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    Summary
    EudraCT Number:2017-004305-40
    Sponsor's Protocol Code Number:CSL222-3001
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-09-28
    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
    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 ConcernedSweden - MPA
    A.2EudraCT number2017-004305-40
    A.3Full title of the trial
    Phase III, open-label, single-dose, multi-center multinational trial investigating a serotype 5 adeno-associated viral vector containing the Padua variant of a codon-optimized human factor IX gene (AAV5-hFIXco-Padua, AMT-061) administered to adult subjects with severe or moderately severe hemophilia B
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase III trial investigating a gene therapy (AAV-hFIXco-Padua, AMT-061), in adult patients with severe or moderately severe haemophilia B, to firstly evaluate if it's effective, and secondly further describe it's safety profile.
    A.3.2Name or abbreviated title of the trial where available
    Phase III trial of AMT-061 in subjects with severe or moderately severe hemophilia B.
    A.4.1Sponsor's protocol code numberCSL222-3001
    A.5.4Other Identifiers
    Name:INDNumber:016248
    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 SponsorCSL Behring LLC
    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 supportCSL Behring LLC
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCSL Behring LLC
    B.5.2Functional name of contact pointTrial Registration Coordinator
    B.5.3 Address:
    B.5.3.1Street Address1020 First Avenue
    B.5.3.2Town/ cityKing of Prussia, PA
    B.5.3.3Post code19406-0901
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1610878-4000
    B.5.5Fax number+1 610878-4009
    B.5.6E-mailclinicaltrials@cslbehring.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 HEMGENIX®
    D.2.1.1.2Name of the Marketing Authorisation holderCSL Behring 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 Yes
    D.2.5.1Orphan drug designation numberEU/3/18/1999
    D.3 Description of the IMP
    D.3.1Product nameAAV5-hFIXco-Padua; etranacogene dezaparvovec
    D.3.2Product code CSL222 (AMT-061)
    D.3.4Pharmaceutical form Solution for infusion
    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 INNetranacogene dezaparvovec
    D.3.9.1CAS number No
    D.3.9.2Current sponsor codeCSL222 (formerly: AMT-061)
    D.3.9.3Other descriptive nameAAV5-hFIXco-Padua
    D.3.10 Strength
    D.3.10.1Concentration unit IU/ml international unit(s)/millilitre
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number1 x 10^13
    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) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    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 No
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    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
    Hemophilia B
    E.1.1.1Medical condition in easily understood language
    Hemophilia B - Bleeding disorder
    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 20.0
    E.1.2Level LLT
    E.1.2Classification code 10018939
    E.1.2Term Haemophilia B (Factor IX)
    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
    demonstrate the non-inferiority of CSL222 (formerly AMT-061 [2 x 10^13 gc/kg]) during the 52 weeks following establishment of stable factor IX expression (months 6 to 18) post-treatment (CSL222) follow-up compared to standard of care continuous routine factor IX prophylaxis during the lead-in phase, as measured by
    the annualized bleeding rate (ABR).
    E.2.2Secondary objectives of the trial
    The secondary objective is to demonstrate additional efficacy and safety aspects of systemic administration of CSL222 (formerly AMT-061) on:
    - Endogenous factor IX activity 6 months, 12 months, and 18 months
    - Bleeding prevention
    - Trough FIX activity
    - Discontinuation of previous continuous routine prophylaxis
    - Consumption of FIX replacement therapy
    - Occurrence & resolution of target joints
    - Estimated ABR during the 52 weeks following stable factor IX expression
    - Correlation of pre-IMP anti-AAV5 antibody titers
    - Exploratory efficacy objectives
    Safety objectives include:
    - monitoring of AEs
    - changes in abdominal ultrasound
    - formation of anti-AAV5 antibodies (total IgM & IgG neutralizing antibodies)
    - AAV5 capsid-specific T cell response
    - anti-FIX antibodies
    - FIX inhibitors and recovery
    - hematology & serum chemistry
    - shedding of vector DNA (blood & semen)
    - inflammatory markers
    - AST/ALT increase and alpha-fetoprotein (AFP)
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    1. Patient Reported Outcomes, Burdens, and Experiences (PROBE) Questionnaire (optional):
    - PROBE Questionnaire is a novel, patient-developed, patient-reported outcome tool specific to hemophilia and intended to capture clinical outcomes that are considered relevant by subjects.
    - The objective of this sub-study is to provide data complementary to the compendium of established PRO tools regarding the impact of gene therapy on subject relevant outcomes and quality of life over time.
