7. The subject has a history of severe psychiatric or neurological disorders.
    8. The subject has a history of depression associated with suicidal ideation or behavior.
    9. The subject has congestive heart failure severity grade IV according to NYHA Functional Classification.
    10. The subject has hemodynamically significant cardiac arrhythmias or heart valve deformations.
    11. The subject has CT or chest x-ray findings indicating an acute pulmonary disease other than COPD (eg, tuberculosis, severe bronchiectasis, tumors).
    12. The subject has severe immunological diseases (eg, known human immune deficiency virus (HIV) infection, multiple sclerosis, lupus erythematosus, progressive multifocal leukoencephalopathy).
    13. The subject has liver impairment Child-Pugh B or C and/or active viral hepatitis.
    14. The subject has severe acute infectious diseases (eg, tuberculosis, or acute hepatitis).
    15. The subject has a history of malignant disease (except basal cell carcinoma) within 5 years before Screening (Visit V0).
    16. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within one year before Screening (Visit V0).
    17. The subject has a history of hypersensitivity or allergies to roflumilast or rescue medication or ingredients thereof, or any other contraindication for the use thereof.
    18. If female, the subject is pregnant or lactating or intending to become pregnant before, during, or within 30 days after participating in this study; or intending to donate ova during such time period.
    19. The subject intends to donate blood, organs, or bone marrow during the course of the study.
    20. The subject has received any investigational compound within 30 days prior to Screening (Visit V0), is currently participating in another interventional clinical study, or has been previously enrolled in this study.
    21. The subject is suspected to be unable or unwilling to comply with study procedures (eg, language problems, psychological disorders, number and timing of visits at the center).
    22. The subject suffers from any concomitant disease that might interfere with study procedures or evaluations.
    23. The subject is required to take excluded medications (see Section 7.4).
    24. The subject is an immediate family member, study center employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling), or may consent under duress.
    E.5 End points
    E.5.1Primary end point(s)
    Percentage of subjects prematurely discontinuing study treatment due to any reason (during main period ie, Visit V1 to Vend).
    E.5.1.1Timepoint(s) of evaluation of this end point
    up to week 12
    E.5.2Secondary end point(s)
    • Percentage of subjects with adverse events of interest to evaluate tolerability - diarrhea, nausea, headache, decreased appetite, insomnia and abdominal pain (main period, V1 to Vend)
    • Change in pre-bronchodilator FEV1 during the down-titration period, from V0DT to VendDT
    • Percentage of subjects prematurely discontinuing study treatment due to any reason (during down-titration period, V0DT to VendDT)
    Other secondary endpoints for this study are:
    • Change in pre-bronchodilator FVC and pre-bronchodilator FEV1 from V1 to V2, V3, V4 and Vend (during main period of the study)
    • To characterize the efficacy of roflumilast 250μg OD on lung function during a down-titration period, in subjects who do not tolerate roflumilast 500μg OD
    • Change in subject-assessed treatment satisfaction scores from V1 to V2, V3, V4 and Vend (during main period of the study)
    • To characterize subject-assessed treatment satisfaction of roflumilast 250μg OD during a down-titration period, in subjects who do not tolerate roflumilast 500μg OD.
    E.5.2.1Timepoint(s) of evaluation of this end point
    as shown in the list above, up to week 12
    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 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 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.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 Yes
    E.8.1.7.1Other trial design description
    open-label in down titration period
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Lower dose of drug (250ug) and a different dosing regime of the 500 ug dose
    E.8.2.4Number of treatment arms in the trial3
    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 concerned11
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA126
    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, Republic of
    Philippines
    Russian Federation
    South Africa
    Thailand
    Ukraine
    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
    The end-of-trial is defined as database hard-lock, which will be subsequent 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 years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 1000
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 400
    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 state172
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 700
    F.4.2.2In the whole clinical trial 1400
    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)
    subjects will return to 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 Decision2014-07-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-08-21
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-11-30
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