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    The EU Clinical Trials Register currently displays   37950   clinical trials with a EudraCT protocol, of which   6228   are clinical trials conducted with subjects less than 18 years old.
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    EudraCT Number:2012-002064-27
    Sponsor's Protocol Code Number:ROF-ASTHMA_202
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-06-27
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2012-002064-27
    A.3Full title of the trial
    A Phase 2, Randomized, Double-blind, 4-week Cross-over Trial to Investigate The Effect of a Once-daily Combination of 500 µg Roflumilast plus 10 mg Montelukast versus 10 mg Montelukast Alone on Pulmonary Function, Asthma Symptoms and Inflammatory Markers in Subjects with Severe Asthma not Adequately Controlled with a Combination of at Least Medium Dose Inhaled Corticosteroids and Long-acting Beta Agonists Maintenance Therapy.

    Roflumilast (500 µg) Plus Montelukast for Asthma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy of Roflumilast and Montelukast in the treatment of severe uncontrolled asthma
    A.4.1Sponsor's protocol code numberROF-ASTHMA_202
    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 Pharma A/S
    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 Pharma A/S
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTakeda Pharma A/S
    B.5.2Functional name of contact pointClinical Trial Manager
    B.5.3 Address:
    B.5.3.1Street AddressLangebjerg 1
    B.5.3.2Town/ cityRoskilde
    B.5.3.3Post code4000
    B.5.4Telephone number+4546771625
    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 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 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. 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
    Pulmonary Function, Asthma Symptoms and Inflammatory Markers in Subjects with Severe Asthma
    E.1.1.1Medical condition in easily understood language
    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 15.1
    E.1.2Level PT
    E.1.2Classification code 10003553
    E.1.2Term Asthma
    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 assess the effect of roflumilast 500 µg QD plus montelukast 10 mg QD versus 10 mg montelukast QD alone on pre-dose (trough) pre-bronchodilator forced expiratory volume in 1 second (FEV1).
    E.2.2Secondary objectives of the trial
    To assess the effect of roflumilast 500 µg QD plus montelukast 10 mg QD versus 10 mg montelukast QD alone on further spirometry parameters, including:
    • Forced Vital Capacity (FVC); expiratory, pre-bronchodilator
    • Forced Expiratory Flow 25-75% (FEF 25-75), pre-bronchodilator
    • Peak Expiratory Flow Rate (PEF), pre-bronchodilator
    Additional Objective:
    To assess the Safety and tolerability of roflumilast 500 µg QD and montelukast 10mg QD versus 10 mg montelukast QD alone.
    To assess the effect of roflumilast 500 µg QD plus montelukast 10 mg QD versus montelukast 10 mg QD alone on:
    • The level of Inflammatory Biomarkers in blood and induced sputum/ sputum supernatant.
    • Fractioned exhaled nitric oxide.
    • Short-acting Beta Agonist (SABA) use.
    • Asthma Control Questionnaire (ACQ).
    • Asthma Exacerbations.
    • Drop-outs due to Adverse Events.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. The subject has a documented physician diagnosis of severe asthma consistent with Global Initiative for Asthma (GINA 2011) step 4 clinical features for at least 6 months prior to Visit 1.
    2. The subject has been treated with a fixed or free combination of at least medium-dose ICS (ie, ≥250 µg fluticasone propionate daily or equivalent ICS) plus LABA for at least 3 months prior to Baseline Visit 1 and a stable ICS dose for at least 4 weeks before Visit 2.
    3. The subject shows GINA-defined uncontrolled asthma or an asthma control questionnaire (ACQ-7) score ≥1.5 despite at least medium dose ICS/LABA therapy within 4 weeks prior to at both Visit 1 and Visit 2.
    4. The subject shows a pre-bronchodilator forced expiratory volume in 1 second (FEV1) of >55% and ≤ 85% of predicted at Visit 1. For subjects performing induced sputum FEV1 must be in addition >1 liter.
    5. Subject has airway obstruction proven to be reversible by an improvement of FEV1 of at least 12% and 200 ml after inhalation of a short-acting bronchodilator. This may be documented either in the medical history (with supporting spirometry recordings) in the previous 12 months or demonstrated during Screening.
    E.4Principal exclusion criteria
    1. Severe asthma exacerbation not resolved 4 weeks prior to Baseline Visit 1, (defined by the need for oral or parenteral glucocorticosteroid intake for at least 3 days and/or hospitalization or emergency room visit with the need for oral or parenteral corticosteroid use).
    2. Lower respiratory tract infection not resolved 4 weeks prior to Baseline Visit 1.
    3. A diagnosis of chronic obstructive pulmonary disease (based on GOLD criteria) and/or other relevant forms of lung disease (eg, history of primary bronchiectasis, cystic fibrosis, idiopathic (pan)bronchiolitis or bronchiolitis obliterans, bronchopulmonary allergic aspergillosis, Churg-Strauss Syndrome, paradoxical vocal cord closure, lung resection, lung cancer, interstitial lung disease [eg, fibrosis, silicosis, sarcoidosis], or active tuberculosis) that may interfere with the evaluation of a treatment response.
    4. Current participation in a pulmonary rehabilitation program or completion of a pulmonary rehabilitation program within 3 months preceding Visit 1.
    E.5 End points
    E.5.1Primary end point(s)
    Change from Visit 2 (end of Baseline) and Visit 4 (end of Washout Period) to the Week 4 measurement of the respective Treatment Period in pre-dose (trough) FEV1.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 1, Day 28, Day 56, Day 84
    E.5.2Secondary end point(s)
    • Change from Visit 2 (end of Baseline) and Visit 4 (end of Washout Period) to the Week 4 measurement of the respective Treatment Period in
    - FVC.
    - FEF25-75%.
    - PEF.
    • Change from Visit 2 (end of Baseline) and Visit 4 (end of Washout Period) to the Week 4 measurement of the respective Treatment Period in Morning PEF from home PEF measurements and day- and nighttime asthma symptoms.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Day 1, Day 28, Day 56, Day 84
    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
    Biomarkers will be investigated in an exploratory manner
    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) 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 No
    E.8.1.6Cross over Yes
    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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    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
    South Africa
    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
    End of the trial is defined as last visit of the last subject (LVLS) + 30 days for AE follow-up.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months12
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months12
    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: 55
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 40
    F.4.2.2In the whole clinical trial 60
    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)
    None. Patients will receive standard clinical care after study completion.
    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 Decision2012-07-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-02-01
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-10-24
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