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    Summary
    EudraCT Number:2014-001882-28
    Sponsor's Protocol Code Number:2014-05ED
    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:2014-08-07
    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 ConcernedGermany - BfArM
    A.2EudraCT number2014-001882-28
    A.3Full title of the trial
    Early Treatment of Borderline Pulmonary Arterial Hypertension Associated with Systemic Sclerosis (SSc-APAH)
    Frühe Behandlung von grenzwertig erhöhten Lungendrucken bei Patienten mit Sklerodermie/systemischer Sklerose
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Drug treatment of patients with systemic sclerosis to prevent deterioration of pulmonary hypertension
    Medikamentöse Behandlung der systemischen Sklerodermie zur
    Vermeidung einer Verschlimmerung eines Lungenhochdruckes
    A.3.2Name or abbreviated title of the trial where available
    EDITA
    EDITA
    A.4.1Sponsor's protocol code number2014-05ED
    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 SponsorThoraxklinik-Heidelberg gGmbH
    B.1.3.4CountryGermany
    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 supportGlaxoSmithKline GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationThoraxklinik am Universitätsklinikum Heidelberg
    B.5.2Functional name of contact pointDirector of the clinic
    B.5.3 Address:
    B.5.3.1Street AddressRöntgenstraße 1
    B.5.3.2Town/ cityHeidelberg
    B.5.3.3Post code69126
    B.5.3.4CountryGermany
    B.5.4Telephone number+496221 396 2100
    B.5.5Fax number+4962213962102
    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 Volibris
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxo Group Ltd
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/05/273
    D.3 Description of the IMP
    D.3.1Product nameAmbrisentan
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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
    D.8 Placebo: 2
    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
    Systemic sclerosis-patients (SSc) with borderline pulmonary arterial hypertension
    Patienten mit Sklerodermie/systemischer Sklerose und grenzwertig erhöhten Lungendrucken
    E.1.1.1Medical condition in easily understood language
    Patients with systemic sclerosis and borderline pulmonary hypertension
    Patienten mit systematischer Sklerodermie und grenzwertig erhöhtem Lungenhoch
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Determine whether mPAP of SSc patients with borderline - PAH (mPAP 21 24 mmHg, TPG >11 mmHg) can be reduced by 15% following treatment with ambrisentan 10 mg/die (initiated with 5 mg/die and elevated up to 10 mg/die) over 6 months compared to baseline and placebo.
    E.2.2Secondary objectives of the trial
    2) Determine whether exercise induced elevated mPAP-values (>30 mmHg without left heart or severe lung disease or systemic arterial hypertension) and further measures of exercise capacity, symptoms and quality of life can be reduced by ambrisentan 10 mg/die over 6 months.
    3) Analyze if the progression (adverse events, hospitalization, initiation of pulmonary hypertension treatment) of borderline-PAH to manifest PH can be avoided by ambrisentan-treatment (descriptive, observational).
    4) Assessment of tolerability and safety
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female SSc patients with borderline - PAH and:
    2. mPAP 21-24 mmHg, transpulmonary gradient >11 mmHg, as defined by the current ESC Guidelines, PAWP <15 mmHg and/or
    3. Exercise induced elevated mPAP-values >30 mmHg, (PAWP <18 mmHg; TPG ≥15 mmHg, as defined in Saggar et al. (2012)) without left heart or severe lung disease or systemic arterial hypertension
    4. Adult patients having completed his/her 18th birthday
    5. Patients with definite diagnosis of Systemic Sclerosis using the scleroderma criteria of the American Rheumatism Association
    6. SSc - disease duration >3 years
    7. Able to understand and willing to sign the Informed Consent Form
    8. Negative pregnancy test at the start of the trial and appropriate contraception throughout the study for women with child-bearing potential.
