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    Summary
    EudraCT Number:2014-000650-11
    Sponsor's Protocol Code Number:HEP002
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-07-01
    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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2014-000650-11
    A.3Full title of the trial
    A prospective, open label, multicountry, efficacy and safety study of several infusions of HepaStem in Urea Cycle Disorders pediatric patients.
    Etude clinique prospective, ouverte, multi-pays visant à évaluer l’efficacité et la sécurité de plusieurs infusions de 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 demonstrate the functional efficacy of HepaStem at 6 months after initiation of infusion in terms of ureagenesis improvement based on a functional test (13C tracer method).
    A stopping rule is introduced as a particular measure to protect pediatric patients: If the positive benefit risk ratio for the study is confirmed after the first five patients having completed FU visit 3 (6 m post first infusion), the study will be continued.
    Démontrer l’efficacité fonctionnelle de HepaStem 6 mois après le début des infusions en terme d’amélioration de l’uréogenèse basée sur un test fonctionnel (méthode de traceur au C13).
    Une règle d’arrêt de l’étude est prévue comme mesure particulière afin de protéger les patients pédiatriques: si une balance bénéfice / risque positive est confirmée une fois que les 5 premiers patients ont complété leur visite 3 de suivi (6 mois post-première infusion), l’étude sera poursuivie.
    E.2.2Secondary objectives of the trial
    1. To evaluate the efficacy of HepaStem in terms of functional, clinical, and biochemical parameters up to one year after initiation of HepaStem infusion.
    2. To evaluate the safety of HepaStem up to one year after initiation of HepaStem infusion.
    1. Evaluer, en terme de paramètres fonctionnels, cliniques et biochimiques, l’efficacité de HepaStem jusqu’à un an après le début des infusions.
    2. Evaluer la sécurité de HepaStem jusqu’à un an après le début des infusions.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    A patient who meets all of the following inclusion criteria will be eligible for participation in the study:
    1. The patient is a pediatric patient <12 years prior to infusion.
    2. The patient presents with one of the following UCDs (carbamoylphosphate synthetase 1 deficiency [CPS1 D], ornithine transcarbamylase deficiency [OTCD], argininosuccinic acid synthetase deficiency [ASSD], argininosuccinic acid lyase deficiency [ASLD], arginase deficiency [ARGD].
    3. The patient has severe disease with impaired protein tolerance defined as: chronic protein restricted diet AND chronic treatment with at least one nitrogen scavenger.
    4. The following retrospective data are available:
    - at least 1 metabolic evaluation and 1 global energy balance evaluation (diet evaluation) have been performed within 3 months before study inclusion
    - at least 2 height measurements have been performed at least 3 months apart within 1 year before inclusion
    - 1 neurocognitive evaluation (such as Wechsler test) has been performed 6 to 18 months before study inclusion.
    5. The patient shows patency of the portal vein and its branches including mesenteric veins, with normal flow velocity as confirmed by Doppler US and accessibility of the portal vein and /or affluants.
    6. The patient (if capable of signing) and parents or legal representative have signed a written informed assent/consent form.
    E.4Principal exclusion criteria
    A patient who meets any of the following exclusion criteria will not be enrolled in the study:
    1. The patient presents acute liver failure.
    2. The patient presents clinical or radiological evidence of liver cirrhosis.
    3. The patient presents or has a history of hepatic or extrahepatic malignancy.
    4. The patient has a known clinically significant cardiac malformation.
    5. The patient has a personal history of venous thrombosis, or has a clinically significant abnormal value for protein S, protein C, anti-thrombin III, and /or activated Protein C Resistance (aPCR) at screening. In case of known family history, a complete coagulation work-up should be performed. In all above described cases, results need to be discussed with PB before enrolling the patient in the study.
    6. The patient participates currently in another clinical trial – except disease registry and observational HepaStem study.
    7. The patient underwent previous mature liver cell or stem cell transplantation or received an organ liver transplant or received HepaStem infusion.
    8. The patient has a contraindication to methylprednisolone, tacrolimus.
    9. The patient has a known hypersensitivity or allergy to bivalirudin.
    10. 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.
    11. The patient had or has a renal insufficiency treated by dialysis.
    12. The patient requires valproate therapy.
    13. The patient has a known hypersensitivity or allergy to contrast agents (if applicable) that cannot be treated adequately.
