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    Summary
    EudraCT Number:2007-002440-14
    Sponsor's Protocol Code Number:AC-055-302
    National Competent Authority:Slovakia - SIDC (Slovak)
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2008-04-18
    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 ConcernedSlovakia - SIDC (Slovak)
    A.2EudraCT number2007-002440-14
    A.3Full title of the trial
    A multicenter, double-blind, randomized, placebo-controlled, parallel group, event-driven, Phase III study to assess the effects of ACT-064992 on morbidity and mortality in patients with symptomatic pulmonary arterial hypertension
    A.3.2Name or abbreviated title of the trial where available
    SERAPHIN
    A.4.1Sponsor's protocol code numberAC-055-302
    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 nameACT-064992
    D.3.2Product code ACT-064992
    D.3.4Pharmaceutical form 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.3.9.1CAS number 441798-33-0
    D.3.9.2Current sponsor codeACT-064992
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number to 3
    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 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 nameACT-064992
    D.3.2Product code ACT-064992
    D.3.4Pharmaceutical form 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.3.9.1CAS number 441798-33-0
    D.3.9.2Current sponsor codeACT-064992
    D.3.9.3Other descriptive nameACT-064992
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number to 10
    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 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
    To assess the effects of ACT-064992 on morbidity and mortality in patients with symptomatic pulmonary arterial hypertension
    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
    •To demonstrate that either dose of ACT-064992 prolongs the time to the first morbidity or mortality event in patients with symptomatic pulmonary arterial hypertension.
    E.2.2Secondary objectives of the trial
    •To demonstrate that either dose of ACT-064992 improves exercise capacity and WHO functional class, and prolongs the time to death or hospitalization for PAH in patients with symptomatic pulmonary arterial hypertension.
    •To evaluate the safety and tolerability of ACT-064992 in patients with symptomatic pulmonary arterial hypertension.
    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.Patients with symptomatic pulmonary arterial hypertension (PAH) in modified WHO functional class II to IV.
    3.Patients with the following types of PAH belonging to groups 1.1 to 1.3 of the Venice classification:
    a.Idiopathic (IPAH);
    b.Familial (FPAH); or
    c.Related to:
    i.Collagen vascular disease;
    ii.Simple, congenital systemic-to-pulmonary shunts at least 1 year post surgical repair;
    iii.HIV infection; or
    iv.Drugs and toxins.
    4.PAH diagnosis confirmed by hemodynamic evaluation performed prior to randomization and showing all of the following:
    a.Mean pulmonary artery pressure (mPAP) >= 25 mmHg at rest;
    b.Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) < 15 mmHg; and
    c.Pulmonary vascular resistance (PVR) at rest >= 240 dyn*sec/cm5.

    For patients who participate in the pharmacokinetic/ pharmacodynamic substudy, hemodynamic evaluation must have been performed within 3 months prior to randomization.
    For all other patients, hemodynamic evaluation must have been performed within 1 year prior to randomization.
    5.6-minute walk distance (6MWD) >= 50 m and ≤ 475 m.
    6.Men or women >= 12 years of age (women of childbearing potential must have a negative pre-treatment serum pregnancy test and must use a reliable method of contraception).
    E.4Principal exclusion criteria
    1.PAH associated with portal hypertension, thyroid disorders, glycogen storage disease, Gaucher’s disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders or splenectomy.
    2.PAH associated with non corrected simple congenital systemic-to-pulmonary shunts, and combined and complex systemic-to-pulmonary shunts, corrected or non corrected.
    3.PAH associated with significant venous or capillary involvement (PCWP > 15 mmHg), known pulmonary veno-occlusive disease, and pulmonary capillary hemangiomatosis.
    4.Persistent pulmonary hypertension of the newborn.
    5.Pulmonary Hypertension belonging to groups 2 to 5 of the Venice classification.
    6.Moderate to severe obstructive lung disease: forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) < 70% and FEV1 < 65% of predicted value after bronchodilator administration.
    7.Moderate to severe restrictive lung disease: total lung capacity (TLC) < 60% of predicted value.
    8.Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.
    9. Estimated Creatinine clearance <30mL/min
    10.Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 times the upper limit of normal.
    11.Hemoglobin < 75% of the lower limit of the normal range.
    12.Systolic blood pressure < 100 mmHg.
    13.Acute or chronic physical impairment (other than dyspnea), limiting the ability to comply with study requirements.
    14.Pregnant or breast-feeding.
    15.Known concomitant life-threatening disease with a life expectancy < 12 months.
    16.Body weight < 40 kg.
    17.Any condition that prevents compliance with the protocol or adherence to therapy.
    18.Recently started (< 8 weeks prior to randomization) or planned cardio-pulmonary rehabilitation program based on exercise.
    19.Treatment with endothelin receptor antagonists (ERAs) within 3 months prior to randomization.
    20.Systemic treatment within 4 weeks prior to randomization with cyclosporine A or tacrolimus, everolimus, sirolimus (calcineurin or mTOR inhibitors).
    21. Treatment with CYP3A inducers within 4 weeks prior to randomization.
    22.Known hypersensitivity to drugs of the same class as the study drug, or any of their excipients.
    23.Planned treatment, or treatment, with another investigational drug within 1 month prior to randomization.
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint
    Time from start of treatment to first morbidity or mortality event, defined as follows:
    1.Death, or
    2.Atrial septostomy, or
    3.Lung transplantation, or
    4.Initiation of intravenous or subcutaneous prostanoids (e.g., epoprostenol, treprostinil), or
    5.Other worsening of pulmonary arterial hypertension.
    Other worsening of pulmonary arterial hypertension is defined by the combination of all of the three following components:
    •A decrease in 6MWD of at least 15% from baseline that should be confirmed by two 6-minute walk tests, performed on different days, within 2 weeks
    AND
    •Worsening of PAH symptoms (1)
    AND
    •Need for new treatment(s) for PAH (2)
    (1) Worsening of PAH symptoms must include at least one of the following:
    WHO functional class increased, or no change in patients in WHO class IV at baseline
    Appearance or worsening of signs/symptoms of right heart failure that did not respond to oral diuretic therapy
    (2) New treatments for PAH are:
    oral or inhaled prostanoids (e.g., iloprost)
    oral phosphodiesterase inhibitors (e.g., sildenafil)
    endothelin receptor antagonists (e.g., bosentan, ambrisentan, sitaxsentan) only after discontinuation of the study drug
    intravenous diuretics
    An independent Clinical Event Committee (CEC) will review and confirm all reported mortality and morbidity events in a blinded fashion.
    The observation period for the primary endpoint will start with first study drug intake, and end with EOT plus 1 week.
    Patients who prematurely discontinue study treatment without a morbidity or mortality event will be censored at the time of study treatment discontinuation plus 1 week (censoring rate is expected to be 5%/year, and to be similar in all treatment groups).
    The hazard of a morbidity/mortality event in one group relative to the other is not expected to change with time, and the event rate in the placebo group is expected to be 35% per year. The treatment effect to be detected is a reduction of 40% of the event rate to 21%.
    Secondary endpoints
    These will be analyzed in the following sequence:
    1.Change from baseline to Month 6 in 6MWD
    2.Change from baseline to Month 6 in modified WHO functional class
    3.Time to death due to PAH or hospitalization for PAH up to EOT
    4.Time to death of all causes up to EOT
    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 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 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 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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA51
    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 years4
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months1
    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 Yes
    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) Yes
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 250
    F.4.2.2In the whole clinical trial 525
    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)
    SERAPHIN open label study AC-055-303
    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 Decision2008-05-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-05-14
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2012-03-15
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