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    The EU Clinical Trials Register currently displays   37191   clinical trials with a EudraCT protocol, of which   6121   are clinical trials conducted with subjects less than 18 years old.
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    EudraCT Number:2005-005697-71
    Sponsor's Protocol Code Number:060402
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-05-07
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2005-005697-71
    A.3Full title of the trial
    Antihemophilic Factor (Recombinant) Plasma/Albumin-Free Method (rAHF PFM): A Phase 3/4, Prospective, Controlled, Randomized, Multi-Center Study to Compare the Efficacy and Safety of Continuous Infusion (CI) versus Intermittent Bolus Infusion (BI) in Subjects with Severe or Moderately Severe Hemophilia A Undergoing Major Orthopedic Surgery
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The main goal of the study is to compare the safety and effectiveness of administering ADVATE using either continuous infusion or single, large dose infusions during and post surgery for patients requiring major orthopedic surgery
    A.3.2Name or abbreviated title of the trial where available
    Advate Randomized Surgery
    A.4.1Sponsor's protocol code number060402
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT00357656
    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 SponsorBaxalta Innovations GmbH
    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 supportBaxalta Innovations GmbH
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBaxalta Innovations GmbH
    B.5.2Functional name of contact pointJudit Koranyi, MD - ClinOps
    B.5.3 Address:
    B.5.3.1Street AddressIndustriestraße 67
    B.5.3.2Town/ cityVienna
    B.5.3.3Post code1221
    B.5.4Telephone number+431201003301
    B.5.5Fax number+43120100534
    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 (rAHF - PFM)
    D. of the Marketing Authorisation holderBaxter AG
    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.3.9.3Other descriptive namehuman coagulation factor VIII (rDNA)
    D.3.9.4EV Substance CodeSUB16449MIG
    D.3.10 Strength
    D.3.10.1Concentration unit IU international unit(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number500 to 1000
    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
    Subjects with Severe or Moderately Severe Hemophilia A (baseline
    factor VIII (FVIII) level <= 2% of normal) hemophilia A undergoing major orthopedic surgery
    E.1.1.1Medical condition in easily understood language
    Subjects with Severe or Moderately Severe Hemophilia A (baseline
    factor VIII (FVIII) level <= 2% of normal) hemophilia A undergoing major orthopedic surgery
    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 18.0
    E.1.2Level LLT
    E.1.2Classification code 10060612
    E.1.2Term Hemophilia A
    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 is to compare the hemostatic efficacy of CI versus intermittent BI in the peri- and post-operative setting employing rAHF-PFM in PTPs with severe or moderately severe hemophilia A (baseline FVIII level ≤ 2% of normal) undergoing
    elective unilateral major orthopedic surgery that requires drain
    placement by assessing the cumulative packed red blood cell (PRBC)
    volume in the drainage fluid during the first 24 hours following surgery.
    E.2.2Secondary objectives of the trial
    • Efficacy
    1. To assess and compare the total amount of hemoglobin in the
    drainage fluid
    2. To determine the blood loss compared with the predicted blood loss
    3. To determine the blood loss compared with the predicted blood loss until removal of drain
    4. To determine the number of bleeding episodes during treatment with CI or BI
    5. To record the occurrence and dimensions of any clinically relevant
    postoperative hematomas
    6. To assess the number of units of PRBCs transfused
    7. To assess and compare the global hemostatic efficacy of rAHF-PFM
    using an exploratory score between subjects receiving CI versus BI.
    8. To determine the total weight-adjusted dose of rAHF-PFM per subject
    9. To calculate the total daily intra- and post-operative weight-adjusted dose of rAHF-PFM during administration of CI or BI
    • Safety
    1. To record the number of adverse experiences (AEs) related to the
    administration of the study product
    2. To identify the incidence of FVIII antibody formation
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.The subject or the subject’s legally authorized representative has provided signed informed consent.
    2.The subject is within 18 to 70 years of age.
    3.The subject has severe or moderately severe hemophilia A, defined by a baseline FVIII level ≤ 2% of normal, as tested at screening. A subset of 15 subjects per group must have baseline FVIII levels < 1% of normal.
    4.The aPTT must be within the range of normal after administration of FVIII concentrate, as determined in the preoperative pharmacokinetic evaluation, or as documented in the medical history, if available.
    5.The subject is scheduled to undergo an elective unilateral major orthopedic surgery that requires drain replacement.
    6.The subject was previously treated with FVIII concentrate(s) for a minimum of at least 150 exposure days prior to study entry.
    7.Human immunodeficiency virus (HIV) positive subjects must be immunocompetent as determined with a CD4 count ≥ 200 cells/mm³ (CD4 count at screening), but HIV negative subjects with a CD count < 200 cells/mm³ qualify, if immunocompetency is documented.
    8.The subject has a life expectancy of at least 28 days from the day of surgery.
    E.4Principal exclusion criteria
    1. The subject has a detectable FVIII inhibitor at screening, with a titer ≥ 0.4BU (Nijmegen modification of the Bethesda Assay) in the central laboratory.
    2.The subject has a history of FVIII inhibitors with a titer ≥ 0.4BU (by
    Nijmegen assay) or ≥ 0.5 BU (by Bethesda assay) at any time prior to
    3.The subject is scheduled to undergo any other concurrent minor or
    major surgery during the course of the study. The placement of central venous lines and the performance of fine needle aspiration biopsies are permitted.
    4. Excluding hemophilia-related physical impairments, the subject is
    assigned to NYHA class ≥ III according to the New York Heart Association (NYHA).
    5.The subject has an abnormal renal function (serum creatinine > 1.5
    6.The subject has active hepatic disease (alanine aminotransferase
    [ALT] or aspartate aminotransferase [AST] levels > 5 times the upper
    limit of normal).
    7.The subject has severe chronic liver disease as evidenced by, but not limited to, any of the following: International Normalized Ratio (INR) >1.4, hypoalbuminemia, portal vein hypertension including presence of otherwise unexplained splenomegaly and history of esophageal varices.
    8.The subject has clinical and/or laboratory evidence of abnormal
    hemostasis from causes other than hemophilia A (e.g., late-stage chronic liver disease, immune thrombocytopenic purpura).
    9.The subject is currently receiving, or is scheduled to receive during the course of the study, an immunomodulating drug other than antiretroviral chemotherapy (e.g., α-interferon, corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day).
    10.The subject has a known hypersensitivity to mouse or hamster
    11.The subject has received another investigational drug within 30 days prior to screening and/or is scheduled to receive additional
    investigational drug during the course of the trial in the context of
    another investigational drug study.
    12.The subject is identified by the investigator as being unable or
    unwilling to cooperate with study procedures.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint will be a comparison of the cumulative PRBC volume in the drainage fluid during the first 24 hours following surgery in subjects receiving rAHF-PFM by BI or CI.
    E.5.1.1Timepoint(s) of evaluation of this end point
    postoperative day 1
    E.5.2Secondary end point(s)
    1. Efficacy
    1. Actual postoperative blood loss during the first 24 hours compared
    with the average blood loss as predicted preoperatively by the operating surgeon
    2. Actual postoperative blood loss compared to the expected average
    blood loss until drain removal as predicted preoperatively by the surgeon
    3. Number of bleeding episodes during treatment with CI or BI through postoperative Day 7
    4. Number of units of PRBCs transfused

