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    Summary
    EudraCT Number:2014-000650-11
    Sponsor's Protocol Code Number:HEP002
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-06-26
    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 ConcernedFrance - ANSM
    A.2EudraCT number2014-000650-11
    A.3Full title of the trial
    A prospective, open label, multicenter, efficacy and safety study of several infusions of Promethera HepaStem in Urea Cycle Disorders pediatric patients
    Etude clinique prospective, ouverte, multicentrique visant à évaluer l’efficacité et la sécurité de plusieurs infusions d'HepaStem chez des patients pédiatriques atteints d’un désordre du cycle de l’urée
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    HEP002 is a clinical study designed for paediatric patients with urea cycle disorders (UCD). UCD patients will receive several infusions of HepaStem. The efficacy as well as the safety of the medicinal product will be assessed during the year following infusions.
    HEP002 est une étude clinique proposée à des patients pédiatriques atteints d'un désordre du cycle de l'urée. Ces patients recevront plusieurs infusions d'HepaStem. L'efficacité et la sécurité du produit seront évalués chez le patient durant l'année qui suit.
    A.3.2Name or abbreviated title of the trial where available
    HEP002
    A.4.1Sponsor's protocol code numberHEP002
    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, 507_057, 058, 059, 060, 061, 062, 063
    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.3.9.2Current sponsor codeHHALPC
    D.3.10 Strength
    D.3.10.1Concentration unit million organisms/ml million organisms/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 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 ref nr: EMA/CAT/243155/2011
    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
    The urea cycle disorders are inborn errors of metabolism that affect the transfer of nitrogen into urea. There are seven disorders to be investigated: carbamoylphosphate synthetase I deficiency [CPS ID], ornithine transcarbamylase deficiency [OTCD], argininosuccinic acid synthetase deficiency [ASSD], argininosuccinic acid lyase deficiency [ASLD], arginase deficiency [ARGD], N-acetylglutamate synthase deficiency [NAGSD], and citrine deficiency.
    E.1.1.1Medical condition in easily understood language
    metabolic disease of the urea cycle in the liver that result in failed detoxification of ammonia.
    Trouble du métabolisme du cycle de l'urée résultant en l'absence partielle ou totale de la détoxification de l'ammoniac.
    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 18.0
    E.1.2Level LLT
    E.1.2Classification code 10013373
    E.1.2Term Disorders of urea cycle metabolism
    E.1.2System Organ Class 100000004861
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To asses the efficacy during the year following HepaStem infusions (functional parameters).
    Evaluation de l'efficacité d'HepaStem au cours de l'année qui suit les infusions (paramètres fonctionnels).
    E.2.2Secondary objectives of the trial
    1. To assess the efficacy during the year following HepaStem infusions (biological and clinical parameters)

