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    Summary
    EudraCT Number:2004-000478-30
    Sponsor's Protocol Code Number:AC-052-364
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2004-11-26
    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 ConcernedCzechia - SUKL
    A.2EudraCT number2004-000478-30
    A.3Full title of the trial
    Endothelin antagonist trial in mildly symptomatic PAH patients. A randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy, safety, and tolerability of bosentan in patients with mildly symptomatic pulmonary arterial hypertension.
    A.3.2Name or abbreviated title of the trial where available
    EARLY
    A.4.1Sponsor's protocol code numberAC-052-364
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorActelion Pharmaceuticals Ltd.
    B.1.3.4CountrySwitzerland
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 Tracleer
    D.2.1.1.2Name of the Marketing Authorisation holderActelion registration 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/3/01/019
    D.3 Description of the IMP
    D.3.1Product namebosentan
    D.3.2Product code Ro 47-0203
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNbosentan monohydrate
    D.3.9.1CAS number 157212-55-0
    D.3.9.2Current sponsor codeRo47-0203/029
    D.3.9.3Other descriptive name------------
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number to 62.5
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.8Extractive medicinal product Information not present in EudraCT
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    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 Tracleer
    D.2.1.1.2Name of the Marketing Authorisation holderActelion Registration Ltd.
    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/3/01/019
    D.3 Description of the IMP
    D.3.1Product namebosentan
    D.3.2Product code Ro 47-0203
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNbosentan monohydrate
    D.3.9.1CAS number 157212-55-0
    D.3.9.2Current sponsor codeRo47-0203/029
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number to 125
    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) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product Information not present in EudraCT
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Information not present in EudraCT
    D.3.11.7Plasma derived medicinal product Information not present in EudraCT
    D.3.11.8Extractive medicinal product Information not present in EudraCT
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms Information not present in EudraCT
    D.3.11.11Herbal medicinal product Information not present in EudraCT
    D.3.11.12Homeopathic medicinal product Information not present in EudraCT
    D.3.11.13Another type of medicinal product Information not present in EudraCT
    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
    Patients with modified NYHA functional Class II PAH have mild symptoms, but their pulmonary artery pressures are elevated which leads to increased wall stress and silent heart damage progression. Therefore Class I-II patients have a better survival rate than Class III-IV patients (Odds ratio = 1.9) but will eventually deteriorate if untreated.
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10064911
    E.1.2Term Pulmonary arterial hypertension
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to demonstrate that bosentan improves exercise capacity and/or cardiac hemodynamics in mildly symptomatic PAH patients.
    E.2.2Secondary objectives of the trial
    To evaluate the effect of bosentan on time to clinical worsening,
    dyspnea, NYHA Class, and quality of life.
    To demonstrate that bosentan is safe and well tolerated in this
    patient population.
    To evaluate the effects of bosentan on hemodynamics and exercise
    capacity in two groups of mildly symptomatic PAH patients
    (subgroup analysis), those who are treated with sildenafil at
    baseline and those who are not on sildenafil treatment at baseline.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    a)Men or women aged 12 years of age and over (except for countries where this age limit is contrary to specific regulatory requirements).
    Women of childbearing potential must have a negative pre-treatment pregnancy test and use a reliable method of contraception during study treatment and for at least 3 months after study treatment termination.
    – Reliable method of contraception are:
    Barrier type devices (e.g., female condom, diaphragm, contraceptive sponge) only in combination with a spermicide.
    Intra-uterine devices.
    Oral, injectable or implantable contraceptives only in combination with a barrier method.
    – Hormone-based contraceptives alone, regardless of the route of administration, are not considered as reliable methods of contraception.
    – Abstention, rhythm method, and contraception by the partner alone are not acceptable methods of contraception.
    Women not of childbearing potential are defined as prepubescent, postmenopausal (i.e., amenorrhea for at least 1 year), or surgically or naturally sterile.