    E.4Principal exclusion criteria
    1. Any connective tissue diseases (CTD) other than SSc
    2. Pulmonary hypertension (PH) confirmed by right heart catheter (RHC) before enrolment, i.e. mPAP ≥25 mmHg at rest
    3. Patients presenting normal mPAP values, i.e. mPAP<21 mmHg at rest, and mPAP ≤30 mmHg during exercise, and/or PAWP ≥15 mmHg at rest or ≥18 mmHg during exercise
    4. Ongoing or a history of >2 weeks of continued use of therapies that are considered definitive PH treatment: endothelin receptor antagonists (ERA; e.g. bosentan, ambrisentan), phosphodiesterase type 5 inhibitors (PDE5; e.g. sildenafil, tadalafil, vardenafil), and prostanoids (e.g. epoprostenol, treprostinil, iloprost, beraprost) and soluble guanylate cyclase stimulator (e.g. Riociguat). Intermittent use of PDE5 inhibitors for male erectile dysfunction is permitted.
    5. Except for diuretics and corticosteroids medical treatment should not be expected to change 4 weeks prior inclusion into the study and during the entire 12-week study period.
    6. Known intolerance to ambrisentan or one of its excipients
    7. Clinically significant anemia (hemoglobin concentration of less than 75% of the lower limit of normal, LLN)
    8. Forced vital capacity (FVC) <60%, forced expiratory volume in first second (FEV1) <65%
    9. Severe interstitial lung disease, idiopathic pulmonary fibrosis
    10. Renal insufficiency (glomerular filtration rate [GFR] <60 mL/min/1.73m2 at least for the last 3 months before inclusion)
    11. Baseline values of hepatic aminotransferases (ALT and/or AST) >3 x upper limit of normal (ULN)
    12. Systolic blood pressure <85 mmHg;
    13. evidence of inadequately treated blood pressure >160/90 mmHg and/or blood pressure during exercise >220/120 mmHg
    14. Patients referred with clinically significant overt heart failure
    15. Clinically significant fluid retention
    16. Previous evidence or diagnosis of clinically relevant left heart disease, i.e. at least one of the following: Previous echocardiography with estimated left ventricular (LV) ejection fraction <50%, previous history of cardiogenic pulmonary edema, increased size of left atrium (>50 mm)
    17. Known significant diastolic dysfunction associated with clinical heart failure
    18. Known coronary disease or significant valvular heart disease
    19. Known congenital heart defects such as single ventricle, transposition, Eisenmenger
    20. Known hypertrophic cardiomyopathy or left ventricular hypertrophy (interventricular septum thickness (IVS) or posterior wall thickness (PWD) >1.2 cm)
    21. Participation in any clinical drug trial within 4 weeks prior to screening of this study and/or who is scheduled to receive another investigational medicinal product (IMP) during the course of this study
    22. Pregnancy or lactation
    E.5 End points
    E.5.1Primary end point(s)
    1) Determine whether mPAP of SSc patients with borderline - PAH (mPAP 21 24 mmHg, TPG >11 mmHg) can be reduced by 3 mm Hg (absolute change baseline vs. 6 months; equals 15%) by treatment with ambrisentan 10 mg/die (initiated with 5 mg/die and elevated up to 10 mg/die) over 6 months (primary endpoint) compared to baseline and placebo
    E.5.1.1Timepoint(s) of evaluation of this end point
    At 6 months of treatment start with study medication
    E.5.2Secondary end point(s)
    Analyze if in patients with SSc and borderline-PAP show an improvement by treatment with ambrisentan 10 mg/die over 6 months in:
    - 6-Minute-walking test
    - Quality of life (SF-36)
    - Lung function tests (DLCo, DLCo/VA, FVC, FEV1, TLC, residual volume)
    - Echocardiography (RA-area, RV-area, Tei, TAPSE, sPAP)
    - Borg Dyspnea Index
    - WHO-functional class
    - further invasively measured hemodynamic parameters evaluated by RHC: right atrial pressure, pulmonary vascular resistance, cardiac output (CO), cardiac index (CI), PAWP, venous oxygen saturation (SvO2)
    - Raynaud-syndrome and skin involvement, assessed by the modified Rodnan-Skin score and Symptoms of Scleroderma (descriptive)
    E.5.2.1Timepoint(s) of evaluation of this end point
    At 6 months of treatment start with study medication
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    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 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 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    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: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 18
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state38
    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)
    After 6 months treatment, therapy with ambrisentan may be prescribed to all patients who might benefit from the treatment. This decision will be based on the physician’s and the patient’s estimation. Patient care and monitoring will be performed in the patients’ specialized centers.
    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 Decision2014-09-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-10-13
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-11-27
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