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    Summary
    EudraCT Number:2011-000410-18
    Sponsor's Protocol Code Number:061002
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-05-30
    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 ConcernedGermany - PEI
    A.2EudraCT number2011-000410-18
    A.3Full title of the trial
    A PHASE 3b CLINICAL STUDY TO ASSESS WHETHER REGULAR ADMINISTRATION OF ADVATE IN THE ABSENCE OF IMMUNOLOGICAL DANGER SIGNALS REDUCES THE INCIDENCE RATE OF INHIBITORS IN PREVIOUSLY UNTREATED PATIENTS WITH HEMOPHILIA A
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical study to find out whether regular infusions of ADVATE in the absence of immunological danger signals (eg. tissue damage/viral or bacterial infections) reduces the possibility of inhibitor in PUPs with hemophilia A
    A.3.2Name or abbreviated title of the trial where available
    EARLY PROPHYLAXIS IMMUNOLOGIC CHALLENGE (EPIC) STUDY
    A.4.1Sponsor's protocol code number061002
    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 SponsorBaxter Innovations GmbH
    B.1.3.4CountryAustria
    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 supportBaxter Innovations GmbH
    B.4.2CountryAustria
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBaxter Innovations GmbH
    B.5.2Functional name of contact pointJudit Koranyi, MD - ClinOps
    B.5.3 Address:
    B.5.3.1Street AddressWagramer Strasse 17-19
    B.5.3.2Town/ cityVienna
    B.5.3.3Post code1221
    B.5.3.4CountryAustria
    B.5.4Telephone number+431201003301
    B.5.5Fax number+43120100534
    B.5.6E-mailjudith_koranyi@baxter.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 Yes
    D.2.1.1.1Trade name ADVATE (rAHF-PFM)
    D.2.1.1.2Name of the Marketing Authorisation holderBaxter AG Austria
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 (rAHF-PFM)
    D.3.2Product code not applicable
    D.3.4Pharmaceutical form Powder and solvent 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.3.8INN - Proposed INNOCTOCOG ALFA
    D.3.9.1CAS number 139076-62-3
    D.3.9.4EV Substance CodeSUB16449MIG
    D.3.10 Strength
    D.3.10.1Concentration unit IU international unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250 IU and 500 IU
    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 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
    Prevention of inhibitor formation, and immune tolerance induction in patients with severe and moderately severe hemophilia A by early and low-dose prophylactic ADVATE therapy
    E.1.1.1Medical condition in easily understood language
    Coagulation Factor VIII deficiency
    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 14.1
    E.1.2Level LLT
    E.1.2Classification code 10060612
    E.1.2Term Hemophilia A
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Determine the incidence rate of inhibitor formation in PUPs with severe and moderately severe hemophilia A during the first 50 exposure days (EDs) to starting with a once weekly prophylactic regimen together with the minimization of immunological danger signals
    E.2.2Secondary objectives of the trial
    •Determine the general safety and efficacy during the first 50 EDs to ADVATE of an once weekly early prophylactic regimen starting once weekly in PUPs with severe and moderately severe hemophilia A
    •Gather information about the temporal associations and molecular and cellular mechanisms involved in the development of an immune response to factor VIII (FVIII) during the first 50 EDs to ADVATE
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    •Subjects who meet all of the following criteria are eligible for this study:
    •Subjects with severe and moderately severe hemophilia A (FVIII ≤2%)
    Certain FVIII mutation types (eg, large multi-domain deletions; nonsense mutations; insertions/deletions/inversions that result in a premature stop codon; intron 22 inversions) can be used to corroborate a severe hemophilia A phenotype when laboratory assays show FVIII levels ≥1% because of rounding errors or carryover effect from a previous FVIII administration; a central laboratory FVIII assay is required to confirm subject eligibility.
    •Subjects < 1 year of age.
    •Subjects must have ≤3 EDs to any FVIII concentrate or FVIII-containing product used for treatment of minor bleeds (bleeds requiring no more than 2 infusions per event), or for preventative or precautionary infusions following possible injury.
    •Subjects with prior circumcision are allowed to enroll only if bleeding issues related to circumcision were the cause for the original diagnosis of hemophilia A and if no more than 2 EDs of FVIII were required.
