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    Summary
    EudraCT Number:2015-002136-40
    Sponsor's Protocol Code Number:261203
    Clinical Trial Type:Outside EU/EEA
    Date on which this record was first entered in the EudraCT database:2022-12-21
    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
    H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED
    Expand All   Collapse All
    A. Protocol Information
    A.2EudraCT number2015-002136-40
    A.3Full title of the trial
    Phase 3, prospective, multi-center, open label study to investigate safety, immunogenicity, and hemostatic efficacy of PEGylated Factor VIII (BAX 855) in previously untreated patients (PUPs) < 6 years with severe hemophilia A (FVIII < 1%)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of safety, effect on the immune system and blood clotting of BAX855 (factor VIII of blood clotting) in pediatric patients who have not received treatment for their severe hemophilia A.
    A.4.1Sponsor's protocol code number261203
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02615691
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/302/2021
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBaxalta 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 supportBaxalta Innovations GmbH
    B.4.2CountryAustria
    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 pointClinical Trial Transparency
    B.5.3 Address:
    B.5.3.1Street AddressIndustriestrasse 67
    B.5.3.2Town/ cityVienna
    B.5.3.3Post code1221
    B.5.3.4CountryAustria
    B.5.6E-mailClinicalTransparency@takeda.com
    B.Sponsor: 2
    B.1.1Name of SponsorTakeda Development Center Americas, 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 supportTakeda Development Center Americas, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTakeda Development Center Americas, Inc.
    B.5.2Functional name of contact pointClinical Trial Transparency
    B.5.3 Address:
    B.5.3.1Street Address95 Hayden Avenue
    B.5.3.2Town/ cityLexington
    B.5.3.3Post codeMA 02421
    B.5.3.4CountryUnited States
    B.5.6E-mailClinicalTransparency@takeda.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 Adynovi
    D.2.1.1.2Name of the Marketing Authorisation holderBaxalta Innovations GmbH
    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.3.4Pharmaceutical 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.3.11 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
    Severe hemophilia A (FVIII <1%)
    E.1.1.1Medical condition in easily understood language
    Hemophilia A
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    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 determine safety including immunogenicity of BAX 855 based on the incidence of inhibitor development to FVIII (≥ 0.6 Bethesda unit (BU)/mL using the Nijmegen modification of the Bethesda assay).
    E.2.2Secondary objectives of the trial
    Safety
    - To determine the immunogenicity of BAX 855 in terms of binding IgG and IgM antibodies to FVIII, PEG-FVIII and PEG
    - To determine the safety of BAX 855 based on AEs and SAEs 7.3.2

    Hemostatic Efficacy
    - To assess the efficacy of prophylactic treatment with BAX 855
    - To characterize the efficacy of BAX 855 in the control of bleeding episodes
    - To evaluate the efficacy of BAX 855 for perioperative management, if surgery is required

    Pharmacokinetics
    - To determine incremental recovery (IR) of BAX 855 at baseline and over time
    - To determine abbreviated half-life at baseline (optional)

    ITI Objectives
    - To evaluate efficacy and safety of ITI with BAX 855
    - To determine the rate of success, partial success and failure of ITI with BAX 855
    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:
    1. Subject is <6 years old at the time of screening
    2. Subject is previously untreated with <3 EDs to ADVATE, BAX 855 or plasma transfusion at any time prior to screening
    3. Subject has severe hemophilia A (FVIII <1%) as determined by the central laboratory, or a historical FVIII level <1% as determined at any local laboratory, optionally supported by an additional FVIII gene mutation consistent with severe hemophilia A
    4. Subject is immune competent with a CD4+ count >200 cells/mm3, as confirmed by the central laboratory at screening
    5. Parent or legally authorized representative is willing and able to comply with the requirements of the protocol

