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    Summary
    EudraCT Number:2017-001163-20
    Sponsor's Protocol Code Number:995
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-08-10
    Trial 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 number2017-001163-20
    A.3Full title of the trial
    A randomized, active-controlled, multicenter, phase III study investigating efficacy and safety of intra-operative use of BT524 (human fibrinogen concentrate) in subjects undergoing major spine surgery (AdFIrst).
    Estudio de fase III, aleatorizado, comparativo con tratamiento activo, multicéntrico, para evaluar la eficacia y seguridad del uso intraoperatorio de BT524 (concentrado de fibrinógeno humano) en pacientes sometidos a una operación de cirugía mayor de columna vertebral (AdFIrst).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical study investigating efficacy and safety of BT524 in intra-operative use in patients undergoing major spine surgery
    Estudio para evaluar la eficacia y seguridad de BT524 en pacientes sometidos a una operacion de cirugia mayor de columna vertebral.
    A.3.2Name or abbreviated title of the trial where available
    AdFIrst
    AdFIrst
    A.4.1Sponsor's protocol code number995
    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 SponsorBiotest AG
    B.1.3.4CountryGermany
    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 supportBiotest AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBiotest AG
    B.5.2Functional name of contact pointCorporate Clinical Research
    B.5.3 Address:
    B.5.3.1Street AddressLandsteinerstrasse 5
    B.5.3.2Town/ cityDreieich
    B.5.3.3Post code63303
    B.5.3.4CountryGermany
    B.5.4Telephone number004961038016395
    B.5.5Fax number00496103801341
    B.5.6E-mail995@biotest.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 nameHuman Fibrinogen Concentrate
    D.3.2Product code BT524
    D.3.4Pharmaceutical form Powder for solution for injection/infusion
    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 INNHuman fibrinogen concentrate
    D.3.9.1CAS number 9001-32-5
    D.3.9.2Current sponsor codeBT524
    D.3.9.3Other descriptive nameHUMAN FIBRINOGEN
    D.3.9.4EV Substance CodeSUB12502MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number14 to 26
    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 Yes
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    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 RoleComparator
    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.2.5The 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.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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 Yes
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Elective spine surgery with expected major blood loss
    operacion de columna vertebral con importante pérdida de sangre esperada
    E.1.1.1Medical condition in easily understood language
    Acquired Fibrinogen deficiency
    Deficiencia de fibrinógeno adquirida
    E.1.1.2Therapeutic area Not possible to specify
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10051125
    E.1.2Term Hypofibrinogenaemia
    E.1.2System Organ Class 10005329 - Blood and lymphatic system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The main purpose of this phase III study is to demonstrate the efficacy of BT524 as a complementary therapy to management of uncontrolled severe hemorrhage in subjects undergoing elective major spine surgery.
    The primary objective of this study is to demonstrate that BT524 is therapeutically equivalent that means not worse than fresh frozen plasma (FFP) with a non-inferiority margin of 150 mL in reducing intra-operative blood loss by intravenous (IV) administration in subjects with acquired hypofibrinogenaemia undergoing elective major spine surgery.
    If therapeutical equivalence has been demonstrated, therapeutical superiority of BT524 compared with FFP will also be assessed.
    El objetivo principal de este estudio de fase III consiste en demostrar la eficacia de BT524 como terapia complementaria para el tratamiento de las hemorragias graves incontroladas en sujetos sometidos a operaciones de cirugía mayor programada de columna vertebral.
    El objetivo principal de este estudio consiste en demostrar que BT524 es terapéuticamente equivalente, lo que significa que no es peor que el plasma congelado en fresco (PCF) con un margen de no inferioridad de 150 ml en la reducción de la pérdida de sangre intraoperatoria mediante administración intravenosa (i.v.) en sujetos con hipofibrinogenemia adquirida sometidos a operaciones de cirugía mayor programada de columna vertebral.
    Si se ha demostrado la equivalencia terapéutica, también se evaluará la superioridad terapéutica de BT524 con respecto al PCF.
    E.2.2Secondary objectives of the trial
    Secondary objectives are to demonstrate the efficacy of BT524 by assessing the correction of the fibrinogen level intra-operatively, the transfusion requirements, 24 hours post-operative blood loss, the number of subjects with rebleeds, the hospital length of stay and the in-hospital mortality. Secondary objectives also comprise the safety of BT524 by documenting the number of adverse events (AE) including changes in laboratory parameters, the virus status, and the frequency and severity of thrombosis and of thromboembolic events (TEEs).
    Los objetivos secundarios consisten en demostrar la eficacia de BT524 evaluando la corrección intraoperatoria del nivel de fibrinógeno, las necesidades de transfusiones, la pérdida de sangre en las 24 horas siguientes a la operación, el número de sujetos con hemorragias recidivantes, la duración de la estancia hospitalaria y la mortalidad intrahospitalaria. Los objetivos secundarios también comprenden la seguridad de BT524 mediante la documentación del número de acontecimientos adversos (AA), lo que incluye los cambios en los parámetros analíticos, el estado vírico y la frecuencia y gravedad de las trombosis y de los episodios tromboembólicos (ETE).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    At screening:
    1.Written informed consent
    2.Subjects scheduled for elective major spine surgery with expected major blood loss
    3.Male or female, aged ≥ 18 years
    4.No increased bleeding risk as assessed by standard coagulation tests and medical history

    Intra-operative:
    5.Intra-operative bleeding > 1,000 mL (total blood loss), resulting in a high risk for the need of FFP transfusion during surgery.
