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    Summary
    EudraCT Number:2018-004024-11
    Sponsor's Protocol Code Number:SHP648-101
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2019-07-31
    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 number2018-004024-11
    A.3Full title of the trial
    An Open-Label, Multinational, Phase 1/2 Study of the Safety and Dose Escalation of SHP648, an Adeno-Associated Virus Serotype 8 (AAV8) Vector Expressing FIX Padua in Hemophilia B Subjects
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 1/2 study of SHP648, an Adeno-Associated Viral Vector for Gene Transfer in Hemophilia B Subjects
    A.4.1Sponsor's protocol code numberSHP648-101
    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.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 pointJudit Koranyi
    B.5.3 Address:
    B.5.3.1Street AddressIndustriestrasse 67
    B.5.3.2Town/ cityVienna
    B.5.3.3Post codeA-1221
    B.5.3.4CountryAustria
    B.5.4Telephone number+431201002473301
    B.5.5Fax number+43120100-2475990
    B.5.6E-mailjudit.koranyi@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 No
    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 nameSHP648 (TAK748)
    D.3.4Pharmaceutical form 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 INNnot applicable
    D.3.9.2Current sponsor codeSHP648
    D.3.9.3Other descriptive nameTAK-748
    D.3.10 Strength
    D.3.10.1Concentration unit vector genomes (vg)/mL
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4.1E12
    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 Yes
    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 is a X-linked recessive bleeding disorder caused by mutations in the gene encoding clotting factor IX (FIX) that result in disruption of the normal clotting pathway. Hemophilia B affects 1 in 25,000 male births. Disease severity correlates directly with the concentration of functional FIX protein in the plasma. Severe disease is characterized as having <1% of normal plasma levels of FIX (100% = 1 IU activity/mL or approximately 5000 ng protein/mL).
    E.1.1.1Medical condition in easily understood language
    Hemophilia B is an inherited bleeding disorder caused by a lack of the
    blood clotting factor IX (9) in your blood. Without enough factor
    IX, the blood cannot clot properly to stop bleeding.
    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 10060614
    E.1.2Term Hemophilia 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 of the study is to assess the safety of single, escalating, IV doses of SHP648.
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are as follows:
    • Evaluate plasma FIX levels before and after SHP648 infusion and study the relationship
    between change in FIX activity and SHP648 dose.
    • Evaluate bleeding episodes post SHP648 administration.
    • Assess humoral and cellular immune responses to FIX and the viral capsid.
    • Determine the duration of SHP648 genomes present in bodily fluids.
    • Compare the consumption of exogenous FIX before and after gene transfer
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    The subject will not be considered eligible for the study without meeting all of the criteria below.
    1. Male, aged 18 to 75 years at the time of screening.
    2. Established severe or moderately severe hemophilia B (plasma FIX activity
    ≤ 2% measured following ≥ 5 half-lives of most recent exposure to exogenous FIX)
    and either ≥ 3 hemorrhages per year requiring treatment with exogenous FIX or use
    of prophylactic therapy.
    3. History of > 50 exposure days to exogenously administered FIX concentrates or
    cryoprecipitates.
    4. Sexually active men must agree to use barrier contraception (combination of a condom and spermicide) or limit sexual intercourse to post-menopausal, surgically sterilized, or contraception-practicing partners for a minimum of 6 months after administration of SHP648, or until SHP648 genomes are no longer detected in the semen (whichever is sooner).
    5. Signed informed consent.
    E.4Principal exclusion criteria
    The subject will be excluded from the study if any of the following exclusion criteria are met.
    1. Bleeding disorder(s) other than hemophilia B.
    2. Documented laboratory evidence of having developed inhibitors (≥ 0.6 BU on any single test) to FIX proteins at any time.
    3. Documented prior allergic reaction to any FIX product.
    4. Anti-AAV8 neutralizing antibody titer ≥ 1:5.
    5. Known hypersensitivity to prednisolone or prednisone, or to any of the excipients.
    6. Having a disease in which treatment with prednisolone or prednisone is not tolerated
    (including, but not limited to osteoporosis with vertebral fractures, severe labile
    hypertension, and brittle diabetes).
