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    Summary
    EudraCT Number:2004-001319-71
    Sponsor's Protocol Code Number:F1K-MC-EVBQ
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-04-13
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2004-001319-71
    A.3Full title of the trial
    A Phase IIIb Study to Determine Efficacy and Safety of
    Extended Drotrecogin Alfa (Activated) Therapy in
    Patients With Persistent Requirement for Vasopressor
    Support After 96-Hour Infusion With Commercial
    Drotrecogin Alfa (Activated).
    Título completo del ensayo: ?Estudio de fase IIIb para determinar la eficacia y la seguridad de la prolongación del tratamiento con drotrecogina alfa (activada) en pacientes con necesidad mantenida de soporte vasopresor después de la infusión de drotrecogina alfa (activada) comercial durante 96 horas?.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    to Determine Efficacy and Safety of
    Extended Drotrecogin Alfa (Activated) Therapy in
    Patients With Persistent Requirement for Vasopressor
    Support After 96-Hour Infusion With Commercial
    Drotrecogin Alfa (Activated
    Estudio para determinar la eficacia y la seguridad de la prolongación del tratamiento con drotrecogina alfa (activada) en pacientes con necesidad mantenida de soporte vasopresor después de la infusión de drotrecogina alfa (activada) comercial durante 96 horas
    A.4.1Sponsor's protocol code numberF1K-MC-EVBQ
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorLilly S.A.
    B.1.3.4CountrySpain
    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 supportLilly S.A.
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLilly S.A.
    B.5.2Functional name of contact pointClinical Operations
    B.5.3 Address:
    B.5.3.1Street AddressAvda de la industria 30
    B.5.3.2Town/ cityAlcobendas Madrid
    B.5.3.3Post code28108
    B.5.3.4CountrySpain
    B.5.4Telephone number34916633485
    B.5.5Fax number34916633481
    B.5.6E-mailjulian_inmaculada@lilly.com
    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 nameXIGRIS
    D.3.2Product code LY203638
    D.3.4Pharmaceutical form Powder for injection
    D.3.4.1Specific paediatric formulation No
    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 INNDrotrecogina Alfa Activada
    D.3.9.1CAS number 98530-76-8
    D.3.9.2Current sponsor codeXigris
    D.3.9.3Other descriptive nameLY203638
    D.3.10 Strength
    D.3.10.1Concentration unit µg/kg microgram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number24
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 Yes
    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 Yes
    D.3.11.13.1Other medicinal product typeProteina C Activada humana de origen recombinante
    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 placeboSolution for injection
    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
    in severe sepsis patients with persistent vasopressordependent
    hypotension
    Sepsis grave con hipotensión dependiente de vasopresores.
    E.1.1.1Medical condition in easily understood language
    Sepsis
    Sepsis
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To investigate, in severe sepsis patients with persistent vasopressordependent
    hypotension at the end of a 96-hour infusion of commercial
    drotrecogin alfa (activated), whether continued administration of
    drotrecogin alfa (activated) for up to 72 additional hours results in
    more rapid resolution of vasopressor-dependent hypotension versus
    placebo.
    Objetivo principal: Investigar si la administración continuada de drotrecogina alfa (activada) durante 72 horas adicionales resulta en una más rápida resolución de la hipotensión dependiente de vasopresores, en comparación con placebo, en los pacientes con sepsis grave e hipotensión dependiente de vasopresores que han recibido una infusión del fármaco comercial de drotrecogina alfa (activada) durante 96 horas.
    E.2.2Secondary objectives of the trial
    To evaluate if extended treatment with drotrecogin alfa (activated)
    compared with placebo reduces 28-day* all cause mortality (i.e.,
    mortality assessed 28-days from the start of commercial drug therapy)
    and in hospital mortality.
    ? To evaluate the effects of extended administration of drotrecogin alfa
    (activated) compared with placebo on cardiovascular, hematology,
    hepatic, renal, and respiratory function as assessed by available
    laboratory and physiologic parameters over the 14-day interval from
    the start of commercial drug therapy.
    ? To evaluate the effects of extended administration of drotrecogin alfa
    (activated) compared with placebo on the concentrations of various
    biomarkers (e.g., Protein C, D-Dimer, Prothrombin Time) at the start
    and stop of the extended infusion.
    ? To investigate the safety profile (e.g. study drug related bleeding
    events) of an extended infusion of drotrecogin alfa (activated) over a
    24-day study.