    b) PAH in modified NYHA functional class II due to:
    1. PAH idiopathic (Primary Pulmonary Hypertension)
    2. PAH secondary to human immunodeficiency virus (HIV)
    3. PAH secondary to anorexigens
    4. PAH secondary to atrial septum defect (ASD) < 2 cm, ventricular septum defect (VSD) < 1 cm or patent ductus arteriosus (PAD)
    5. PAH secondary to connective tissue or auto-immune diseases

    c) 6-minute walk test (6MWT) distance < 80% of normal predicted value (see Appendix 3 in protocol)

    d) Mean pulmonary arterial pressure (mPAP) 25 mmHg and over, pulmonary capillary wedge pressure (PCWP) < 15 mmHg, and pulmonary vascular resistance (PVR) at rest 500 dyn.sec.cm-5 and over

    e) Signed informed consent prior to initiation of any study-mandated procedure.
    E.4Principal exclusion criteria
    PAH associated with conditions other than those mentioned
    above, e.g., PAH secondary to portal hypertension, complex
    congenital heart disease or reverse shunt
    • Severe obstructive lung disease: FEV1/FVC < 0.5
    • Total lung capacity < 80% of normal predicted value
    • Significant vasoreactivity during right heart catheterization: i.e.,
    a fall in mPAP to < 40 mmHg with a decrease ≥ 10 mmHg and
    with a normal cardiac index (≥ 2.5 l/min.m2)
    • Acute or chronic impairment (other than dyspnea), limiting the
    ability to comply with study requirements (in particular with
    6MWT)
    • Psychotic, addictive or other disorder limiting the ability to
    provide informed consent or to comply with study requirements
    • Symptomatic lower limb vascular disease
    • HIV patient with opportunistic infection
    • Moderate to severe hepatic impairment, i.e., Child-Pugh Class
    B or C
    • AST and/or ALT > 3 times the upper limit of normal ranges.
    • Hemoglobin concentration < 75% the lower limit of normal
    ranges
    • Systolic blood pressure < 85 mmHg
    • Pregnancy or breast-feeding
    • Recently started (< 8 weeks prior to randomization) or planned
    cardio-pulmonary rehabilitation program based on exercise
    • Treatment or planned treatment with another investigational
    drug within 3 months of randomization
    • Treatment with an endothelin receptor antagonist or with
    prostanoids (excluding acute administration during a
    catheterization procedure to test vascular reactivity) within 3
    months of randomization
    • Treatment for PAH within one month of randomization,
    excluding sildenafil treatment (if present for at least 2 months
    before randomization, at a stable dose not lower than 20 mg
    TID), calcium channel blockers (if present for at least 1 month
    before randomization) and anticoagulants
    • Treatment with calcineurin-inhibitors (e.g., cyclosporine A and
    tacrolimus), fluconazole, glibenclamide (glyburide) within 1
    week of randomization
    • Known hypersensitivity to bosentan or any of the excipients
    • Previous exposure to bosentan
    E.5 End points
    E.5.1Primary end point(s)
    Primary Endpoints
    • PVR at rest at EOS expressed as percent of baseline value.
    geometric mean in the active group showing a reduction
    least 20% when compared to the placebo geometric mean
    considered clinically relevant. The natural logarithm of this
    parameter is expected to be normally distributed with a standard
    deviation of 0.280
    • Change from baseline to End-of-Study (EOS) in 6MWT
    distance. A mean difference from placebo of at least 35 m
    considered clinically relevant. This parameter is expected
    normally distributed with a standard deviation of 65 m
    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 Information not present in EudraCT
    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 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 Yes
    E.8.2.3Other No
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial has a data monitoring committee Information not present in EudraCT
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months2
    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.1.3Elderly (>=65 years) Yes
    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 Information not present in EudraCT
    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 state31
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 104
    F.4.2.2In the whole clinical trial 170
    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 Decision2004-11-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2004-08-02
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2011-02-11
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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