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    Summary
    EudraCT Number:2004-000478-30
    Sponsor's Protocol Code Number:AC-052-364
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2004-07-20
    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 ConcernedSweden - MPA
    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.2.1.2Country 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.3.10 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 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 No
    D.3.11.8Extractive medicinal product No
    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.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
    The secondary objectives are to demonstrate that bosentan delays time to clinical worsening, and improves dyspnea, modified NYHA functional class, and quality of life, and to demonstrate that bosentan is safe and well tolerated in this patient population.
    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
    1) PAH associated with conditions other than those mentioned above, e.g., PAH secondary to portal hypertension, complex congenital heart disease or reverse shunt
    2) Severe obstructive lung disease: FEV1/FVC < 0.5
    3) Total lung capacity (TLC) < 80% of normal predicted value (see Appendix 4 in protocol)
    4) Significant vasoreactivity during right heart catheterization: i.e., a fall in mPAP to < 40 mmHg with a decrease of 10 mmHg and over and with a normal cardiac index ( 2.5 l/min.m2 and over)
    5) Acute or chronic impairment (other than dyspnea) limiting the ability to comply with study requirements (in particular with 6MWT)
    6) Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements
    7) Symptomatic lower limb vascular disease
    8) HIV patient with opportunistic infection
    9) Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C
    10) Aminotransferases, i.e., aspartate aminotransferases (AST) and/or alanine aminotransferases (ALT) > 3 times the upper limit of the normal (ULN) range
    11) Hemoglobin concentration < 75% of the lower limit of the normal range
    12) Systolic blood pressure (BP) < 85 mmHg
    13) Pregnancy or breast-feeding
    14) Recently started (< 8 weeks prior to randomization) or planned cardio-pulmonary rehabilitation program based on exercise
    15) Treatment or planned treatment with another investigational drug within 3 months of randomization.
    16) 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.
    17) Treatment for PAH within one month of randomization, excluding calcium channel blockers (if present for at least 1 month before randomization) and anticoagulants.
    18) Treatment with calcineurin-inhibitors (e.g., cyclosporine A, tacrolimus), fluconazole, glibenclamide (glyburide) within 1 week of randomization.
    19) Known hypersensitivity to bosentan or any of the excipients
    E.5 End points
    E.5.1Primary end point(s)
    There are two primary efficacy endpoints to be tested independently to assess the superiority of bosentan over placebo on exercise capacity or cardiac hemodynamics in mildly symptomatic PAH patients, namely:

    Change from baseline to Month 6 in 6MWT distance
    Change from baseline to Month 6 in PVR at rest.

    The main analysis of the primary efficacy endpoints is performed on the All-Randomized set for this superiority study. The All-Treated and Per-Protocol sets are used for the supplementary analysis of the primary efficacy endpoints meant to test the robustness of the main results.
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    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
    End-of-Study: when the last enrolled patient not prematurely withdrawn has completed the Month 6 assessments.
    Double-blind treatment extension period: will last until the study results are released; i.e., approximately 3 months. It is considered appropriate to continue the drug that might be efficacious while awaiting the study results.
    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 state3
    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 Decision2004-08-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2004-10-28
    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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