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    Summary
    EudraCT Number:2011-004074-28
    Sponsor's Protocol Code Number:UKHEP001
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-09-28
    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 ConcernedUK - MHRA
    A.2EudraCT number2011-004074-28
    A.3Full title of the trial
    A prospective, open label, multicenter, randomized, safety and preliminary efficacy study of one cycle of Promethera HepaStem® in Urea Cycle Disorders and Crigler-Najjar Syndrome patients
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase I/II trial for evaluating both safety and preliminary efficacy of one cycle of Promethera HepaStem® in Urea Cycle Disorders and Crigler-Najjar Syndrome patients
    A.3.2Name or abbreviated title of the trial where available
    UKHEP001
    A.4.1Sponsor's protocol code numberUKHEP001
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/313/2013
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorPromethera Biosciences
    B.1.3.4CountryBelgium
    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 supportPromethera Biosciences
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPromethera Biosciences
    B.5.2Functional name of contact pointVinciane Wouters
    B.5.3 Address:
    B.5.3.1Street AddressRue Granbonpré, 11
    B.5.3.2Town/ cityMont-Saint-Guibert
    B.5.3.3Post code1435
    B.5.3.4CountryBelgium
    B.5.4Telephone number3210394311
    B.5.5Fax number3210394301
    B.5.6E-mailvinciane.wouters@promethera.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/3/07/506 and EU/3/08/530
    D.3 Description of the IMP
    D.3.1Product nameHepaStem
    D.3.4Pharmaceutical form Suspension for injection
    D.3.4.1Specific paediatric formulation Yes
    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 INNHeterologous Human Adult Liver-derived Progenitor Cells
    D.3.9.1CAS number NA
    D.3.9.2Current sponsor codeHHALPC
    D.3.9.3Other descriptive nameNA
    D.3.10 Strength
    D.3.10.1Concentration unit million organisms/ml million organisms/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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) Yes
    D.3.11.3.1Somatic cell therapy medicinal product Yes
    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 Yes
    D.3.11.3.5.1CAT classification and reference numberSomatic Cell Therapy Product
    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 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
    Crigler-Najjar syndrome is associated with a complete or partial hepatic deficit of bilirubin glucuronosyltransferase activity and is apparent during the neonatal period by intense jaundice. The urea cycle disorders are inborn errors of metabolism that affect the transfer of nitrogen into urea. There are six disorders: N-Acetylglutamate synthase deficiency, Carbamoyl phosphate synthetase I deficiency, Ornithine transcarbamylase deficiency, citrullinemia, argininosuccinic aciduria and argininemia
    E.1.1.1Medical condition in easily understood language
    Liver metabolic diseases: Crigler-Najjar disease and Urea Cycle disorders
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level LLT
    E.1.2Classification code 10021601
    E.1.2Term Inborn error of metabolism NOS
    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 assess the safety of one cycle of HHALPC infusions up to six months in paediatric patients suffering from CN or UCD in terms of clinical status, portal-vein hemodynamics, morphology of the liver, de novo detection of circulating anti-HLA antibodies, and/or other immune related markers as well as Serious Adverse Events (SAEs) and clinically significant Adverse Events (AEs) related to infusion.
    E.2.2Secondary objectives of the trial
    1. To assess the long term safety (up to 12 months) of one cycle of HHALPC infusions in paediatric patients (CN or UCD) in terms of clinical status, portal-vein hemodynamics, morphology of the liver, de novo detection of circulating anti-HLA antibodies, and/or other immune related markers as well as SAE’s and clinically significant AEs related to infusion.
    2. To appraise the efficacy post infusion of one cycle of HHALPC for each individual patient and for all patients for a min of 6 and up to 12 months by as compared to his/her prior medical condition.
    3. To investigate the engraftment of HHALPC in the liver (at 6 month, and optional at 12 month) by quantitative measurement of enzymatic activity on the biopsies and/or establishing donor sequences by real time PCR or in FISH or immunohistochemistry
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Sub-study PBMC_version 2.0_01 August 2012.
    Ref: Protocol UKHEP001 PBMC "Peripheral Blood Mononuclear Cells".

    The purpose of the study is to learn more about the kinetics of an
    immune response following infusion of undifferentiated progenitor cells
    in patients suffering from urea cycle disorder and Crigler Najjar
    syndrome.
    The study is conducted to evaluate the risk of rejection by determining
    the presence of activated T-cells against donor cells in patients after
    infusion with HepaStem. The presence or absence of activated T-cells
    might be seen as a surrogate marker of potential rejection.