    •Adequate venous access (without need for central venous access device [CVAD]-placement) as determined by the physician
    •Written informed consent from legally authorized representative(s)
    E.4Principal exclusion criteria
    •Life-threatening conditions (intracranial hemorrhage, severe trauma), or requirement for surgery at the time of enrollment
    •Evidence of inhibitor ≥0.6 BU in Njimegen-modified Bethesda Assay at study start (samples may be retested using lupus-insensitive inhibitor tests to reduce the number of false positive inhibitortesting for lupus anticoagulant will be done to eliminate false positives)
    •Inherited or acquired hemostatic defect other than hemophilia A
    •Any clinically significant, chronic disease other than hemophilia A
    •Known hypersensitivity to ADVATE or any of its constituents
    •Any planned elective surgery that cannot be postponed until after the first 20 EDs
    •Participation in the Hemophilia Inhibitor PUP Study (HIPS)
    •Application of red blood cell, platelet, or leukocyte concentrates, or plasma
    •Administration of any medication affecting coagulation or platelet function
    •Systemic administration of any immunomodulatory drug (eg, chemotherapy, intravenous glucocorticoids)
    •Participation in another clinical study involving an investigational product (IP) or device within 30 days prior to study enrollment or during the course of this studySubjects who meet any of the following criteria are not eligible for this study:
    •Life-threatening conditions (intracranial hemorrhage, severe trauma), or requirement for surgery at the time of enrollment
    •Evidence of inhibitor ≥0.6 BU in Njimegen-modified Bethesda Assay at study start (samples may be retested using lupus-insensitive inhibitor tests to reduce the number of false positive inhibitor)
    •Inherited or acquired hemostatic defect other than hemophilia A
    •Any clinically significant, chronic disease other than hemophilia A
    •Known hypersensitivity to ADVATE or any of its constituents
    •Any planned elective surgery that cannot be postponed until after the first 20 EDs
    •Participation in the Hemophilia Inhibitor PUP Study (HIPS)
    •Application of red blood cell, platelet, or leukocyte concentrates, or plasma
    •Administration of any medication affecting coagulation or platelet function
    •Systemic administration of any immunomodulatory drug (eg, chemotherapy, intravenous glucocorticoids)
    •Participation in another clinical study involving an investigational product (IP) or device within 30 days prior to study enrollment or during the course of this study
    E.5 End points
    E.5.1Primary end point(s)
    •Incidence of inhibitor formation in severe and moderately severe hemophilia A (FVIII ≤2%) within the first 50 EDs to ADVATE (prior exposure to FVIII up to a maximum of 3 EDs but maximum 2 exposures per event - to any FVIII concentrate are allowed, and infusions for bleed management will be included in the 50-ED calculation)
    E.5.1.1Timepoint(s) of evaluation of this end point
    end of study
    E.5.2Secondary end point(s)
    •Incidence of inhibitor formation in severe hemophilia A (FVIII ≤1% within the first 50 EDs of ADVATE
    •Time to inhibitor formation
    •Incidence rate for low-titer, high-titer, transient, and all inhibitors
    •Incidence of SAEs and non-serious AEs at least possibly related to ADVATE
    •Number, type, and severity of all bleeds experienced (eg, intracranial hemorrhage, joint, soft tissue)
    •Number, type, and severity of all bleeds experienced when different prophylactic dosing frequencies are used (once per week versus 2-3 times per week)
    •Number and type of surgeries (which cannot be postponed until after 20 EDs)
    •Association of known risk factors to inhibitor formation: FVIII gene mutation type, FVIII haplotype, HLA haplotypes, family history of inhibitors, infections, immunomodulatory gene polymorphisms (tumor necrosis factor-alpha [TNF-α], interleukin-10 [IL-10], cytotoxic T-lymphocyte antigen 4 [CTLA4])
    •Total FVIII consumption (in international units [IU]) for each subject
    •FVIII-specific antibody isotype for all subjects at study entry and every 10 ED
    E.5.2.1Timepoint(s) of evaluation of this end point
    end of study
    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 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 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 Yes
    E.8.2.3.1Comparator description
    Historically controlled
    E.8.2.4Number of treatment arms in the trial1
    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.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA55
    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
    Austria
    Belgium
    Bulgaria
    Canada
    Denmark
    France
    Germany
    Greece
    Ireland
    Italy
    Latvia
    Lithuania
    Netherlands
    Norway
    Poland
    Portugal
    Romania
    Russian Federation
    Slovakia
    Spain
    Sweden
    Switzerland
    Turkey
    Ukraine
    United Kingdom
    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 subject / last visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    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: 100
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Yes
    F.1.1.3Newborns (0-27 days) Yes
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.5Children (2-11years) No
    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.3.3.6.1Details of subjects incapable of giving consent
    Subjects < 1 year of age.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 70
    F.4.2.2In the whole clinical trial 100
    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)
    not different from the expected normal treatment of hemophilia A
    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 Decision2011-07-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-06-21
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2012-10-19
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