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    Summary
    EudraCT Number:2011-000582-13
    Sponsor's Protocol Code Number:RO-2455-402-RD
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-10-17
    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 number2011-000582-13
    A.3Full title of the trial
    A 16-week, randomized, placebo-controlled, double blind, and parallel group trial to assess the anti-inflammatory effects of Roflumilast in chronic obstructive pulmonary disease
    The ROBERT study (Roflumilast Biopsy European Research Trial)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The trial investigates the anti-inflammatory effects of 500 µg roflumilast tablets once daily in patients with chronic obstructive pulmonary disease (COPD)
    A.4.1Sponsor's protocol code numberRO-2455-402-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 Trial Operations
    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+442031168166
    B.5.5Fax number+442031168199
    B.5.6E-mailclinicaloperations@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 Yes
    D.2.1.1.1Trade name Daxas
    D.2.1.1.2Name of the Marketing Authorisation holderTakeda 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 162401-32-3
    D.3.9.2Current sponsor codeBY217
    D.3.9.3Other descriptive nameN/A
    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 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 17.1
    E.1.2Level LLT
    E.1.2Classification code 10010952
    E.1.2Term COPD
    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 ug tablest once daily versus placebo on inflammation parameters in bronchial biopsy tissue specimen.
    E.2.2Secondary objectives of the trial
    To investigate inflammation parameters in sputum and blood serum.

    Safet status will be assessed by vital signs, physical examination (including electrocardiogram [ECG]), clinical laboratory tests, and monitoring of adverse events.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The interaction between changes in the lung microbiota,
    airway inflammation and mucin production resulting from
    roflumilast therapy
    Date of Sub-Study Protocol: 30 May2012
    Version no.: FINAL 1.1

    Objectives:
    This substudy hypothesizes that roflumilast exerts a beneficial effect by altering the inflammatory response to the lung microbiota and decreasing mucin.
    This will be tested in three specific aims:
    a) We will examine the longitudinal change in microbiota in
    roflumilast- and placebo-treated patients over 16 weeks of therapy.
    Sub aim – We will examine the interaction of mucosal
    inflammatory response with changes in microbiota.
    b) We will examine the longitudinal change in epithelial MUC5AC
    gene expression in roflumilast- and placebo-treated patients over 16 weeks of therapy.
    Sub aim – We will examine the interaction of mucosal
    inflammatory response with changes in mucin gene expression.
    c) We will examine the interaction of roflumilast- versus placebotherapy on the changes in microbiota, mucosal inflammation and mucin production.

    The HULL sub study of the Roflumilast ‘biopsy study’ RO-2455-402-RD
    Date of Sub-Study Protocol: 12 June 2012
    Version no.: FINAL 1