    2. To evaluate the safety during the year following HepaStem infusions.
    1. Evaluation de l'efficacité d'HepaStem au cours de l'année qui suit les infusions (paramètres biologiques et cliniques).
    2. Evaluation de l'efficacité d'HepaStem au cours de l'année qui suit les infusions
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. The patient is a pediatric patient.
    2. The patient presents with one of the following UCDs (carbamoylphosphate synthetase I [CPS I] deficiency [CPS ID], ornithine transcarbamylase [OTC] deficiency [OTCD], argininosuccinic acid synthetase [ASS] deficiency [ASSD], argininosuccinic acid lyase [ASL] deficiency [ASLD], arginase [ARG] deficiency [ARGD], N-acetylglutamate synthase [NAGS] deficiency [NAGSD]) and citrine deficiency of such severity that liver transplantation or alternatives are warranted despite full conservative therapy, and/or experiences serious impairment in quality of life (QoL) despite full conservative therapy.
    3. The patient shows patency of the portal vein and branches, with normal flow velocity in the main portal vein as confirmed by Doppler US and accessibility of the portal vein and /or affluants, or of the umbilical vein.
    4. 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.
    5. The patient (if capable of signing) and parents or legal representative have signed a written informed assent/consent form.
    E.4Principal exclusion criteria
    1. The patient has mild disease severity, easily controlled under standard of care therapy, with no recurrent metabolic crises.
    2. The patient is registered on a liver transplant waiting list or is scheduled for living donor liver transplantation before the end of the study.
    3. The patient presents acute liver failure.
    4. The patient presents clinical or radiological evidence of liver cirrhosis.
    5. The patient presents or has a history of hepatic or extrahepatic malignancy.
    6. The patient has a known clinically significant cardiac malformation.
    7. The patient has a personal history of venous thrombosis. In case of known family history, a complete coagulation work-up should be performed, and results need to be discussed with PB before enrolling the patient in the study.
    8. The patient participates currently in another clinical trial – except disease registry and observational HepaStem study.
    9. The patient underwent previous mature liver cell or stem cell transplantation or received an organ liver transplant or received HepaStem infusion.
    10. The patient has a contraindication to solumedrol, tacrolimus.
    11. The patient has a known hypersensitivity or allergy to bivalirudin.
    12. The patient has a known hypersensitivity or allergy to the antibiotics preventing post-operative infections that are prescribed according to institutional guidelines, and no alternative prophylaxis can be found.
    13. The patient had or has a renal insufficiency treated by dialysis.
    14. The patient requires valproate therapy.
    15. The patient has a known hypersensitivity or allergy to contrast agents (if applicable) that cannot be treated adequately.
    16. The patient has a thrombosis of the portal vein or persisting impairment of anterograde portal blood flow.
    17. The patient has a porto systemic shunt or fistula assessed by Doppler US.
    18. For permanent catheter: the prospective placement site has previously suffered from venous thrombosis or vascular surgical procedures.
    19. For umbilical vein access: the patient has any contraindication for umbilical vein catheterization (e.g. history of peritonitis, necrotizing enterocolitis, etc).
    20. The patient has an ongoing infection or suffered from an infection in the last 2 weeks.
    21. There is any significant condition that, in the Investigator’s opinion, may interfere with the patient’s optimal participation in the study.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint will be the change in urea formation during the year following HepaStem infusions. A 13C tracer method will be used to measure ureagenesis (fasten condition).
    E.5.1.1Timepoint(s) of evaluation of this end point
    13C tracer method to measure ureagenesis (fasting condition) measured at baseline, 3m, 6m, 9m, and 12m follow-up.
    E.5.2Secondary end point(s)
    1. Efficacy up to 12 months post-first infusion day for each individual patient and for all patients as compared to his/her prior medical condition based on:
    - Ammonia (NH3) values (fasting condition)
    - Full aminoacidogram in plasma (fasting condition)
    - Evaluation of UCD condition (report of metabolic decompensations, report on actual supportive treatment and adjustment of protein restriction [low protein diet], amino acids supplements, report on behavior, cognitive skills and health-related QoL indicators).

    Exploratory: engraftment capacity of HepaStem in the liver of all patients 2 months post-first infusion day by establishing donor sequences by real time polymerase chain reaction (RT-PCR) or fluorescence in situ hybridization (FISH) or immunohistochemistry on biopsies.

    2. Safety during the year following HepaStem infusions in terms of:
    - Clinical status (physical examination and vital signs)
    - Portal-vein hemodynamics
    - Morphology of the liver, bile ducts and portal system
    - Laboratory tests
    - De novo detection of donor-specific circulating anti-human leukocyte antigen (HLA) antibodies, and/or other immune-related markers
    - Serious Adverse Events (SAEs) and clinically significant Adverse Events (AEs) related to HepaStem (infusion and follow-up), technical intervention, and concomitant treatments.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy periods:
    - Active Treatment
    - Follow-up.

    The safety parameters will be assessed for 5 time windows:
    1) Screening Period
    - Time window 1 = first visit - end of Screening Period.
    2) Active Treatment Period
    - Time window 2 (inpatient period) = D0 - Ddischarge.
    - Time window 3 = Ddischarge - next infusion day or end of Active Treatment Period.
    3) Follow-up Period
    - Time window 4 (outpatient period) = Visit (V)3 months post-first infusion day - V12 months post-first infusion day.
    - Time window 5 = screening - V12 months post-first infusion day.
    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 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) 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.8.3 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 EEA11
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    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 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) Yes
    F.1.1.3.1Number of subjects for this age range: 2
    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: 10
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 5
    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
    Paediatric patients
    enfants
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state9
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 20
    F.4.2.2In the whole clinical trial 20
    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)
    All patients having received HepaStem will be invited to enter the long term safety follow-up study SAF001 that is active (EudraCT 2013-001045-14). When the patient is ending his/her participation in the former interventional study, the patient will be enrolled in the SAF001 study if a written informed consent is given. The primary endpoint is to characterise the long term safety profile of HepaStem therapy.
    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 Decision2015-02-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-10-14
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-08-01
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