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    Summary
    EudraCT Number:2017-004305-40
    Sponsor's Protocol Code Number:CT-AMT-061-02
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Restarted
    Date on which this record was first entered in the EudraCT database:2018-07-10
    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 ConcernedGermany - PEI
    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
    Offene, multizentrische, multinationale Einzeldosisstudie der Phase III zur Untersuchung eines adeno-assoziierten Virusvektors des Serotyps 5 mit der Padua-Variante eines codon-optimierten Gens des humanen Faktors IX (AAV5-hFIXco-Padua, AMT-061), der erwachsenen Teilnehmern mit schwerer oder mittelschwerer Hämophilie B verabreicht wird
    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 numberCT-AMT-061-02
    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 SponsoruniQure biopharma B.V.
    B.1.3.4CountryNetherlands
    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 supportuniQure biopharma B.V.
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationuniQure biopharma B.V.
    B.5.2Functional name of contact pointRegulatory Affairs
    B.5.3 Address:
    B.5.3.1Street AddressPaasheuvelweg 25a
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1105 BP
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31(0)202406000
    B.5.6E-maile.destree@uniqure.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 No
    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
    D.3.2Product code 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 codeAMT-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 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 demonstrate the effect of AMT-061 on endogenous factor IX (FIX) activity 6 months after a single AMT-061 treatment.
    E.2.2Secondary objectives of the trial
    1. Demonstrate non-inferiority of AMT-061 as compared to standard of care continuous routine (CR) FIX prophylaxis in terms of bleeding prevention
    Investigating effect of 2 x 10^13 gc/kg AMT-061 on
    - Bleeding prevention
    - Trough FIX activity
    - Discontinuation of previous CR prophylaxis
    - Consumption of FIX replacement therapy
    - Occurrence & resolution of target joints
    - Correlation of FIX activity levels after dosing & pre-IMP anti-AAV5 antibody titers
    - Endogenous FIX activity 52 weeks after dosing.
    - Exploratory efficacy objectives
    2. Demonstrate additional efficacy and safety aspects of systemic administration of AMT-061.
    - monitoring of AEs
    - formation of anti-AAV5 antibodies (total IgM & IgG neutralizing antibodies)
    - AAV5 capsid-specific T cell response
    - anti-FIX antibodies
    - FIX inhibitors
    - hematology & serum chemistry
    - shedding of vector DNA (blood & semen)
    - inflammatory markers
    - AST/ALT increase (corticosteroids use required to preserve FIX activity)
    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 patient 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 three 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 extracellular antigen (HBeAg),
    • 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 × 109/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)
    Endogenous factor IX activity after AMT-061 dosing
    E.5.1.1Timepoint(s) of evaluation of this end point
    26 weeks after AMT-061 dosing.
    E.5.2Secondary end point(s)
    Secondary efficacy endpoints
    - ABR comparison between AMT-061 and prophylaxis for non-inferiority between the lead-in and the 52 week post-treatment (AMT-061) followup
    - Annualized consumption of factor IX replacement therapy during the 52-week
    post-treatment follow-up, 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-week post-treatment follow-up
    - Comparison of the percentage of subjects with trough factor IX activity <12%
    of normal between the lead-in phase and after treatment with AMT-061
    at Week 26
    - Endogenous factor IX activity at 52 weeks after AMT-061 dosing
    - ABR comparison between AMT-061 and prophylaxis for superiority between the lead-in and the 52-week post-treatment (AMT-061) followup
    - Rate of spontaneous (unprovoked) bleeding events during the 52-week post-treatment follow-up compared to lead-in phase
    - Rate of joint bleeding events during the 52-week post-treatment follow-up
    compared to the lead-in phase
    - Occurrence and resolution of target joints during the 52 weeks following AMT-061 dosing
    - Correlation of factor IX activity levels during the 52-week posttreatment follow-up with pre-IMP anti AAV5 antibody titers using the
    luciferase based NAB assay
    - Rate of traumatic (provoked) bleeding events during the 52-week posttreatment follow-up compared to the lead-in phase
    - Patient reported outcome (PRO) questionnaires: EuroQol (EQ-5D-5L) and iPAQ

    Secondary safety endpoints
    - Adverse events
    - Anti-AAV5 antibodies (total [IgM and IgG], neutralizing antibodies)
    - AAV5 capsid-specific T cells
    - Anti-factor IX antibodies
    - Factor IX inhibitors
    - 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
    - Comparison between 52-week post-treatment follow-up and the lead-in
    phase
    - Comparison between the lead-in phase and after treatment with AMT061
    -
    During the 52-week post-treatment follow-up
    -
    52-week post-treatment follow-up compared to the lead-in phase
    -
    Same as previous entry
    -
    Same as previous entry
    -
    Same as previous entry
    -
    During 52 weeks following AMT-061 dosing
    -
    During the 52-week post-treatment follow-up and pre-IMP anti-AAV5
    antibody
    titers using the luciferase based NAB assay
    -
    At 52 weeks after AMT-061 dosing
    -
    Comparison between 52-week post-treatment follow-up and the lead-in
    phase
    Secondary safety endpoints
    All will be monitored 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 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 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
    Belgium
    Denmark
    Finland
    Germany
    Ireland
    Italy
    Netherlands
    Spain
    Sweden
    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
    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 months0
    E.8.9.1In the Member State concerned days0
    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 state3
    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 are expected to:
    - document factor IX usage & bleeding episode information
    - visit the clinic every 6 months for evaluation of efficacy parameters & safety
    - Complete joint health and questionnaires, every 12 months
    AE occurrence will be continuously monitored (at least quarterly site staff/subject contact).
    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 Decision2019-03-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-12-05
    P. End of Trial
    P.End of Trial StatusRestarted
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