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    Summary
    EudraCT Number:2005-005068-97
    Sponsor's Protocol Code Number:AC-052-414
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2007-05-11
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2005-005068-97
    A.3Full title of the trial
    Effects of combination of bosentan and sildenafil versus sildenafil monotherapy on morbidity and mortality in symptomatic patients with pulmonary arterial hypertension – A multicenter, double - blind, randomized, placebo - controlled, parallel group, prospective, event driven Phase IV study
    A.3.2Name or abbreviated title of the trial where available
    COMPASS 2
    A.4.1Sponsor's protocol code numberAC-052-414
    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 codeRo-47-0203/029
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number62.5
    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 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.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 codeRo-47-0203/029
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number125
    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
    D.8 Placebo: 2
    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 to be included must have PAH belonging to WHO Group I, in agreement with the approved indications for sildenafil in PAH by the US FDA:

    a.Idiopathic (IPAH)
    b.Familial (FPAH)
    c.Associated with (APAH):
    i.Collagen vascular disease with normal left ventricular function (ejection fraction (EF) > 50%)
    ii.Congenital systemic-to-pulmonary shunts at least 2 years post surgical repair
    iii.Drugs and toxins
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10064908
    E.1.2Term Associated with (APAH)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10064909
    E.1.2Term Idiopathic (IPAH)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10064910
    E.1.2Term Familial (FPAH)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    •To demonstrate that the combination of bosentan and sildenafil prolongs the time to the first adjudicated morbidity/mortality event compared with sildenafil monotherapy in symptomatic patients with pulmonary arterial hypertension (PAH)
    E.2.2Secondary objectives of the trial
    To assess:
    - the effects of the combination of bosentan and sildenafil compared with sildenafil monotherapy:

    ·on the 6-minute walk test (6MWT)
    ·on the modified WHO functional class in the patient population investigated,
    ·on the Borg dyspnea index in the patient population investigated,
    ·on the change in Patient Global Self Assessment in the patient population investigated
    ·on the time to event for the first occurrence of hospitalization for worsening or complication of PAH (including initiation of i.v. prostanoids), atrial septostomy, lung transplantation or death in the patient population investigated
    ·on the time to death of all causes in the patient population investigated
    ·on the quality of life in the patient population investigated