    14. The patient has a thrombosis of the portal vein or persisting impairment of anterograde portal blood flow.
    15. The patient has a porto systemic shunt or fistula assessed by Doppler US or an Arantius channel or portal hypertension.
    16. The site where the catheter is intended to be placed has previously suffered from venous thrombosis or vascular surgical procedures.
    17. The patient has an ongoing infection or suffered from an infection in the last 2 weeks (including active EBV infection at screening). The patient may be enrolled after resolution of the infection.
    18. There is any significant condition or disability 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)
    Ureagenesis improvement at 6 month post first infusion day (FU visit 3): absolute 13C blood urea AUC-120 min quantified with the 13C Tracer method at FU visits 3 compared with baseline evaluations (measurements at BL visit 1, BL visit 2 and BL visit 3).

    The results of the first 5 patients will first be assessed. If the positive benefit risk ratio for the study is confirmed after the first five patients having completed FU visit 3 (6 m post first infusion), the study will be continued.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Ureagenesis improvement at 6 month post first infusion day (FU visit 3): absolute 13C blood urea AUC-120 min quantified with the 13C Tracer method at FU visits 3 compared with baseline evaluations (measurements at BL visit 1, BL visit 2 and BL visit 3).
    E.5.2Secondary end point(s)
    1. Functional parameter
    Ureagenesis improvement at month 3, month 9 and month 12 post first infusion day (FU visits 1, 5, 7): absolute 13C blood urea AUC-120 min quantified with the 13C Tracer method at these visits compared with baseline evaluations (measurements at BL visit 1, BL visit 2 and BL visit).
    2. Clinical and biochemical parameters:
    Efficacy up to 12 months post-first infusion day as compared to prior medical condition based on:
    - Chronic protein intake (total and natural protein, reported in mg/kg/day and reported as compared to WHO safe level for age) considering diet evaluations at study visits during baseline period and at scheduled study visits during the follow-up period.
    - Chronic nitrogen scavenger dose (mg/kg/day) considering reported doses at scheduled study visits during baseline period and at scheduled study visits during the follow-up period.
    - Blood ammonia considering values measured at scheduled study visits during screening and baseline periods and at scheduled study visits during the follow-up period.
    - Relevant blood amino acids considering values measured at scheduled study visits during the screening and baseline periods and at scheduled study visits during the follow-up period.
    - Metabolic decompensations (hyperammonemia episodes with evocative symptomatology such as drowsiness, gastrointestinal symptoms and treated at hospital), considering all collected events during screening and baseline periods, during active treatment period, during follow-up period.
    - Chronic single amino acid intake considering reported doses at study visits during baseline period and at study visits during the follow-up period.
    - Growth parameters collected during retrospective period (for a max of 3 years prior to study inclusion) and measured at scheduled study visits.
    - Cognitive skills considering evaluation during the baseline period at baseline visit 1 (BL visit 1) and during follow-up period at 12 month post first infusion (FU visit 7).
    - Behavior and health-related QoL indicators considering evaluations during BL visit 1, during follow-up period at 4.5 m, 7.5 m and 12 m post first fusion (FU visits 2, 4, 7).
    3. Individual medical assessment
    The clinical and biological parameters evaluated as secondary endpoints will be reviewed by a Data Review Committee (DRC) composed of external experts in metabolic diseases. DRC members will evaluate whether there is a clinical improvement or not based on a complete file of each patient after 6 months and after 12 months of initiation of HepaStem administration.

    4. Safety during the study
    Safety evaluation 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 at mean fluorescence intensity (MFI) >1500, 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
    1. Functional parameters: at month 3, month 9 and month 12 post first infusion day (FU visits 1, 5, 7)
    2. Clinical and biochemical parameters: Efficacy up to 12 months post-first infusion day
    3. Individual medical assessment: clinical improvement will be evaluated on a complete file of each patient after 6 months and after 12 months of initiation of HepaStem administration.
    4. The safety parameters will be assessed for 4 periods
    - Screening Period
    - Baseline period
    - Active Treatment Period
    Events will be evaluated according to time from catheter placement, time from the first infusion and time from the last infusion received.
    - Follow-up Period
    Events will be evaluated according to time from the first infusion and time from the last infusion received.
    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: 6
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 12
    F.1.1.6Adolescents (12-17 years) No
    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 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 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 state2
    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 Decision2014-09-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-07-28
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-08-01
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