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    Summary
    EudraCT Number:2013-005579-42
    Sponsor's Protocol Code Number:CT-AMT-060-01
    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:2014-06-30
    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 number2013-005579-42
    A.3Full title of the trial
    A phase I/II, open-label, uncontrolled, single-dose, dose-ascending, multi-centre trial investigating an adeno-associated viral vector containing a codon-optimized human factor IX gene (AAV5-hFIX) administered to adult patients with severe or moderately severe haemophilia B
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase I/II trial investigating a gene therapy (AAV-hFIX) for the first time in humans, in adult patients with severe or moderately severe haemophilia B, to firstly evaluate its safety and identify side effects, and secondly evaluate if it is effective
    A.3.2Name or abbreviated title of the trial where available
    Phase I/II trial of AAV5-hFIX in severe or moderately severe haemophilia B
    A.4.1Sponsor's protocol code numberCT-AMT-060-01
    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 supportChiesi Farmaceutical S.p.A.
    B.4.2CountryItaly
    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 25
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1105 BP
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31202406154
    B.5.5Fax number+31202406020
    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/3/11/938
    D.3 Description of the IMP
    D.3.1Product nameAAV5-hFIX
    D.3.2Product code AMT-060
    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.3.9.2Current sponsor codeAMT-060
    D.3.9.3Other descriptive nameAAV5-HFIX
    D.3.9.4EV Substance CodeSUB167020
    D.3.10 Strength
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number1x10e13
    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
    Haemophilia B
    E.1.1.1Medical condition in easily understood language
    Haemophilia 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
    To investigate the safety of systemic administration of AAV5-hFIX, an adeno-associated viral vector containing a codon-optimized hFIX gene, to adult patients with severe or moderately severe haemophilia B.
    E.2.2Secondary objectives of the trial
    Secondary objectives will be addressing the efficacy and safety of systemic administration of AAV5-hFIX to adult patients with severe or moderately severe haemophilia B:



    Efficacy Objectives

    - To investigate the effect of AAV5-hFIX on FIX activity level

    - To investigate the effect of AAV5-hFIX on the use of FIX replacement therapy

    - To investigate the effect of AAV5-hFIX on bleeding episodes

    - To investigate the effect of AAV5-hFIX on quality of life parameters



    Safety Objectives

    - To monitor shedding of the vector in various body matrices (i.e. fluids/excretions)

    - To monitor the immune responses against AAV5 capsid proteins in response to AAV5-hFIX

    - To monitor for immune responses against FIX protein after administration of AAV5-hFIX

    - To investigate the effect of AAV5-hFIX on inflammatory markers
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male

    2. Age ≥ 18 years

    3. Patients with congenital haemophilia B classified as one of the following:

    - Known severe FIX deficiency with plasma FIX activity level < 1% and a severe bleeding phenotype defined by one of the following:

    o Currently on prophylactic FIX replacement therapy for a history of bleeding

    o Currently on on-demand FIX replacement therapy with a current or past history of frequent bleeding defined as four or more bleeding episodes in the last 12 months or chronic haemophilic arthropathy (pain, joint destruction, and loss of range of motion) in one or more joints

    - Known moderately severe FIX deficiency with plasma FIX activity level between ≥ 1% and ≤ 2% and a severe bleeding phenotype defined by one of the following:

    o Currently on prophylactic FIX replacement therapy for a history of bleeding

    o Currently on on-demand FIX replacement therapy with a current or past history of frequent bleeding defined as four or more bleeding episodes in the last 12 months or chronic haemophilic arthropathy (pain, joint destruction, and loss of range of motion) in one or more joints

    4. More than 150 previous exposure days of treatment with FIX protein.

    5. 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)

    6. Following receipt of verbal and written information about the trial, the subject has provided signed informed consent before any trial related activity is carried out.
    E.4Principal exclusion criteria
    1. History of positive FIX inhibitors test

    2. Positive FIX inhibitor test at Screening (measured by the local laboratory)

    3. Neutralizing antibodies against AAV5 at Screening (measured by the central laboratory)

    4. Screening laboratory values (measured by the central laboratory):

    a. ALT > 2 times upper normal limit

    b. AST > 2 times upper normal limit

    c. total bilirubin > 2 times upper normal limit

    d. ALP > 2 times upper normal limit

    e. creatinine > 1.5 times upper normal limit

    5. Positive HIV serological test at Screening, not controlled with anti-viral therapy as shown by CD4+ counts ≤ 200 per μL or by a viral load of >200 copies per mL (measured by the central laboratory)

    6. Active infection with Hepatitis B or C virus as reflected by Hepatitis B Surface Antigen (HBsAg), Hepatitis B extracellular Antigen (HBeAg), Hepatitis B Virus DeoxyriboNucleic Acid (HBV DNA) or Hepatitis C Virus RiboNucleic Acid (HCV RNA) positivity, respectively, at Screening (measured by the central laboratory).

    7. History of Hepatitis B or C exposure, currently controlled by antiviral therapy

    8. Any coagulation disorder other than haemophilia B

    9. Thrombocytopenia, defined as a platelet count below 50 × 10e9 / L, at Screening (measured by the central laboratory)

    10. Body mass index < 16 or ≥ 35 kg/m2

    11. Planned surgery for the initial 6 months after IMP administration in this trial

    12. Previous arterial or venous thrombotic event (e.g. acute myocardial infarction, cerebrovascular disease and venous thrombosis)

    13. Active severe infection or any other significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, haematological, 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

    14. Known significant medical condition including disseminated intravascular coagulation, fibrinolysis and liver fibrosis which, in the opinion of the investigator, may confound, contraindicate or limit the interpretation of either safety or efficacy data

    15. Known history of an allergic reaction or anaphylaxis to FIX products

    16. Known uncontrolled allergic conditions or allergy/hypersensitivity to any component of the IMP excipients

    17. Previous gene therapy treatment

    18. Receipt of an experimental agent within 60 days prior to Visit 1

    19. 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)
    Adverse events
    E.5.1.1Timepoint(s) of evaluation of this end point
    The individual subjects will be followed for five years after administration of IMP.
    E.5.2Secondary end point(s)
    Secondary endpoints will be addressing efficacy and safety:



    Confirmatory Secondary Efficacy Endpoint

    - FIX-replacement-therapy-free FIX activity



    Supportive Efficacy Endpoints

    - Bleeding rate

    - Total consumption of FIX replacement therapy

    - Short Form-36 (SF-36) Quality of Life (QoL) scores



    Safety Endpoints

    - Vector DNA in semen, blood, saliva, nasal secretions, urine and faeces

    - Neutralizing antibodies to AAV5

    - Total (IgM and IgG) antibodies to AAV5

    - AAV5 capsid-specific T cells

    - Antibodies to FIX

    - FIX inhibitors

    - Inflammatory markers: IL-1β, IL-2, IL-6, INFγ, MCP-1
    E.5.2.1Timepoint(s) of evaluation of this end point
    The individual subjects will be followed for five years after administration of IMP.
    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) Yes
    E.7.1.1First administration to humans Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 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 EEA12
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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 years6
    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: 9
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1
    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 12
    F.4.2.2In the whole clinical trial 12
    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
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-12-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-03-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-04-15
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