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    Summary
    EudraCT Number:2012-003037-41
    Sponsor's Protocol Code Number:MUG-EROS-2012
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2012-08-08
    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 ConcernedAustria - BASG
    A.2EudraCT number2012-003037-41
    A.3Full title of the trial
    Effects of Roflumilast on pulmonary vascular resistance in patients with COPD and sleep apnea (Overlap Syndrome) with and without non-invasive ventilation. A Pilot Study.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effects of Roflumilast on Pulmonary Vascular Resistance in Patients with Chronic Obstructive Pulmonary Disease and Sleep Apnea (the so called Overlap Syndrome) with and without Non-invasive Ventilation. A Pilot Study.
    A.3.2Name or abbreviated title of the trial where available
    Effects of Roflumilast in Overlap Syndrome
    A.4.1Sponsor's protocol code numberMUG-EROS-2012
    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 SponsorMedizinische Universität Graz, Universitätsklinik für Innere Medizin, Klinische Abteilung für Lungenkrankheiten
    B.1.3.4CountryAustria
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMedizinische Universität Graz, Universitätsklinik für Innere Medizin, Klinische Abteilung für Lungenkrankheiten
    B.4.2CountryAustria
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedical University of Graz
    B.5.2Functional name of contact pointClinical Trials Information
    B.5.3 Address:
    B.5.3.1Street AddressAuenbruggerplatz 20
    B.5.3.2Town/ cityGraz
    B.5.3.3Post code8036
    B.5.3.4CountryAustria
    B.5.6E-mailkabor.kovacs@klinikum-graz.at
    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 AuthorisationAustria
    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.3.4Pharmaceutical 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.3.9.4EV 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    This study is about pulmonary hypertension due to lung diseases.
    The lung disease in this study will be the overlap syndrome which is defined as chronic obstructive pulmonary disease concomitant with sleep apnea.
    E.1.1.1Medical condition in easily understood language
    This study is about pulmonary vascular hypertension due to lung diseases.
    The lung disease in this study will be the overlap syndrome (chronic obstructive pulmonary disease and sleep apnea).
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10040976
    E.1.2Term Sleep apnea syndrome
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10037400
    E.1.2Term Pulmonary hypertension
    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
    Our aim is to investigate if there is a measurable effect of roflumilast in patients suffering from overlap syndrome and pulmonary hypertension, who receive a sequential combination therapy of roflumilast as a potent PDE4 inhibitor and nocturnal non-invasive ventilation as add-on therapy. This pilot study could provide a rationale data for further studies addressing the role of PDE4 inhibitors and other novel anti-inflammatory drugs as a new potential treatment option for
    pulmonary hypertension in COPD.
    E.2.2Secondary objectives of the trial
    A secondary objective will be the storage of blood samples in the biobank for further investigation.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    This study is aimed to show the effect of roflumilast on pulmonary vascular resistance in
    patients suffering from both sleep apnea and COPD, the so called overlap syndrome.
    Therefore inclusion criteria are based on gold standards for each disease separately. Adult
    patients with an age of >18 years fulfilling both, COPD and sleep apnea criteria, will be
    invited to participate in this study.

    COPD
    Regarding clinical experience and experimental data, pulmonary hypertension can be observed in patients with overlap syndrome even with only mild to moderate COPD. Hence, according to the GOLD criteria, we decided to include patients with COPD corresponding to a forced expiratory volume in 1 second (FEV1) <60% of the predicted value and a ratio of FEV1 to forced vital capacity (FVC) of ≤70% diagnosed by spirometry. According to the recently published COPD criteria, the inclusion criteria correspond to group B, C and D of the Combined Assessment of COPD test.

    Sleep Apnea
    Patients with moderate to severe sleep apnea will be included in this study. Thus, according to the American Association of Sleep Medicine (AASM) criteria, which is considered to be the current gold standard, patients with an AHI > 15 events per hour (moderate 15-30/h, severe >30/h) diagnosed by overnight polysomnography will be included in this study.

    Pulmonary Hemodynamics
    As the goal of this study is to investigate the effects of roflumilast on an abnormal pulmonary hemodynamical state, only those patients will be included who present with a PVR>150 dyn×s×cm-5 and a mPAP > 20mmHg at the baseline right heart catheterization.
    E.4Principal exclusion criteria
    Underweight is very rare in patients suffering from sleep apnea as significant weight loss is important goal in these patients. Therefore weight loss which is a common side effect of roflumilast may be advantageous in the majority of patients with sleep apnea syndrome.
    Patients with a body mass index less than 20kg/m² will not be included in this study.

    Roflumilast is metabolized in the liver through cytochrome-P450 isoenzymes. Hence, roflumilast is contraindicated in patients with with moderate to severe liver failure. Patients with Child-Pugh class B to C will also be excluded from this study.

    Furthermore, patients working as professional drivers and patients with daytime hypercapnia ( pCO2 >55mmHg) will be excluded from this study.

    Further exclusion criteria:
    pregnancy, pulmonary hypertension due to other reasons, active clinical depression, therapy with roflumilast or NIV in history, immunosupression, treatment with combined CYP3A4/CYP1A2 inhibitors.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint in this study will be the change of pulmonary vascular resistance, measured by right heart catheterization, in patients with overlap syndrome after treatment with roflumilast.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoint in this study will be measured after a 6-month treatment with roflumilast.
    E.5.2Secondary end point(s)
    Secondary endpoints will be changes after treatment with roflumilast and changes after treatment with roflumilast and additional treatment with nocturnal non-invasive ventilation. Measured parameters will be changes of the other right heart catheterization parameters and changes in six-minute walk distance, questionnaires, polysomnographic parameters, lung function parameters including blood gas analysis, clinical chemistry parameters and body weight.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoints will be changes after 6-month treatment with roflumilast and changes after 12 months of roflumilast including 6 months treatment with nocturnal non-invasive ventilation.
    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 No
    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 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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    E.8.2.3Other No
    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
    LVLS
    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 months6
    E.8.9.1In the Member State concerned days
    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: 10
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 state20
    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

    Normal treatment of patients with overlap syndrome/ sleep apnea:
    Atleast 1 year follow-up in the sleep laboratory
    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 Decision2012-09-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-08-20
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2012-09-21
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