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    EudraCT Number:2015-005524-26
    Sponsor's Protocol Code Number:GBI1406
    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:2016-06-16
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2015-005524-26
    A.3Full title of the trial
    A Multicenter Phase 2 Open-Label, Single-Arm, Prospective, Interventional Study of Plasma-Derived Factor VIIIIVWF Alphanate®
    in Immune Tolerance Induction Therapy in Subjects with Congenital Hemophilia A.
    Estudio Multicéntrico de Fase II, Abierto, de un solo brazo, Prospectivo, Intervencional, del Factor Derivado del Plasma VIII/VWF (Alphanate®) en la Terapia de Inducción de Tolerancia inmune en Sujetos con Hemofilia Congénita A.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    This is a multicenter, multinational, prospective,
    single-arm, nonrandomized, open-label study of approximately 25 male subjects with congenital hemophilia A with FVIII inhibitors who will receive their first (primary) ITI treatment with Alphanate.
    The study will be conducted at approximately 20 study centers.
    Se trata de un estudio multicéntrico, multinacional, prospectivo, de un solo brazo, no aleatorizado y abierto en aproximadamente 25 sujetos varones con hemofilia congénita A que recibirán su primer (primario) tratamiento de ITI con Alphanate®.
    El estudio se llevará a cabo en aproximadamente 20 centros de estudio.
    A.4.1Sponsor's protocol code numberGBI1406
    A.5.4Other Identifiers
    Name:IND/CTA NumberNumber:016703
    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 SponsorGrifols Biologicals Inc.
    B.1.3.4CountryUnited States
    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 supportGrifols Biologicals Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGrifols Therapeutics Inc.
    B.5.2Functional name of contact pointSenior Mgr, Clinical Development
    B.5.3 Address:
    B.5.3.1Street Address79 T.W. Alexander Drive, 4101 Research Commons
    B.5.3.2Town/ cityResearch Triangle Park, NC
    B.5.3.3Post code27709
    B.5.3.4CountryUnited States
    B.5.4Telephone number0034917088600
    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. name Alphanate
    D. of the Marketing Authorisation holderGrifols Biologicals Inc.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 Powder for solution 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.3.9.3Other descriptive nameAntihemophilic Factor/von Willebrand Factor Complex (Human)
    D.3.9.4EV Substance CodeSUB13813MIG
    D.3.10 Strength
    D.3.10.1Concentration unit IU/ml international unit(s)/millilitre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number80 to 120
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    Inhibitors in patients with severe Congenital Haemophilia A
    Inhibidores en pacientes con Hemofilia Congénita A severa.
    E.1.1.1Medical condition in easily understood language
    Haemophilia A is a genetic deficiency in clotting factor VIII which leads to increased bleeding. Approximately 1/3 of severe hemophilia patients develop antibodies to FVIII
    La hemofilia A es una deficiencia genética en factor VIII de coagulación que provoca un aumento de hemorragias. Aproximadamente 1/3 de pacientes con hemofilia grave desarrollan anticuerpos al FVIII
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level HLT
    E.1.2Classification code 10018847
    E.1.2Term Haematological disorders
    E.1.2System Organ Class 100000004851
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary Objectives:
    • To assess the proportion of subjects who achieve complete immune tolerance within 33
    months of initiating Alphanate for immune tolerance induction (ITI).
    • To assess the safety of Alphanate treatment for ITI
    Objetivos principales:
    • Evaluar la proporción de sujetos que logran una tolerancia inmune completa en los 33 meses siguientes al inicio de Alfanato para la inducción de tolerancia inmune (ITI).
    • Evaluar la seguridad del tratamiento con Alfanato para la ITI.
    E.2.2Secondary objectives of the trial
    Secondary Objective(s) (if applicable)
    • To assess the proportion of subjects who achieve either complete or partial immune tolerance within 33 months of initiating Alphanate for ITI.
    • To assess the maintenance of complete or partial immune tolerance without relapse for 12 months.
    • To assess the annualized frequency of bleeding events
    Objetivo(s) secundario(s) (si procede):
    • Evaluar la proporción de sujetos que logran una tolerancia inmune completa o parcial en los 33 meses siguientes al inicio de Alfanato para ITI.
    • Evaluar el mantenimiento de la tolerancia inmune completa o parcial sin recaídas durante 12 meses.
    • Evaluar la frecuencia anualizada de episodios hemorrágicos.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion Criteria:
    A subject must meet all of the following inclusion criteria at the time of the Screening/Baseline Visit (as specified below) to be eligible for participation in the study:

    1. The subject has a documented diagnosis of severe congenital hemophilia A with FVIII:C <1% of normal.

    2. The subject is a male <8 years of age at the Baseline Visit.

    3. The subject’s documented historical peak inhibitor titer is ≥10 Bethesda units (BU) and ≤200 BU.

    4. The subject has an inhibitor titer >0.6 BU and <10 BU at Screening.

    5. The subject has had a delay ≤24 months from the date of diagnosis of the inhibitor to the start of the subject’s ITI treatment.

