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    EudraCT Number:2013-002686-19
    Sponsor's Protocol Code Number:HIPS-2013
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2013-07-04
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2013-002686-19
    A.3Full title of the trial
    Hemophilia Inhibitor PUP Study - HIPS
    Studio degli inibitori in pazienti emofilici non trattati in precedenza -
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Inhibitor study in patient with hemophilia never treated in the past
    Studio degli inibitori in pazienti emofilici mai trattati in precedenza
    A.4.1Sponsor's protocol code numberHIPS-2013
    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 SponsorFondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBaxter
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - Haemophilia Unit
    B.5.2Functional name of contact pointElena Santagostino, M.D.
    B.5.3 Address:
    B.5.3.1Street AddressVia Pace, 9
    B.5.3.2Town/ cityMilan
    B.5.3.3Post code20122
    B.5.4Telephone number0039255035273
    B.5.5Fax number0039255032072
    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 Advate
    D. of the Marketing Authorisation holderBaxter AG - Wien - Austria
    D.2.1.2Country which granted the Marketing AuthorisationAustria
    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 nameAdvate
    D.3.4Pharmaceutical form Lyophilisate for 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. 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 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 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
    Infants or children with severe haemophilia A previously untreated with factor concentrates.
    Bambini con grave emofilia A non trattati in precedenza con fattori
    E.1.1.1Medical condition in easily understood language
    Infants or children with severe hemophilia A never treated in the past
    for this disease
    Bambini con grave emofilia A che non hanno mai ricevuto una terapia in precedenza per questa malattia.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level LLT
    E.1.2Classification code 10018938
    E.1.2Term Haemophilia A (Factor VIII)
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to evaluate the changes in the
    immune system upon exposure to FVIII in patients with severe
    hemophilia A.
    L'obiettivo primario dello studio è quello di valutare i cambiamenti del
    sistema immunitario che si possono presentare durante le prime
    infusioni con FVIII in pazienti con grave emofilia A.
    E.2.2Secondary objectives of the trial
    The secondary objective of the trial is to identify predictors of FVIII
    inhibitor development or tolerance to FVIII infusions.
    L'obiettivo secondario dello studio è quello di identificare quali variabili possano predire lo sviluppo dell'inibitore al FVIII o determinare la tolleranza alle infusioni del FVIII.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    The principal inclusion criteria are:
    1) An informed consent, approved by the appropriate Institutional
    Review Board(IRB)/Independent Ethics Committee (IEC) has been
    administered, signed and dated by the parents or legal rapresentative
    of the patients
    2) Subject diagnosed with severe haemophilia A defined by a baseline
    FVIII:C < 0,01 IU/mL. The FVIII activity has to be confirmed by a central lab. If the confirmatory level is not < 0,01 IU/mL the child
    must exit the study
    3) Subject weights 3,5 kg or more at the time of his baseline study
    I principali criteri di inclusione sono:
    1) presentazione e spiegazione ai genitori/rappresentante legale del
    paziente minore del modulo di consenso informato, approvato
    dall'Institutional Review Board(IRB)/Comitato Etico Indipendente, da
    firmare e datare.
    2) Soggetti con emofilia grave di tipo A definita con valori alla baseline
    di FVIII:C < 0,01 IU/mL. L'attività del FVIII deve essere confermata
    dal laboratorio centralizzato. Se il valore non risulta confermato, ossia
    non risulta < 0,01 IU/mL, il paziente deve uscire dallo studio.
    3) Soggetti con un peso corporeo di 3,5 kg o più al momento della
    valutazione alla visita basale dello studio.
    E.4Principal exclusion criteria
    The principal exclusion criteria are:
    1) Subjects with prior exposure to clotting factor concentrates or blood
    2) Subjects with a clinically significant chronic disease other than
    hemophilia A.
    3) Subjects that are currently partecipating to other investigational
    clinical trials
    I principali criteri di esclusione sono:
    1) Soggetti con precedente esposizione a concentrati di fattori
    plasmatici o a prodotti ematici.
    2) Soggetti con patologie croniche oltre all'emofilia A.
    3) Soggetti che stanno partecipando ad altri studi clinici sperimentali
    E.5 End points
    E.5.1Primary end point(s)
    In relation to the primary endpoints, an inhibitor is defined by a
    Nijmegen test > 0.6 BU in two consecutive tests conducted in the
    central lab.
    During the first 50 days of exposure to a single FVIII product, the
    following items will be evaluated:
    - FVIII inhibitor;
    - FVIII antibody titer, subclasses and FVIII-binding affinity;
    - FVIII-specific T-cell responses;
    - Total number of FOXP-3positive Treg;
    - RNA expression for the whole transcriptome;
    - F8 gene mutation and other known genomic predictors for inhibitor
    In relazione all'endpoint primario, l'inibitore viene definito dalla
    positività del test Bethesda modificato secondo Nijemegen con valore
    di > 0.6 BU valutato in due differenti test consecutivi eseguiti presso il
    laboratorio centralizzato.
    Nei primi 50 giorni di esposizione ad un singolo concentrato di FVIII
    verranno valutati :
    - presenza dell' inibitore
    - titolo dell'inibitore, sottoclassi anticorpali e affinità di legame al
    - risposte FVIII-specifiche dei linfociti T;
    - numero totale di linfociti Treg FOXP3-positivi;
    - espressione di RNA per l'intero trascrittoma;
    - mutazione del gene del FVIII e altri fattori di rischio genetici noti per
    lo sviluppo di inibitori.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The inhibitor FVIII will be evaluated during the following visits: day 1, day 5, day 10, day 20, day 30, day 40 and day 50.
    L'inibitore FVIII verrà valutato durante le seguenti visite: giorni 1, 5, 10, 20, 30, 40 e 50
    E.5.2Secondary end point(s)
    The secondary endpoints will be evaluated during the first 50 days of
    exposure to a single FVIII product. The items recorded in this period
    are: FVIII usage; bleeding episodes; occurrence of infection and/or
    Gli endpoints secondari verranno valutati durante i primi 50 giorni di esposizione al singolo FVIII. In questo periodo verranno registrati i seguenti dati: utilizzo del FVIII, episodi di
    sanguinamento; insorgenza
    di infezioni e/o di immunizzazione.
    E.5.2.1Timepoint(s) of evaluation of this end point
    At study completion (after 50 exposure days or a maximum of three years)
    Alla conclusione dello studio (dopo 50 giorni di esposizione o dopo un periodo massimo di tre anni)
    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 Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    This is a multinational, multicenter study in which a single source of recombinant FVIII will be used (Advate) and treatment will be
    determined by the patient's physician, including dose, frequency and regimen (prophylaxis or on demand).
    Si tratta di uno studio multinazionale, multicentrico, nel quale verrà
    usata un unico fattore antiemofilico ricombinante (Advate) e il trattamento verrà stabilito da ciascun medico per ciascun caso, inclusi gli aspetti legati alla dose, frequenza e regime (profilassi o su
    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) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA3
    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
    United States
    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
    Last visit last subject (LVLS)
    L'ultima visita dell'ultimo paziente arruolato
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months2
    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.1.1Number of subjects for this age range: 50
    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) Yes
    F. of subjects for this age range: 40
    F.1.1.5Children (2-11years) Yes
    F. of subjects for this age range: 10
    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 No
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 3
    F.4.2.2In the whole clinical trial 50
    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)
    Patients will continue to be treated with Advate
    I pazienti continueranno ad assumere Advate.
    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 Decision2013-08-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-07-09
    P. End of Trial
    P.End of Trial StatusOngoing
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