    2. Musculoskeletal Ultrasound (optional)
    - This sub-study will provide objective assessment of the effects of receiving gene therapy on the progression of physiological joint damage over time.
    - 8 Musculoskeletal ultrasounds to take place starting at screening. If it is not possible to obtain the musculoskeletal ultrasound at screening (Visit S), it is allowed to obtain this first musculoskeletal ultrasound at a later time point (preferably as soon as possible during one of the lead-in visits). Additional ultrasounds may be collected at the investigator’s discretion.
    E.3Principal inclusion criteria
    - Male
    - Age ≥18 years
    - Subjects with congenital hemophilia B with known severe or moderately severe factor IX deficiency (≤2% of normal circulating factor IX ) for which the subject is on continuous routine factor IX prophylaxis (continuous routine prophylaxis is defined as the intent of treating with an a priori defined frequency of infusions [e.g., twice weekly, once every two weeks, etc.] as documented in the medical records).
    - >150 previous exposure days of treatment with factor IX protein
    - Have been on stable prophylaxis for at least 2 months prior to screening
    - Have demonstrated capability to independently, accurately and in a timely manner complete the diary during the lead-in phase as judged by the investigator
    - Acceptance to use a condom during sexual intercourse in the period from IMP administration until AAV5 has been cleared from semen, as evidenced by the central laboratory from negative analysis results for at least 3 consecutively collected semen samples (this criterion is applicable also for subjects who are surgically sterilized)
    - Able to provide informed consent following receipt of verbal and written information about the trial.
    E.4Principal exclusion criteria
    - History of factor IX inhibitors
    - Positive factor IX inhibitor test at screening and Visit L-Final (based on local laboratory results)
    - Screening and Visit L-Final laboratory values (based on central laboratory results):
    a. ALT >2 times upper normal limit
    b. Aspartate aminotransferase (AST) >2 times upper normal limit
    c. Total bilirubin >2 times upper normal limit (except if this is caused by Gilbert disease)
    d. Alkaline phosphatase (ALP) >2 times upper normal limit
    e. Creatinine >2 times upper normal limit
    - Positive human immunodeficiency virus (HIV) serological test at screening and Visit LFinal, not controlled with anti-viral therapy as shown by CD4+ counts ≤ 200/μL (based on central laboratory results)
    - Hepatitis B or C infection with the following criteria present at screening:
    i. Currently receiving antiviral therapy for this/these infection(s)
    and/or
    ii. Positive for any of the following (based on central laboratory results):
    • Hepatitis B surface antigen (HBsAg), except if in the opinion of the investigator this is due to a previous Hepatitis B vaccination rather than active Hepatitis B infection
    • Hepatitis B virus deoxyribonucleic acid (HBV DNA)
    • Hepatitis C virus ribonucleic acid (HCV RNA)
    - Known coagulation disorder other than hemophilia B
    - Thrombocytopenia, defined as a platelet count below 50 × 10^9/L, at screening and Visit L-Final (based on central laboratory results)
    - Known severe infection or any other significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, cardiovascular, hematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease, alcoholism, drug dependency or any other psychological disorder evaluated by the investigator to interfere with adherence to the protocol procedures or with the degree of tolerance to the IMP
    - Known significant medical condition that may significantly impact the intended transduction of the vector and/or expression and activity of the protein, including but not limited to:
    • Disseminated intravascular coagulation
    • Accelerated fibrinolysis
    • Advanced liver fibrosis (suggestive of or equal to METAVIR Stage 3 disease; e.g. a FibroScan™ score of ≥9 kPa is considered equivalent)
    - Known history of an allergic reaction or anaphylaxis to factor IX products
    - Known uncontrolled allergic conditions or allergy/hypersensitivity to any component of the IMP excipients
    - Known history of allergy to corticosteroids
    - Known medical condition that would require chronic administration of steroids
    - Previous gene therapy treatment
    - Receipt of an experimental agent within 60 days prior to screening
    - Current participation or anticipated participation within one year after IMP administration in this trial in any other interventional clinical trial involving drugs or devices.