    6. The subject has a caregiver willing to participate and comply with requirements of the protocol, including home infusions, blood sampling, and daily diary for the duration of the trial.

    7. The subject has provided signed assent, if applicable (per Institutional Review Board or Ethics Committee requirements), and a parent or legal guardian has provided signed informed consent.
    Criterios de inclusión:
    Un sujeto debe cumplir todos los siguientes criterios de inclusión en el momento de la Visita de Selección/Basal (como se indica a continuación) para ser considerado apto para participar en el estudio:

    1. El sujeto tiene un diagnóstico documentado de hemofilia congénita A severa con un FVIII:C <1 % de lo normal.
    2. El sujeto es un varón <8 años de edad en la Visita Basal.
    3. El valor máximo registrado de los títulos de inhibidor en el historial del sujeto es >=10 unidades Bethesda (UB) y <=200 UB.
    4. El paciente tiene un título de inhibidor >0,6 UB y <10 UB en la Visita de Selección.
    5. Ha existido un periodo de <=24 meses desde la fecha del diagnóstico del inhibidor hasta el comienzo del tratamiento de ITI del sujeto.
    6. El paciente cuenta con un cuidador dispuesto a participar y cumplir con los requisitos del protocolo, incluidas las infusiones en el domicilio, toma de muestras de sangre y mantenimiento de un diario durante todo el ensayo.
    7. El sujeto ha dado su asentimiento firmado, si procede (de acuerdo a los requisitos exigidos por el Comité de Revisión Institucional o el Comité Ético) y los padres o tutor legal ha firmado el consentimiento informado.
    E.4Principal exclusion criteria
    Exclusion Criteria:

    A subject meeting any of the following exclusion criteria is not eligible for participation in the study:

    1. The subject has acquired factor VIII (FVIII) deficiency.

    2. The subject has previously received ITI treatment.

    3. The subject has a recent (within 1 month) history of central line infection at the time of Screening.

    4. The subject has a high risk of cardiovascular, cerebrovascular, or thromboembolic event as judged by the investigator.

    5. The subject is currently undergoing treatment with immunosuppressive drugs (eg, systemic corticosteroids), azathioprine, cyclophosphamide, high dose immunoglobulin,
    interferon, or the use of a protein A column or plasmapheresis and is unwilling to discontinue these treatments starting at the screening visit.

    6. The subject is positive for human immunodeficiency virus by nucleic acid amplification technology at Screening.

    7. The subject has a known previous infection with hepatitis B virus or hepatitis C virus or has clinical signs and symptoms consistent with current HBV or HCV infection.

    8. The subject has significant proteinuria, has a history of acute renal failure or severe renal impairment (blood urea nitrogen or creatinine >2 times the upper limit of normal), or is
    receiving dialysis at Screening.

    9. The subject has a value of aspartate transaminase or alanine aminotransferase >2 times the upper limit of normal at Screening.

    10. The subject has clinical evidence of any significant acute or chronic disease that, in the opinion of the investigator, may interfere with successful completion of the trial or place
    the subject at undue medical risk.

    11. The subject has a history of anaphylaxis or severe systemic reaction to any plasma-derived or other blood products.

    12. The subject has participated in another clinical trial of an Investigational Product within 30 days prior to Screening—imaging studies without investigative treatments are
    permitted—or has received any investigational blood product within the previous 3 months.

    13. In the opinion of the investigator, the subject or caregiver may have compliance problems with the protocol or the procedures of the protocol.
    Criterios de exclusión:
    No se debe incluir en el estudio a ningún sujeto que no cumpla los criterios para participar en el estudio:

    1. El sujeto ha contraído deficiencia del factor VIII (FVIII).
    2. El sujeto ha recibido previamente tratamiento ITI.
    3. El sujeto ha tenido una infección reciente (en el último mes) de la vía central antes de la Visita de Selección.
    4. El sujeto presenta un alto riesgo de episodios cardiovasculares, cerebrovasculares o tromboembólicos, según el criterio del investigador.
    5. El sujeto está actualmente sometido a tratamiento médico con un fármaco inmunodepresor (p.ej., corticoesteroides sistémicos), azatioprina, ciclofosfamida, inmunoglobulina a dosis elevadas, interferón o uso de una columna de proteína A o plasmaféresis y no está dispuesto a dejar estos tratamientos a partir de la visita de selección.
    6. El sujeto da positivo en el virus de inmunodeficiencia humana testado por tecnología de amplificación del ácido nucleico en el día de la Visita de Selección.
    7. El sujeto ha tenido anteriormente una infección comprobada del virus de la hepatitis B o el virus de la hepatitis C o presenta en la actualidad signos y síntomas clínicos compatibles con infección por el VHB o VHC.
    8. El sujeto presenta una proteinuria significativa, tiene un historial de insuficiencia renal aguda o insuficiencia renal severa (nitrógeno uréico o creatinina >2 veces el límite superior de la normalidad) o está recibiendo diálisis en la selección.
    9. El sujeto presenta un valor de aspartato transaminasa o alanina aminotransferasa >2 veces el límite superior normal en la Visita de Selección.
    10. El sujeto presenta evidencia clínica de cualquier enfermedad aguda o crónica significativa que, a juicio del investigador, pueden interferir con la finalización con éxito del ensayo o poner al sujeto en un riesgo médico innecesario..
    11. El sujeto tiene un historial de anafilaxia o reacción sistémica severa a cualquier producto derivado del plasma u otros hemoderivados.
    12. El sujeto ha participado en otro ensayo clínico con un producto en investigación en los 30 días previos a la Visita de Selección—los estudios por imágenes sin tratamientos en investigación están permitidos—o ha recibido algún producto derivado de la sangre en investigación en los últimos 3 meses.
    13. En opinión del investigador, el sujeto o su cuidador pueden tener problemas en el cumplimiento del protocolo o los procedimientos establecidos en el mismo.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is the proportion of subjects achieving complete immune tolerance within 33 months of initiation of ITI treatment.
    El objetivo principal de eficacia es la proporción de sujetos que logren la tolerancia inmune completa en los 33 meses siguientes al inicio del tratamiento ITI.
    E.5.1.1Timepoint(s) of evaluation of this end point
    within 33 months of initiation of ITI treatment
    En un periodo de 33 meses a partir del inicio del tratamiento de la ITI.
    E.5.2Secondary end point(s)
    Secondary Efficacy (if applicable):

    1.Time to achieve inhibitor titer <0.6 BU, time to complete immune tolerance, and time to partial immune tolerance. (See protocol section, paragraph 3)

    2.The proportion of subjects who achieve either complete or partial immune tolerance within 33 months of receiving Alphanate for ITI.

    3. The proportion of subjects who maintain complete immune tolerance or partial immune tolerance without relapse for 12 months

    4. The annualized frequencies of bleeding events during the ITI Treatment Phase and the Prophylactic Phase
    Eficacia secundaria (si procede):

    1. Periodo para conseguir un título de inhibidores <0,6 UB, periodo hasta la inmunotolerancia total, y periodo hasta la inmunotolerancia parcial. (Véase la sección del protocolo, párrafo 3)
    2. La proporción de sujetos que consiguen inmunotolerancia total o parcial después de haber recibido Alphanate para la ITI durante un periodo de 33 meses.
    3. La proporción de sujetos que mantienen inmunotolerancia total o inmunotolerancia parcial sin recaída durante 12 meses.
    4. Las frecuencias anualizadas de episodios hemorrágicos durante la fase de tratamiento de la ITI y la fase profiláctica
    E.5.2.1Timepoint(s) of evaluation of this end point
    A. 33 months of receiving Alphanate for ITI for the proportion of subjects who achieve either complete or partial immune tolerance.

    B. 12 months for the proportion of subjects who maintain complete immune tolerance or partial immune tolerance without relapse.

    C. 33 months + 12 months for treatment and prophylactic phases respectively for the proportion of subjects who achieve either complete or partial immune tolerance within annualized frequencies of bleeding events during the ITI Treatment Phase and the Prophylactic Phase
    A. Después de haber recibido Alphanate para la ITI durante 33 meses para la proporción de sujetos que consiguen inmunotolerancia total o parcial.
    B. 12 meses para la proporción de sujetos que mantienen inmunotolerancia total o inmunotolerancia parcial sin recaída.
    C. 33 meses + 12 meses para las fases de tratamiento y profiláctica respectivamente para la proporción de sujetos que consiguen inmunotolerancia total o inmunotolerancia parcial en frecuencias anualizadas de episodios hemorrágicos durante la fase de tratamiento de la ITI y la fase profiláctica.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    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. trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    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 No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    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 EEA4
    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
    Russian Federation
    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
    Última visita del último paciente.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years7
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 25
    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) Yes
    F. of subjects for this age range: 1
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F. of subjects for this age range: 5
    F.1.1.5Children (2-11years) Yes
    F. of subjects for this age range: 19
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female No
    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 No
    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. of subjects incapable of giving consent
    Target subjects are minors from age 0 to less than 8 years of age. Their enrollment in the study will be on the basis of consent from their legal representative and/or legal guardian as well as impartial witness as per GCP.
    La población de pacientes son menores desde 0 hasta menos de 8 años. Su inclusion en el estudio se haría basándose en el consentimiento de sus representantes legales y/o tutores legales así como testigo imparcial según BPC.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 16
    F.4.2.2In the whole clinical trial 25
    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)
    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 Decision2016-07-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-07-21
    P. End of Trial
    P.End of Trial StatusOngoing
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