    Objective:
    This is an exploratory research approach to study the changes of the degree of airway reflux.
    This sub study will only be valid for the site of Professor Alyn H Morice.
    It is becoming apparent that a number of exacerbations of COPD are due to episodes of microaspiration into the airways. To investigate if Roflumilast has an effect on this microaspiration in the airways the site is measuring the pH and the symptoms with the Hull Airways Reflux Questionnaire (HARQ) to determine their degree of airway reflux and ascertain whether roflumilast therapy has any beneficial effect on the frequency of these episodes.
    E.3Principal inclusion criteria
    Subjects meeting the following criteria will be considered for inclusion in the run-in period:
    1) Written informed consent obtained according to local regulations before any trial-related activities. A trial-related activity is any procedure that would not have been performed during the routine management of the Subject.
    2) History of COPD (according to GOLD 2009) for at least 12 months prior to baseline visit V0 associated with chronic productive cough for at least three months in each of the two years prior to baseline visit V0 (with other causes of productive cough ex-cluded)
    3) Outpatients 40-80 years of age
    4) Post-bronchodilator 30% ≤FEV1 ≤80% predicted
    5) Post-bronchodilator FEV1/FVC ratio ≤70%
    6) Current or former smokers with smoking history ≥20 pack years
    E.4Principal exclusion criteria
    1) Clinical instability, defined as experiencing a COPD exacerbation six months prior to V0, as indicated by treatment with a systemically administered glucocorticosteroid and/or antibiotics and/or hospitalization
    2) An upper/lower respiratory tract infection e.g. common cold, sinus symptoms, pneu-monia, which has not resolved four weeks prior to V0
    3) Diagnosis of asthma and/or other relevant lung disease (e.g. history of primary or clinically significant bronchiectases, cystic fibrosis, bronchiolitis, lung resection, lung cancer, interstitial lung disease [e.g. fibrosis, silicosis, sarcoidosis], active tuberculo-sis) or previous episodes of pneumothorax
    4) Known alpha-1-antitrypsin deficiency
    Criteria within ethical considerations in terms of general health:
    5) Duration of oxygen therapy ≥12 h/day
    6) History of intubation for COPD or a respiratory failure of any cause in the past year
    7) Hypoxemia defined as oxyhemoglobin concentration <88% when breathing room air measured by pulse oximetry
    8) Formal contraindications to sputum collection or impossibility to obtain a sample of sputum valid for analysis
    9) Clinically relevant abnormal laboratory values suggesting an undiagnosed disease requiring further clinical evaluation (as assessed by the Investigator)
    10) Suspicion or diagnosis of a bleeding disorders irrespective of its pathophysiological mechanism: Thrombocytopenia (platelets <50000/mL) and platelet dysfunction (e.g. uraemia), thrombotic or coagulation disorders and bleeding due to abnormal blood vessels (e.g. purpura simplex)
    11) Severe psychiatric or neurological disorders
    12)History of depression associated with suicidal ideation or behaviour
    13) Hemodynamic instability (e.g. bradycardia with resting heart rate <60 beats per min, tachycardia with resting heart rate ≥120 beats per min and/or a systolic blood pres-sure <100 or >180 mmHg)
    14)History of increased intracranial pressure, superior vena cava obstruction, pulmonary hypertension, aneurysms and arteriovenous malformations within the lungs
    15)Congestive heart failure severity grade IV according to New York Heart Association Functional Classification (NYHA)
    16)Haemodynamically significant cardiac arrhythmias or heart valve deformations
    17)History of angina pectoris (Class ≥II Canadian Cardiovascular Society Functional Classification of Angina Pectoris Scale) or a myocardial infarction within last 12 months, unless corrected with Percutaneous Transluminal Coronary Angioplasty (PTCA) or Coronary Artery Bypass Surgery (CABG) ≥3 months prior to V0 and as-ymptomatic since then
    18) X-ray Computed Tomography (CT) or X-ray findings indicating a pulmonary disease other than COPD (e.g. tuberculosis, clinically significant bronchiectases, tumours). CT or X-ray results within 12 months prior to visit V0 are required.
    19) Immunological diseases or known infection with Human Immunodeficiency Virus (HIV)
    20) Liver impairment Child-Pugh B/C and/or active viral hepatitis
    21) Severe acute infectious diseases
    22) Any diagnosis of a malignant disease (other than basal or squamous cell carcinoma) within five years before enrolment into the trial
    23) Excessive alcohol intake or drug/substance abuse within the past year
    24) Any history of allergies, suspected hypersensitivity and/or contraindication to local anaesthetics (e.g. xylocaine, lignocaine) and/or sedative agents (e.g. benzodiazepi-nes, propofol, opioids) that would not allow adequate anaesthesia and/or bronchoscopy sedation. Suspected hypersensitivity to the trial treatment (Roflumilast) or in-gredients thereof, or any other contraindication for the use thereof.
    25) Female Subjects of childbearing potential, not using or 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/hysterectomized or post-menopausal >1 year or who are not using any other method of contraception considered sufficiently reliable by the Investigator in individual cases.
    26) Pregnancy, breast feeding, planned oocyte donation or oocyte implantation
    27) Planned donation of germ cells, blood, organs or bone marrow during the course of the trial
    28) Participation in another clinical trial (use of investigational product or device) within 30 days preceding the baseline visit V0 or re-entry of Subjects previously enrolled in this trial (for exemption see Section 6.5)
    29) Suspected inability to comply with trial procedures (e.g. repeated bronchoscopies, bronchial biopsy and sputum induction procedures, language problems, psychologi-cal disorders)
    30) Suffering from any concomitant disease that might interfere with trial procedures or evaluations according to the Investigator’s judgement
    31)Use of disallowed drugs (see below)
    32) Employee at the investigational site, relative or spouse of the Investigator
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint will be the number of inflammatory cells CD8+ in bronchial biopsy tissue specimen (sub-mucosa)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Evaluated from randomization visit V2 (Week 0) to the end of the intervention period in Week 16 (V6).
    E.5.2Secondary end point(s)
    Secondary endpoints will be the following parameters:
    Biopsy Material
    • Cell count in biopsied material (sub-mucosa) [cells/mm2]:
    1) CD68+
    2) Neutrophils
    3) CD4+
    4) CD45+
    • Cell count in biopsied material (bronchial epithelium) [cells/mm2]:
    1) CD8+
    2) CD68+
    Induced Sputum
    • Total and differential cell counts in induced sputum (absolute [cells/mL] and percent-age [%]):
    1) Neutrophils
    2) Macrophages
    3) Eosinophils
    4) Lymphocytes
    • Concentration of inflammatory biomarkers in sputum:
    1) Inflammatory mediators (Human InflammationMAP® v.1; Rules-Based Medicine, Inc. (RBM))
    Blood Serum
    • Concentration of inflammatory biomarkers in blood serum:
    1) Inflammatory mediators (Human InflammationMAP® v.1; Rules-Based Medicine, Inc. (RBM))
    Pulmonary Function Changes in the Course of the Trial
    • Change from randomization (V2) over 16 weeks of treatment for:
    1) Forced expiratory volume in the first 1 second (FEV1 [L])
    2) Forced vital capacity (FVC [L])
    3) FEV1/FVC [%]
    E.5.2.1Timepoint(s) of evaluation of this end point
    Evaluated from visit V1 (Week -2) or V2 (Week 0) (depending on parameter) to the end of the intervention period in Week 16 (V6)
    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 No
    E.6.6Pharmacokinetic No
    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 Yes
    E.6.13.1Other scope of the trial description
    While Roflumilast is an established drug for the reduction of COPD exacerbations, its mechanism in the lungs, particularly its anti-inflammatory activities, are not well understood. Better understanding of its effects on inflammatory cells and the inflammatory cascade may result in a better understanding which patients would benefit most from a treatment with Roflumilast and which measurable parameters might serve as surrogate predictors for the clinical efficaciousness of Roflumilast.
    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 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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA12
    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
    The end of trial is defined as database hard lock. The database will be hard-locked after the Blinded Data Review Meeting (BDRM) when it is declared complete and accurate.
    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 months10
    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 months10
    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.1.1.1In 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: 130
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 state64
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 150
    F.4.2.2In the whole clinical trial 150
    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)
    There are no plans for further treatment by the sponsor.
    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 Decision2011-12-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-12-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-02-11
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