    Additional inclusion criteria for Part B (ITI)
    1. Parent or legal representative has/have voluntarily provided signed informed consent for ITI portion
    2. Subject has a confirmed positive high titer inhibitor (>5.00 BU) or has a positive confirmed low titer inhibitor (≥0.6 BU) as determined by the central laboratory based on a second repeat blood sample with
    - a. poorly controlled bleeding despite increased BAX 855 doses, or
    - b. requires bypassing agents to treat bleeding
    E.4Principal exclusion criteria
    Subjects who meet ANY of the following criteria are not eligible for this study:
    1. Subject has detectable FVIII inhibitory antibodies (≥0.6 BU using the Nijmegen modification of the Bethesda assay) as confirmed by central laboratory at screening
    2. Subject has a history of FVIII inhibitory antibodies (≥0.6 BU using the Nijmegen modification of the Bethesda assay or the Bethesda assay) at any time prior to screening
    3. Subject has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia A (eg, qualitative platelet defect or von Willebrand’s disease)
    4. Subject has been previously treated with any type of FVIII concentrate other than ADVATE or BAX 855, or was administered ADVATE, BAX 855 or plasma transfusion for ≥3 EDs at any time prior to screening
    5. Subject receives >2 EDs of ADVATE in total during the periods prior to enrollment and during the screening period, until the baseline infusion.
    6. The subject’s weight is anticipated to be <5 kg at the baseline visit
    7. Subject’s platelet count is <100,000/mL
    8. Subject has known hypersensitivity towards mouse or hamster proteins, PEG or Tween 80
    9. Subject has severe chronic hepatic dysfunction [eg, >5 times upper limit of normal alanine aminotransferase (ALT), aspartate aminotransferase (AST), or a documented INR >1.5] in his medical history or at the time of screening
    10. Subject has severe renal impairment (serum creatinine >1.5 times the upper limit of normal)
    11. Subject has current or recent (<30 days) use of other PEGylated drugs prior to study participation or is scheduled to use such drugs during study participation
    12. Subject is scheduled to receive during the course of the study a systemic immunomodulating drug (e.g. corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day, or α-interferon) other than anti-retroviral chemotherapy
    13. Subject has participated in another clinical study involving an IP or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP or investigational device during the course of this study
    14. Parent or legally authorized representative has a medical, psychiatric, or cognitive illness or recreational drug/alcohol use that, in the opinion of the investigator, would affect subject safety or compliance
    15. Parent, legally authorized representative or subject are a member of the team conducting this study or is in a dependent relationship with one of the study team members. Dependent relationships include close relatives (ie, children, partner/spouse, siblings, parents) as well as employees of the investigator or site personnel conducting the study.

    Additional exclusion criteria for Part B (ITI)
    1. Spontaneous disappearance of the inhibitor prior to ITI
    2. FVIII inhibitor titer ≥0.6 BU is not confirmed by a second new blood sample and determined at the central laboratory
    3. Inability or unwillingness to comply with the protocol
    E.5 End points
    E.5.1Primary end point(s)
    - Incidence of FVIII inhibitor development
    - The success rate of ITI therapy with BAX 855
    E.5.1.1Timepoint(s) of evaluation of this end point
    - Part A of the study (approximately 5 years)
    - up to 33 months
    E.5.2Secondary end point(s)
    Safety
    - Binding IgG and IgM antibodies to FVIII, PEG-FVIII and PEG
    - AEs and SAEs
    - Clinically significant changes in vital signs and clinical laboratory parameters (hematology and clinical chemistry)

    Efficacy
    - Annualized bleeding rate (ABR) for prophylactic and on-demand treatment
    - Number of BAX 855 infusions per bleeding episode
    - Overall hemostatic efficacy rating at 24 h after initiation of treatment and at resolution of bleed
    - Weight-adjusted consumption of BAX 855 per month, per year and per event (prophylaxis, treatment of bleeding episode and surgery) and the number of infusions per month and per year
    - Assessment of intra-, post- and perioperative hemostatic efficacy in case of surgery
    - Intra- and postoperative blood loss in case of surgery

    Pharmacokinetics
    - IR at baseline and over time
    - Half-life at baseline (optional). This is based on an abbreviated PK using 2 post-infusion timepoints: 15-30 minutes and 24–48 hours

    ITI:
    - The rate of partial success and failure of ITI with BAX 855.
    - ABR during ITI
    - Weight-adjusted consumption of BAX 855 per month and per year for each ITI regimen employed
    - Catheter-related complications
    - Binding IgG and IgM antibodies to FVIII, PEG-FVIII, and PEG
    E.5.2.1Timepoint(s) of evaluation of this end point
    Safety : Throughout Part A and B of the study (approximately 8.5 years)
    Efficacy: Throughout Part A of the study (approximately 5 years)
    Pharmacokinetics: Pre-infusion within 30 minutes; and post-infusion at 15-30 minutes and 24-48 hours
    ITI: Up to 33 months
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    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.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 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 Will this trial be conducted at a single site globally? No
    E.8.4 Will this trial be conducted at multiple sites globally? Yes
    E.8.6 Trial involving sites outside the EEA
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3Specify the countries outside of the EEA in which trial sites are planned
    Canada
    Hong Kong
    Korea, Republic of
    Malaysia
    Singapore
    Taiwan
    Thailand
    United States
    Turkey
    Ukraine
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months6
    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: 120
    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.1.1.4.1Number of subjects for this age range: 40
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 80
    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 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 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
    Pediatric patients under age of 6 years
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 120
    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
    H.4 Third Country in which the Trial was first authorised
    H.4.1Third Country in which the trial was first authorised: United States
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