    and to assess the safety and tolerability of the combination of bosentan and sildenafil in the patient population investigated
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1)Signed informed consent prior to initiation of any study-mandated procedure
    2)Males or females => 18 years of age
    •Women of childbearing potential must have a negative pre-treatment pregnancy test and must use reliable methods of contraception.
    •Women not of childbearing potential are defined as postmenopausal (i.e., amenorrhea for at least 1 year), or documented surgically or naturally sterile.
    3)Patients with symptomatic PAH
    4)Patients with the following types of PAH belonging to WHO Group I:
    a.Idiopathic (IPAH)
    b.Familial (FPAH)
    c.Associated with (APAH):
    i.Collagen vascular disease with normal left ventricular function (ejection fraction (EF) > 50%)
    ii.Congenital systemic-to-pulmonary shunts at least 2 years post surgical repair
    iii.Drugs and toxins
    5)PAH diagnosed by right heart catheter showing:
    a.Mean pulmonary arterial pressure
    (mPAP) => 25 mmHg
    AND
    b.Pulmonary capillary wedge pressure
    (PCWP) =< 15 mmHg or left ventricular end diastolic pressure (LVEDP)  15 mmHg
    If both PCWP and LVEDP are available then the LVEDP value is retained for inclusion
    6)Treatment with a stable dose of sildenafil equal to or greater than 20 mg t.i.d. for at least 12 weeks prior to randomization (no sildenafil dosage adjustment should occur in this period)
    7)150 m =< 6MWT =< 480 m
    E.4Principal exclusion criteria
    1)PAH belonging to WHO group II-V
    2)PAH associated with portal hypertension and HIV infection
    3)PAH associated with thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders and splenectomy
    4)PAH associated with significant venous or capillary involvement (PCWP > 15 mmHg): pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis
    5)Persistent pulmonary hypertension of the newborn
    6)Significant valvular disease with valvular lesions to be excluded by echocardiogram within 2 years prior to randomization (i.e., patients with tricuspid or pulmonary insufficiency secondary to PAH can be included)
    7)Restrictive lung disease: total lung capacity (TLC) < 60% of normal predicted value
    8)Obstructive lung disease: forced expiratory volume/ forced vital capacity (FEV1/FVC) < 0.5
    9)Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C
    10)Known HIV infection
    11)Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements or that may interfere with the safety or the evaluation of the study, such as chronic infection, chronic renal failure etc.
    12)Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements
    13)Pregnancy or breast-feeding
    14)Condition that prevents compliance with the protocol or adherence to therapy
    15)Systolic blood pressure < 85 mmHg
    16)Body weight < 40 kg
    17)Hemoglobin < 75% of the lower limit of the normal range
    18)Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 times the upper limit of normal ranges
    19)Known hypersensitivity or history of drug-related adverse events with bosentan (e.g., increase in liver function test results [LFTs]), or any of the excipients of its formulation
    20)Receipt of an investigational product other than sildenafil within 3 months prior to randomization
    21)Treatment with endothelin receptor antagonists (ERAs), prostanoids or phosphodiesterase (PDE) 5 inhibitors other than sildenafil within 3 months prior to randomization
    22) Concomitant systemic treatment within 1 week prior to randomization with
    • calcineurin inhibitors (e.g., cyclosporine A and tacrolimus), sirolimus and everolimus
    • glibenclamide (glyburide)
    • inhibitors of both CYP2C9 and CYP3A4 (e.g., fluconazole, amiodarone, voriconazole)
    • combination of drugs that inhibit CYP2C9 and CYP3A4
    23)Treatment with nitrates and alpha-blockers at time of randomization
    24) In the opinion of the investigator – patients in need for treatment with any prostanoid up to Visit 4
    25)Significant left ventricular dysfunction
    E.5 End points
    E.5.1Primary end point(s)
    •Time from baseline to first adjudicated morbidity/mortality event, defined as follows:
    a.Death
    b.Hospitalization for worsening or complications of PAH or initiation of i.v. prostanoids
    c.Atrial septostomy
    d.Lung transplantation
    e.Worsening PAH defined by fulfillment of both of the following criteria:
    1)The recognition that the patient’s symptoms are worse using a 7-item Patient Global Self Assessment Scale:
    •If the Patient Global Self Assessment is “moderately worse” or “markedly worse,” confirmatory examinations of worsening PAH may be performed if deemed necessary by the investigator. These examinations include (but are not limited to): right heart catheterization (RHC), 6MWT. However, none of these examinations are mandatory and the investigator can choose the method of evaluation.
    •If the Patient Global Self Assessment is “no change” or “mildly worse,” but in the opinion of the investigator the patient’s condition is bad enough to initiate additional therapy (e.g., for patients in denial), then a 6MWT is mandatory to demonstrate either a decrease by more than 20% from the previous evaluation or a decrease by more than 30% from baseline in order to confirm disease progression.
    The 6MWT should be performed in the absence of any factor, e.g. pneumonia, that may cause a temporary deterioration in 6MWT

    AND
    2)The initiation of s.c. or inhaled prostanoids or the “Disease Progression Package”

    The observation period for all patients will start with the treatment start of the first patient and end when the overall target number of adjudicated morbidity/mortality events is achieved (EOS); the length of the observation period is independent of the duration of treatment. Censoring before EOS will be applied only to patients who are lost to follow-up and is expected to be 5.7%/year.

    The risk of a morbidity/mortality event in one group relative to the other is not expected to change with time, and the risk in the placebo group is expected to be 20%/year. The anticipated treatment effect to be detected is a risk reduction of 40% that corresponds to a Hazard Ratio for bosentan/placebo of 0.5729 i.e., 12% in the bosentan group. Patients' enrollment is expected to be 75 patients per year.
    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 No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    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 Information not present in EudraCT
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    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.8.3 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.8.5.1Number of sites anticipated in the EEA16
    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 Yes
    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 (EOS) is defined as the point in time when the overall target number of adjudicated morbidity/mortality events has been reached. All patients, including those who had an EOT visit, will have an EOS visit once the target number of adjudicated morbidity/mortality events is reached.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months11
    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 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 state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 115
    F.4.2.2In the whole clinical trial 350
    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)
    Expected normal treatment of PAH.
    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 Decision2007-05-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2007-09-12
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-12-06
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