    2. Safety
    1. Number of AEs related to the administration of the study product
    2. Incidence of FVIII inhibitory antibody (≥0.4 BU using the Nijmegen
    modification of the Bethesda assay) formation.

    3. Exploratory Outcome Measures
    1. Total amount of hemoglobin in the cumulative drainage fluid during the first postoperative 24 hours and until time of drain removal, if drainage continues beyond 24 hours
    2. Occurrence and dimensions of any clinically relevant postoperative
    3. Determination of an exploratory global hemostatic efficacy
    assessment score (GHEA), which is composed of 3 different categories:
    a. Assessment of intra-operative hemostatic efficacy of rAHF-PFM
    performed by the operating surgeon, and
    b. Assessment of blood loss in drains within the first 24 hours
    postoperatively performed by the operating surgeon, and
    c. Assessment of postoperative hemostatic efficacy of rAHF-PFM at
    postoperative Day 8 performed by the investigator.
    4. Total weight-adjusted dose of rAHF-PFM per subject through
    postoperative Day 7 (IU/kg body weight/subject)
    5. Total daily intra- and postoperative weight-adjusted dose of rAHF-PFM (IU/kg body weight/subject)
    6. Pharmacokinetic parameters: AUC 0-48h, total AUC, AUMC, T 1/2, CL, MRT, Vss, Cmax and IR
    E.5.2.1Timepoint(s) of evaluation of this end point
    English 1. Efficacy
    1.First postoperative 24 hours.
    2.until time of drain removal, if drainage continues beyond 24 hours
    3.Post-operative day 8
    4.Post-operative day 8

    2. Safety
    1.End-of-study visit.
    2.End-of-study visit.

    3. Exploratory Outcome Measures
    1.First postoperative 24 hours and until time of drain removal, if
    drainage continues beyond 24 hours
    2.Post-operative day 8
    3.Post-operative day 8
    4.Post-operative day 7
    5. end of study period
    6. PK assessment
    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 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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other Yes
    E. description
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    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 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 visit of last subject
    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 months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years10
    E.8.9.2In all countries concerned by the trial months3
    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: 15
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 6
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2013-05-07. Yes
    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 state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 18
    F.4.2.2In the whole clinical trial 21
    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 return to standard care as per the practice of the institution where they are treated
    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 Decision2013-08-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-05-13
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-12-09
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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