    · Evaluar la reducción de la mortalidad por cualquier causa a los 28 días y la mortalidad intrahospitalaria.
    · Evaluar los efectos de la administración prolongada de drotrecogina alfa (activada) sobre la función cardiovascular, hematológica, hepática, renal y respiratoria de acuerdo con los parámetros disponibles de laboratorio y fisiológicos durante los 14 días siguientes al comienzo del tratamiento con el fármaco comercial.
    · Evaluar los efectos de la administración prolongada de drotrecogina alfa (activada) sobre la concentración de varios biomarcadores (p. ej., proteína C, dímero D, tiempo de protrombina) al comienzo y al final de la infusión prolongada.
    · Investigar la seguridad (p. ej., episodios de hemorragia relacionados con el medicamento del estudio) de la infusión prolongada de drotrecogina alfa (activada) durante un estudio de 24 días.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    [1] Are adult (?18 year old) with severe sepsis that have been treated with
    at least 84 hours of a planned 96-hour infusion of commercial
    drotrecogin alfa (activated) under the applicable label in the
    investigative site country.
    [2] Continues to require vasopressor support (epinephrine, phenylephrine,
    vasopressin, or norepinephrine) at any dose or dopamine ?5?g/kg/min
    at the completion of at least 84 hours of a planned 96-hour infusion of
    therapy with commercial drotrecogin alfa (activated).
    Adultos (³18 años) con sepsis grave, tratada durante al menos 84 de las 96 horas previstas de la infusión del fármaco comercial de drotrecogina alfa (activada) según la indicación aprobada del país donde el paciente es reclutado[2] Necesidad continuada de soporte vasopresor (epinefrina, fenilefrina, vasopresina o norepinefrina en cualquier dosis o dopamina en cantidades ³5 mg/kg/min) al finalizar al menos 84 de las 96 horas previstas para la infusión del fármaco comercial de drotrecogina alfa (activada).
    E.4Principal exclusion criteria
    [3] Expected to require extensive and/or multiple surgical procedure(s)
    (i.e. staging surgery for burn patients) within the next 3 days.
    [4] Patients with a platelet count <30,000/mm3.
    [5] Are receiving therapeutic heparin, defined as ?15,000 IU per day.
    Unfractionated heparin up to 15 U/kg/hr may be used in conjunction
    with acute hemodialysis or continuous renal replacement therapy.
    [6] Are not expected to survive the 24 day (maximum) Study Treatment
    and Post Study Treatment Period given their preexisting uncorrectable
    medical condition.
    [7] Are moribund and death is perceived to be imminent within 24 hours.
    [8] Patients whose family and/or primary physician have not committed to
    aggressive management of the patient. For instance patients or
    patients? authorized representative is unwilling to allow red blood cell
    transfusions or an advanced directive to withhold life-sustaining
    treatment, with the exception of cardiopulmonary resuscitation (CPR),
    is present.
    [9] Have received treatment within the last 30 days with a drug that has
    not received regulatory approval for any indication at the time of study
    entry.
    [10] Are pregnant or are lactating and the milk is to be ingested by the
    child.
    [11] Are contraindicated for treatment with drotrecogin alfa (activated)
    under the applicable label in the investigative site country.
    [12] Have no completed written informed consent signed by the patient or
    the patient?s legal representative.
    [13] No longer dependent upon vasopressors
    1. Previsión de procedimientos quirúrgicos extensos o múltiples (por ejemplo cirugía estadificadora de los pacientes quemados) durante los 3 días siguientes.
    2. Recuento plaquetario <30.000/mm3.
    3. Tratamiento con heparina terapéutica (definido como ³15.000 UI al día). Se puede administrar heparina no fraccionada, en dosis de hasta 15 U/kg/hora, junto con la hemodiálisis aguda o tratamiento de reemplazo renal continuo.
    4. Expectativas de vida inferior a 24 días (como máximo) más allá del tratamiento del estudio y del período posterior, debido a un trastorno médico previo incorregible.
    5. Pacientes moribundos en los que se percibe muerte inminente en 24 horas.
    6. Pacientes, cuya familia o médico que le atiende no estén comprometidos en la aceptación de una terapia agresiva para el paciente. Por ejemplo, el paciente o su representante legal no desean que se administren transfusiones de sangre, o voluntad anticipada de abstención del tratamiento de apoyo para mantenimiento de la vida, con excepción de la reanimación cardiopulmonar (RCP).