    7. Evidence of markers of potential underlying risk for autoimmune mediated hepatic disease:
    a. Anti-smooth muscle antibody (ASMA) titer ≥ 1:40. Values of 1:31 to 1:39 will be
    flagged as possibly abnormal and the Investigator and Medical Monitor will evaluate the subject for eligibility.
    b. Elevated anti-liver-kidney microsomal antibody type 1 (LKM1) titers.
    c. Total IgG > 1.5x ULN.
    d. Antinuclear antibody (ANA) titer > 1:320 OR ANA titer > 1:80 if demonstrated
    concurrently with ALT that is > ULN.
    8. Active Hepatitis C: As indicated by detectable HCV RNA by PCR.
    9. Hepatitis B: If surface HBV antigen is positive.
    10. Receiving chronic systemic antiviral and/or interferon therapy within 4 weeks prior to enrollment.
    11. Clinically significant infections (e.g., systemic fungal infections) requiring systemic treatment.
    12. Known immune disorder (including myeloma and lymphoma).
    13. Concurrent chemotherapy or biological therapy for treatment of neoplastic disease or other disorders.
    14. An absolute neutrophil count < 1000 cells/mm3.
    15. Markers of hepatic inflammation or cirrhosis as evidenced by 1 or more of the following:
    a. Platelet count < 150,000/μL.
    b. Albumin ≤ 3.5 g/dL.
    c. Total bilirubin > 1.5x ULN and direct bilirubin ≥ 0.5 mg/dL.
    d. ALT or AST > 1.0x ULN.
    e. Alkaline phosphatase > 2.0x ULN.
    f. History of liver biopsy or imaging indicating moderate or severe fibrosis
    (Metavir staging of F2 or greater).
    g. History of ascites, varices, variceal hemorrhage, or hepatic encephalopathy.
    h. FibroSURE Score ≥ 0.4.
    i. Prothrombin time INR ≥ 1.4.
    16. Serum creatinine > 1.5 mg/dL.
    17. HIV if CD4+ cell count ≤200 mm3 and/or viral load >20 copies/mL.
    18. Urine protein > 30 mg/dL.
    19. Body mass index > 38.
    20. Orthopedic or other major surgery planned within 6 months after enrollment.
    21. Acute or chronic disease that, in the opinion of the Investigator, would adversely affect subject safety or compliance or interpretation of study results.
    22. Received an AAV vector previously or any other gene transfer agent in the previous 12 months prior to Study Day 0.
    23. Significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, congestive heart failure, myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina) or significant pulmonary disease (including obstructive pulmonary disease).
    24. History of arterial or venous thrombosis / thromboembolism, or a known pro-thrombotic condition.
    25. Recent history of psychiatric illness or cognitive dysfunction (including drug or alcohol abuse) that, in the opinion of the Investigator, is likely to impair subject’s ability to comply with protocol mandated procedures.
    26. Participation in another study involved with an investigational agent.
    27. Subject is family member or employee of the Investigator
    E.5 End points
    E.5.1Primary end point(s)
    Incidence of AEs (serious or non-serious) related to IP
    that include development of FIX inhibitory antibodies,
    ECG findings, and clinically significant changes in
    standard laboratory parameters and in vital signs
    E.5.1.1Timepoint(s) of evaluation of this end point
    Subjects will be monitored for 1 year after dosing. Every effort will be made to enroll subjects to an extension study and follow them for approximately 4 additional years until a 5 year total post-gene transfer period is attained.
    E.5.2Secondary end point(s)
    •Circulating plasma FIX activity and antigen levels
    •ABR in comparison to before gene transfer
    •Neutralizing and Binding antibody titers to AAV8
    • T-cell response to AAV8 and FIX transgene products
    •Presence of SHP648 genome by type of bodily fluid
    •Percentage of change in consumption of exogenous FIX before and after gene transfer
    E.5.2.1Timepoint(s) of evaluation of this end point
    Subjects will be monitored for 1 year after dosing. Every effort will be made to enroll subjects to an extension study and follow them for approximately 4 additional years until a 5 year total post-gene transfer period is attained.
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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 Yes
    E.8.1.7.1Other trial design description
    Dose Escalation
    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 trial3
    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 EEA19
    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
    Austria
    France
    Germany
    Hungary
    Italy
    Spain
    Turkey
    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
    The end of the trial is defined by LVLS
    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 months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months8
    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: 19
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2
    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 17
    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)
    No aftercare is planned for this study. Subjects completing the current Phase 1/2 Study
    (SHP648-101) will be highly encouraged to enroll seamlessly into a follow-up interventional
    study (Extension Study), in which they will be observed for an additional 4 years.
    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 Decision2020-03-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-05-04
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2021-01-27
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