    E.3Principal inclusion criteria
    General:
    1.Subject shows patency of the portal vein and branches, with normal flow velocity in the main portal vein as confirmed by Doppler ultrasound and accessibility of the portal vein, or respectively, accessibility of the umbilical vein.
    2.Subject (if capable of signing) and parents or legal representative have provided a written informed assent/consent.
    3.Female subjects of childbearing potential need to have a negative pregnancy test and must agree to use an acceptable method of contraception throughout the study.
    Crigler-Najjar Syndrome specific:
    4.Patient presents with Crigler-Najjar syndrome type 1 and diagnosis must be confirmed by genetic mutation analysis if not available.
    5.Patient presents with Crigler-Najjar syndrome type 2
    -poorly controlled under phenobarbital treatment, or
    -experiencing serious impairment in quality of life.
    Diagnosis must be confirmed by genetic mutation analysis if not available.
    Urea Cycle Disorders specific
    6.Diagnosis of one of the urea cycle disorders (CPSID, OCTD, ASSD, ASLD, Arginase deficiency and NAGSD)
    - of which the disease is of such severity to warrant liver transplantation or alternatives despite full conservative therapy, or
    - subject experiencing serious impairment in quality of life despite full conservative therapy.
    Diagnosis must be confirmed by genetic mutation analysis if not available.
    E.4Principal exclusion criteria
    1.The subject is 16 years or older at time of screening.
    2.The subject presents acute liver failure.
    3.The subject presents clinical or radiological evidence of liver fibrosis or cirrhosis
    4.The subject presents or has a history of hepatic or extrahepatic malignancy
    5.The patient has a non-corrected cardiac malformation.
    6.The subject has a known medical or family history of coagulopathy.
    7.The subject participates currently in another clinical trial – except disease registry and observational HepaStem study.
    8.The subject underwent previous mature liver cell or stem cell transplantation or received an organ liver transplant.
    9.The subject has a contraindication to immunosuppressive therapy.
    10.The subject has a known hypersensitivity or allergy to the recommended antibiotics to prevent post-operative infections according to institutional guidelines, and basiliximab, solumedrol or tacrolimus unless alternative drugs can be used without risk for the patient.
    11.The subject has a known hypersensitivity or allergy to bivalirudin.
    12.The subject had or has a renal insufficiency treated by dialysis.
    13.The subject requires valproate therapy.
    14.The subject has a known hypersensitivity or allergy to contrast agents that cannot be treated adequately.
    15.The subject has a thrombosis of the portal vein or persisting impairment of anterograde portal blood flow.
    16.The subject has a porto systemic shunt or fistula assessed by Doppler US.
    17.For umbilical vein access: The subject has any contraindication for umbilical vein catheterization (eg omphalitis, peritonitis, necrotizing enterocolitis etc)
    18.Any significant condition which in the Investigator’s opinion may interfere with the subject’s optimal participation in the study
    19. Patients with disease of such severity that liver transplantation is an absolute indication.
    20. Patients with mild disease severity, easily controlled under standard of care therapy with no recurrent metabolic crises.
    E.5 End points
    E.5.1Primary end point(s)
    -Safety of the technical intervention (infusion of HepaStem in portal vein) common to both indications and to different weight cohorts (short-and mid-term safety)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Four time windows will be assessed:
    1. Inpatient period : Vo-Vdischarge: reactogenicity of infusion
    2. Outpatient period: Vdischarge-V1month: short-term safety of infusion
    3. Outpatient period: V1m-V6m: mid-term safety of infusion
    4. Overall period: Vo-V6m
    E.5.2Secondary end point(s)
    -To characterize the safety profile of HepaStem for both indications and for different weight cohorts (long-term safety).
    -To characterize the preliminary efficacy of HepaStem for both indications and for different weight cohorts (0-6 months; 6-12 months).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Assessment of reactogenicity and safety of the treatment during 6 to 12 months post infusion (long-term safety) will be evaluated
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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 No
    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 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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA16
    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 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
    Last patient, last visit.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months32
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months32
    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 Yes
    F.1.1Number of subjects for this age range: 20
    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: 3
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 11
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 6
    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 Yes
    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
    Peadiatric patients (< 17 years old)
    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)
    A long term safety surveillance of the patients following infusion with HepaStem is planned. The surveillance will mimic as much as possible the standard follow-up of the respective diseases (standard of care). The surveillance in the remit of this trial, will end when the patient is undergoing an organ transplant or takes part in another research study.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Medicines for Children Research Network
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2011-12-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-07-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-11-04
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