    7. Administración, en los 30 últimos días, de un medicamento que todavía no haya recibido la aprobación de las autoridades sanitarias para alguna indicación en el momento de la inclusión en el estudio.
    8. Mujeres embarazadas o durante el periodo de lactancia si van a dar de mamar al niño.
    9. Contraindicación para el tratamiento con drotrecogina alfa (activada) según el indicación aprobada del país donde el paciente es reclutado.
    10. Ausencia de la firma del consentimiento informado por el paciente o su representante legal.
    11. Ausencia de dependencia de los vasopresores.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy measurement will be time to resolution of vasopressor-dependent hypotension.
    La variable principal de eficacia será el tiempo que tarde en desaparecer la hipotensión dependiente de vasopresores.
    E.5.1.1Timepoint(s) of evaluation of this end point
    later than 72 hours after initiation of the study drug
    Despues de las 72 horas de el comienzo con la medicacion
    E.5.2Secondary end point(s)
    Secondary efficacy measurements will be obtained by comparing organ function
    (assessed by SOFA, including cardiovascular SOFA) between patients administered
    drotrecogin alfa (activated) or placebo for the extended infusion period and retrospective
    to 1 day prior to the initiation of commercial drotrecogin alfa (activated). This
    assessment will be done each day the patient is receiving study drug, in the ICU and
    hospitalized in the study hospital (up to and including Study Day 14).
    Biomarker evaluation. All patients will have central laboratory specimens drawn for
    specific biomarker assessment at the start and end of the study drug infusion. These
    biomarkers will include D-dimer, Protein C levels and Prothrombin Time.
    28-day all cause mortality and in-hospital mortality. All patients will be classified at
    Day 28 as either ?alive? or ?dead.? Patients who are discharged from the study hospital
    before Day 28 will be contacted to determine their survival status. For example, a patient
    who is discharged from the study hospital on Study Day 16 and dies while at home on
    Study Day 20 will be classified as ?dead.? Patients who die while hospitalized in the
    study hospital will be classified as ?dead.? Patients who are still hospitalized after Study
    Day 28 will be followed up through hospital discharge or a maximum of 90 days,
    whichever comes first, to assess in-hospital mortality.
    Las variables secundarias de eficacia se obtendrán comparando la función orgánica (evaluada mediante SOFA, incluido el SOFA cardiovascular) de los pacientes que reciban drotrecogina alfa (activada) o placebo durante el período prolongado de infusión y de manera retrospectiva hasta un día antes del inicio del tratamiento con la preparación comercial de drotrecogina alfa (activada). Esta evaluación se efectuará cada día que el paciente reciba el medicamento del estudio, cada día que permanezca en la UCI o cada día que se encuentre en el hospital del estudio (hasta el 14º día del estudio, inclusive).

    Evaluación de los biomarcadores. Se extraerán muestras a todos los pacientes al comienzo y al final de la infusión del medicamento del estudio para evaluar biomarcadores específicos y se enviarán al laboratorio central. Estos biomarcadores incluirán dímero D, niveles de proteína C y el tiempo de protrombina.

    Mortalidad por cualquier causa a los 28 días y mortalidad intrahospitalaria. Se catalogará a cada paciente como ?vivo? o ?muerto? a los 28 días. Se establecerá contacto
    con los pacientes que reciban el alta del hospital del estudio antes del día 28 para conocer su estado de vida. Por ejemplo, si un paciente es dado de alta del hospital del estudio a los 16 días de la investigación y fallece en su domicilio al día 20 del estudio será calificado como ?muerto?. Los pacientes que fallezcan en el hospital del estudio también serán catalogados como ?muertos?. Los pacientes que continúen hospitalizados después del día 28 del estudio serán vigilados hasta el alta hospitalaria o hasta un máximo de 90 días, si esta fecha es anterior, para evaluar la mortalidad intrahospitalaria.
    E.5.2.1Timepoint(s) of evaluation of this end point
    90 days
    90 dias
    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 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 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.8.2.4Number of treatment arms in the trial1
    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 concerned5
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Afghanistan
    United States
    E.8.7Trial has a data monitoring committee No
    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
    Last patient visit
    ultima visita del estudio
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months5
    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.1.2.1Number of subjects for this age range: 135
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 135
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Pacientes ingresados en UCI que pueden estar en coma y/o con sedación.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 270
    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)
    Standar treatment in intensive care unit
    Tratamiento standard Unidad de Cuidados Intensivos.
    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 Decision2004-08-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2004-04-26
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2007-05-08
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