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    Summary
    EudraCT Number:2006-002907-15
    Sponsor's Protocol Code Number:AC-051-350
    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:2007-01-24
    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 number2006-002907-15
    A.3Full title of the trial
    Multicenter, double-blind, randomized, placebo-controlled, parallel-group study to assess the efficacy, safety and tolerability of tezosentan in patients with pre-operative pulmonary hypertension, due to left heart disease, undergoing cardiac surgery
    A.4.1Sponsor's protocol code numberAC-051-350
    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 No
    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.3.1Product nameTezosentan
    D.3.2Product code ACT-050089 (Ro 61-0612)
    D.3.4Pharmaceutical form Intravenous infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTezosentan dissodium
    D.3.9.1CAS number 180384-58-0
    D.3.9.2Current sponsor codeACT-050089 (Ro 61-0612)
    D.3.9.3Other descriptive nameTezosentan
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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 placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Cardiac Surgery, Separation from cardiopulmonary bypass
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10063082
    E.1.2Term Acute right ventricular failure
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate that tezosentan, in patients undergoing cardiac surgery with cardiopulmonary bypass, reduces the incidence of clinically relevant right ventricular failure resulting in difficult separation from bypass or need for return to cardiopulmonary bypass or use of ventricular assist device or death.
    E.2.2Secondary objectives of the trial
    · To evaluate the effect of tezosentan on the incidence of major clinical events up to 28 days after study drug start.

    · To evaluate the effect of tezosentan on the time to weaning off cardiopulmonary bypass and time to final discharge from intensive care unit (ICU).

    · To evaluate the tolerability and safety of tezosentan in this patient population.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    · Patients >=18 years of age

    · Male or female patients (females of child-bearing potential must have been surgically sterilized or use a reliable method of contraception).
    Females can only participate in the study if they are postmenopausal, naturally amenorrheic for at least 1 year, surgically sterile or practicing a reliable method of contraception.

    Reliable methods of contraception, which must be used for the entire duration of the study and for at least 3 months after last study drug intake are:

    ·Intrauterine devices
    ·Oral, injectable, transdermal or implantable hormonal contraceptives only in combination with a barrier method (e.g., female condom, diaphragm, contraceptive sponge) or use of a condom by her partner.
    ·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.


    ·Patients undergoing complex* cardiac surgery on CPB and having sPAP > 40 mmHg or mPAP > 30 mmHg (measured by RHC or echocardiography at screening).

    * Complex cardiac surgery is defined as:
    o Surgery on two valves
    o Surgery on one valve plus revascularization
    o Re-operation of previous valve surgery.
    Or
    Patients undergoing cardiac surgery on CPB and having pre-operative pulmonary hypertension due to left heart disease (measured by RHC or echocardiography at screening) defined as
    o sPAP > 60 mmHg with mPAP/MAP > 0.5
    or
    o sPAP > 60 mmHg with signs and/or symptoms of right ventricular dysfunction.

    · Signed informed consent prior to any study-mandated procedure.

    MAP = mean arterial pressure; mPAP = mean pulmonary arterial pressure; sPAP = systolic pulmonary arterial pressure; RHC = right heart catheterization.
    E.4Principal exclusion criteria
    · Sitting systolic blood pressure < 100 mmHg (measured at hospital admission).

    · Significant chronic lung disease that might interfere with the ability to interpret the study results (e.g., severe chronic obstructive pulmonary disease).

    · Emergency surgery.

    · Pregnant or breast-feeding females.

    · Use of another investigational drug within 28 days prior to randomization.

    · Complex adult congenital heart disease.

    · Severe concomitant illness limiting life expectancy (< 6 months).

    · Participation in a device study that will affect the outcome of the study.

    · Pre-operative use of balloon pump.

    · Pre-operative use of inotropes/vasopressor drugs.

    · Pre-operative treatment of pulmonary arterial hypertension (PAH).

    · Known hypersensitivity to tezosentan or drugs of the same class, or any of their excipients.

    · Severe liver impairment.
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of patients during weaning from CPB, with clinically relevant right ventricular failure defined as absence of or significant reduction of right ventricular wall motion by direct visual inspection peri-operatively and/or severe reduction of right ventricular fraction area change (>20%) measured by 2-D echocardiography, requiring the use of 3 or more inotropic/vasopressor treatments or 2 at high doses*, return to CPB, use of rescue therapy for high PAP, use of ventricular assist device or with fatal outcome (all causes, up to 24 hours after start of weaning).

    *Definition of high dose of vasopressor/inotropic drugs:

    · Dopamine > 5 ug/kg/min
    · Dobutamine > 5ug/kg/min
    · Norepinephrine (noradrenalin) > 0.05 ug/kg/min
    · Epinephrine (adrenalin) > 0.05 mg/kg/min
    · Milrinone bolus >= 50 ug/kg, and > 0.5 ug/kg/min
    · Phenylephrine > 2.5 ug/kg/min
    · Isoproterenol > 0.01 ug/min
    · Vasopressin at a cumulative dose of > 10 units
    · Levosimendan >= 0.2 ug/kg/min
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    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 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 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 concerned3
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months18
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months18
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    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 state35
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 80
    F.4.2.2In the whole clinical trial 270
    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)
    not applicable, as the study medication is only an acute, short term treatment peri-operative to avoid or reduce post-operative complications as hemodynamic instability.
    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 Decision2007-03-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2007-01-26
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2008-02-08
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