    En la selección:
    1.Consentimiento informado por escrito.
    2.Sujetos que tengan programadas operaciones de cirugía mayor de columna vertebral en las que se prevea una pérdida de sangre importante.
    3.Hombre o mujer de Eedad ≥18 años.
    4.Ausencia de aumento del riesgo de hemorragia, evaluada mediante las pruebas de coagulación estándar y el historial medico.

    Intraoperatorios:
    5.Hemorragia intraoperatoria >1000 ml (pérdida total de sangre) que conlleve un riesgo elevado de necesidad de transfusión de PCF durante la intervención.
    E.4Principal exclusion criteria
    1.Pregnancy or unreliable contraceptive measures or lactation period (women only)
    2.Hypersensitivity to proteins of human origin or known hypersensitivity reactions to components of the Investigational Medicinal Products (IMP)
    3.Participation in another clinical study within 30 days before entering the study or during the study and/or previous participation in this study
    4.Treatment with any fibrinogen concentrate and/or fibrinogen-containing product within 30 days prior to infusion of BT524
    5.Employee or direct relative of an employee of the Contract Research Organization (CRO), the study site, or Biotest
    6.Inability or lacking motivation to participate in the study
    7.Medical condition, laboratory finding (e.g. clinically relevant biochemical or hematological findings outside the normal range), or physical exam finding that in the opinion of the investigator precludes participation
    8.Presence or history of venous/arterial thrombosis or TEE in the preceding 6 months
    1.Embarazo, métodos anticonceptivos poco fiables o periodo de lactancia (solo mujeres).
    2.Hipersensibilidad a las proteínas de origen humano o reacciones de hipersensibilidad conocidas a algún componente de los productos en investigación (PEI).
    3.Participación en otro estudio clínico dentro de los 30 días anteriores al ingreso en el estudio o durante el estudio y/o participación previa en este studio.
    4.Tratamiento con algún concentrado de fibrinógeno y/o producto con fibrinógeno dentro de los 30 días anteriores a la infusión de BT524.
    5.Empleado o familiar directo de un empleado de la organización de investigación por contrato (CRO), del centro del estudio o de Biotest.
    6.Incapacidad o falta de motivación para participar en el studio.
    7.Afección médica, resultado analítico (p. ej., resultados de bioquímica o hematología clínicamente relevantes fuera del intervalo normal) o hallazgo de la exploración física que, en opinión del investigador, impida la participación.
    8.Presencia o antecedentes de trombosis venosa/arterial o de ETE en los 6 meses anteriores.
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy: Intra-operative blood loss after decision to treat the subject with IMP until the end of surgery as measured by amount of blood from blood suction unit and amount of blood from surgical cloths and compresses.
    Eficacia: perdida de sangre intraoperatoria despues de tomar la decision de tartar al sujeto con el PEI hasta el final de la operacion, medida a traves de la cantidad de sangre de los paños y compresas quirurgicos.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Intra-operative blood loss after decision to treat the subject with IMP until the end of surgery
    perdida de sangre intraoperatoria después detomar la decision de tartar al paciente con el PEI hasta el final de la operacion.
    E.5.2Secondary end point(s)
    Efficacy:
    Proportion (%) of subjects with successful correction of fibrinogen level 15 minutes after start of IMP administration
    •First time of successful correction of fibrinogen level
    •Total amount of transfusion products (allogenic blood products) or autologous blood transfusion infused after IMP administration until end of surgery
    •Amount of red blood cells (allogenic and autologous RBCs) infused after IMP administration until end of surgery
    •24 hours post-operative blood loss
    •Proportion (%) of subjects with rebleeds after the end of surgery until Day 8
    •Hospital length of stay after surgery
    •In-hospital mortality
    Safety
    Eficacia:
    •Proporción (%) de sujetos con una corrección satisfactoria del nivel de fibrinógeno 15 minutos después del inicio de la administración del PEI.
    •Primer momento de corrección satisfactoria del nivel de fibrinógeno.
    •Cantidad total de productos de transfusión (hemoderivados alógenos) o de transfusión de sangre autóloga infundida después de la administración del PEI hasta el final de la operación.
    •Cantidad de eritrocitos (alógenos y autólogos) infundida después de la administración del PEI hasta el final de la operación.
    •Pérdida de sangre en las 24 horas siguientes a la operación.
    •Proporción (%) de sujetos con hemorragias recidivantes después del final de la operación hasta el día 8.
    •Duración de la estancia hospitalaria después de la operación.
    •Mortalidad durante la hospitalización.
    Seguridad
    E.5.2.1Timepoint(s) of evaluation of this end point
    Until closing visit (up to 70 days)
    Hasta la visita de cierre (hasta 70 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 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 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 No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Parcialmente ciego
    Partially blinded
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Plasma Fresco Congelado
    fresh frozen plasma (FFP)
    E.8.2.4Number of treatment arms in the trial2
    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 EEA20
    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
    European Union
    Switzerland
    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
    LVLS
    Ultima visita ultimo paciente
    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 months26
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months26
    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: 160
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    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 state32
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 165
    F.4.2.2In the whole clinical trial 200
    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)
    None
    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 Decision2017-09-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-21
    P. End of Trial
    P.End of Trial StatusOngoing
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