    E.5 End points
    E.5.1Primary end point(s)
    ABR comparison between CSL222 (formerly: AMT-061) and prophylaxis for non-inferiority between the lead-in phase and the 52 weeks following stable factor IX expression (months 6-18 post treatment)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Comparison between 52-week post-treatment follow-up and the lead-in phase
    E.5.2Secondary end point(s)
    Secondary efficacy endpoints
    - Endogenous factor IX activity at 6 months after CSL222 dosing
    - Endogenous factor IX activity at 12 months after CSL222 dosing
    - Endogenous factor IX activity at 18 months after CSL222 dosing
    - Annualized consumption of factor IX replacement therapy during the 52 weeks following stable factor IX expression (months 6-18 post- treatment), excluding factor IX replacement for invasive procedures, compared to the lead-in phase
    - Annualized infusion rate of factor IX replacement therapy during the 52 weeks following stable factor IX expression (months 6-18 post-treatment), excluding factor IX replacement for invasive procedures, compared to the lead-in phase
    - Proportion of subjects remaining free of previous continuous routine prophylaxis during the 52 weeks following stable factor IX expression (months 6-18 post-treatment)
    - Comparison of the percentage of subjects with trough factor IX activity <12% of normal between the lead in phase and after treatment with CSL222 over the 52 weeks following stable factor IX expression (months 6-18 post-treatment)
    - ABR comparison between CSL222 and prophylaxis for superiority between the lead-in phase and the 52 weeks following stable factor IX expression (months 6-18 post-treatment)
    - Rate of spontaneous bleeding events during the 52 weeks following stable factor IX expression (months 6-18 post-treatment) compared to the lead in phase
    - Rate of joint bleeding events during the 52 weeks following stable factor IX expression (months 6-18 post treatment) compared to the lead-in phase
    - Estimated ABR – during the 52 weeks following stable factor IX expression (months 6-18 post-treatment) – as a function of pre-IMP anti-AAV5 antibody titers using the luciferase based NAB assay (as a “correlation” analysis)
    - Correlation of factor IX activity levels during the 52 weeks following stable factor IX expression (months 6-18 post-treatment) with pre-IMP anti-AAV5 antibody titers using the luciferase based NAB assay
    - Occurrence of (and resolution of) new target joints during the 52 weeks following stable factor IX expression (months 6-18 post-treatment) and resolution of pre-existing target joints following CSL222 dosing
    - Proportion of subjects with zero bleeds during the 52 weeks following stable factor IX expression (months 6-18 post-treatment)
    - PRO questionnaire scores from the international Physical Activity Questionnaire (iPAQ; total physical activity score) during the 12 months following CSL222 dosing compared with the lead-in phase
    - PRO questionnaire scores from the EuroQol-5 dimensions-5 levels (EQ 5D 5L) visual analogue scale (VAS) score during the 12 months following CSL222 dosing compared with the lead-in phase

    Secondary safety endpoints
    - Adverse events
    - Changes in abdominal ultrasound
    - Anti-AAV5 antibodies (total [IgM and IgG], neutralizing antibodies)
    - AAV5 capsid-specific T cells
    - Anti-factor IX antibodies
    - Factor IX inhibitors and recovery
    - Hematology and serum chemistry parameters
    - ALT/AST levels, and corticosteroid use for ALT/AST increases
    - Vector DNA in blood and semen
    - Inflammatory markers: IL-1β, IL-2, IL-6, IFNγ, MCP-1
    - Alpha-fetoprotein (AFP)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary efficacy endpoints
    - 6, 12, 18 months after CSL222 dosing
    - Months 6-18 compared to the lead-in phase
    - Months 6-18 compared to the lead-in phase
    - Months 6-18 compared to the lead-in phase
    - Months 6-18 compared to the lead-in phase
    - Months 6-18 compared to the lead-in phase
    - Months 6-18 compared to the lead-in phase
    - Months 6-18 compared to the lead-in phase
    - Months 6-18 compared to the lead-in phase
    - Months 6-18 compared to the lead-in phase
    - Months 6-18 compared to the lead-in phase
    - Months 6-18 compared to the lead-in phase
    - During the 12 months following CSL222 dosing compared with the lead-in phase
    - During the 12 months following CSL222 dosing compared with the lead-in phase

    Secondary safety endpoints
    For the duration of the trial.
    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 No
    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 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.8.2.4Number 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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA26
    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
    Belgium
    Denmark
    Germany
    Ireland
    Italy
    Netherlands
    Sweden
    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.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years7
    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 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: 63
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 12
    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 state
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 44
    F.4.2.2In the whole clinical trial 75
    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)
    After the post-treatment follow-up phase, subjects will enter a long-term follow-up phase for an additional 4 years to assess sustainability of efficacy and long-term safety
    Subjects will:
    - document FIX usage & bleeding episode information in study-specific paper diaries
    - visit the clinic every 6 mo. for testing
    - Complete joint health and questionnaires, every 12 months
    - Abdominal U/S 6 monthly
    AE occurrence will be continuously monitored
    - option to participate in CSL222_3003 trial
    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 Decision2018-11-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-11-22
    P. End of Trial
    P.End of Trial StatusOngoing
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