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    Summary
    EudraCT Number:2006-000136-27
    Sponsor's Protocol Code Number:CCD02
    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:2007-09-04
    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 number2006-000136-27
    A.3Full title of the trial
    Open, Prospective, Uncontrolled, Multicentre Study to Evaluate The Safety and Efficacy of Multiple Applications of Liver Cell Suspension Into The Portal Vein in Children with Urea Cycle Disorders (UCDs)
    A.4.1Sponsor's protocol code numberCCD02
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT00718627
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/237/2012
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCytonet GmbH & Co KG
    B.1.3.4CountryGermany
    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 supportCytonet GmbH & Co KG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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/3/07/470; EU/3/10/818; EU/3/10/821
    D.3 Description of the IMP
    D.3.1Product nameHuman heterologous liver cells (for infusion)
    D.3.2Product code HHLivC
    D.3.4Pharmaceutical form Infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    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 numberHuman Heterologous Liver Cells (for infusion) does fulfil the requirement of medicinal product and cell therapy medicinal product as stated by EMEA/412541/2005 (Emea answer to an eligibility request)
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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
    Neonates and Infants up to 3 months including with prenatally or postnatally confirmed urea cycle disorder with below listed deficiency and children aged > 3 months up to 5 years including with confirmed urea cycle disorder and unstable metabolism with deficiency of either:
    - Carbamyl-phosphate Synthetase I Deficiency (CPS1D)
    - Ornithine Transcarbamylase Deficiency (OTCD)
    - Argininosuccinate Synthetase Deficiency (ASSD/Citrullinaemia)

    can be included.

    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 18.1
    E.1.2Level PT
    E.1.2Classification code 10052450
    E.1.2Term Ornithine transcarbamoylase deficiency
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level PT
    E.1.2Classification code 10058298
    E.1.2Term Argininosuccinate synthetase deficiency
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level PT
    E.1.2Classification code 10058297
    E.1.2Term Carbamoyl phosphate synthetase deficiency
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Main objective of the trial is to investigate the safety and efficacy of multiple applications of liver cell suspension in neonates, infants and children with the above defined subset of urea cycle disorders (UCD).

    Primary variables:
    • Safety of the application of liver cells as measured by oxygen saturation, portal blood pressure and flow during the infusion
    • Safety of the placement of an application catheter to the portal vein
    • Safety of the placement of an application catheter to the portal vein by evaluation of all adverse events judged to be related to the catheter placement
    E.2.2Secondary objectives of the trial
    Efficacy variables
    •Change in respective enzyme activity in explanted liver after OLT compared to enzyme activity in liver prior first cell application
    •Changes in 13C urea formation from baseline to 2/4 months after HHLivC infusion, and if available up to month 24 after Final Visit in case further 13C-ureagenesis tests after HHLivC infusion
    •Detection of donor cell material in samples from explanted liver taken after orthotopic liver transplantation compared with liver biopsy taken prior first liver cell application
    •Number, duration and severity of metabolic crises (maximum ammonia concentration, duration of coma)
    •Laboratory parameters: ammonia and amino acids in plasma and orotic acid in urine (except CPS1D)
    •Growth and protein intake
    •Nutritional status
    •Use of ammonia scavenging drugs
    •Time to death and survival 6 months after liver cell infusion

    Safety variables
    -Vital signs
    -Lab Parameters to monitor safety of the procedures+immunosuppression
    -AEs




    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Neonates and Infants up to 3 months including with prenatally or postnatally confirmed urea cycle disorder with deficiency of either:
    - Carbamyl-phosphate Synthetase I Deficiency (CPS1D)
    - Ornithine Transcarbamylase Deficiency (OTCD)
    - Argininosuccinate Synthetase Deficiency (ASSD/Citrullinaemia)

    and children aged > 3 months up to 5 years including with confirmed urea cycle disorder and unstable metabolism with deficiency of either

    - Carbamyl-phosphate Synthetase I Deficiency (CPSD)
    - Ornithine Transcarbamylase Deficiency (OTCD)
    - Argininosuccinate Synthetase Deficiency (Citrullinaemia)
    can be included.
    - Accessibility of the portal vein.
    - Plasma ammonia level </= 250 µmol/l
    - Written informed consent from parents or legal guardian(s).
    E.4Principal exclusion criteria
    - Structural liver disease (cirrhosis, portal hypertension), or venoocclusive diseases,
    - Portal vein thrombosis
    - Body Weight less than/equal 3.5 kg
    - Carrier of the human immuno-deficieny virus (HIV),
    - Any other contraindication for immunosuppression,
    - Presence of acute infection at the time of inclusion,
    - Participation in other clinical trials or received experimental medication within last 30 days,
    - Live vaccination planned during the course of the study
    - Live vaccination within 4 weeks prior to beginning of study
    - Allergic disposition against contrast medium used in study and/or antibiotics used in the manufacturing process,
    - Required valproate therapy
    - Severe coagulopathy or thrombocytopenia,
    - Known diagnosis of hereditary thrombophilia (e.g. Factor V Leiden, Prothrombin 20210A variant) or parental history of hereditary thrombophilia and absence of thrombophilia testing in subject
    - Cancer, severe systemic or chronic disease other than study indication (urea cycle deficiency).
    E.5 End points
    E.5.1Primary end point(s)
    The primary variable is:
    - safety of the application of liver cells as measured by oxygen saturation, portal blood pressure and flow during the infusion
    - safety of the placement of an application catheter to the portal vein
    - safety of the placement of an application catheter to the portal vein by evaluation of all adverse events judged to be related to the catheter placement
    E.5.2Secondary end point(s)
    Secondary safety variables:
    • Vital signs
    • Laboratory Parameters III to V to monitor the safety of the procedures and the immunosuppression
    • Adverse events
    Secondary efficacy variables:
    • Change in the respective enzyme activity in samples from the explanted liver taken after orthotopic liver transplantation compared to
    the enzyme activity in the liver biopsy taken prior to the first liver cell
    application
    • Changes in 13C urea formation from baseline to 2 and 4 months (or earlier, if OLT is performed during listing period) after first infusion of HHLivC, and if available, up to month 24 (FUV 5) after the Final Visit in case further 13C-ureagenesis tests were performed after infusion of HHLivC.
    • Detection of donor cell material in samples from the explanted liver taken after orthotopic liver transplantation compared with the liver biopsy taken prior to first liver cell application
    • Number, duration and severity of metabolic crises (maximum ammonia concentration, duration of coma)
    • Laboratory parameters I and II: ammonia and amino acids in plasma and orotic acid in urine (except CPS1D)
    • Growth and protein intake
    • Nutritional status
    • Use of ammonia scavenging drugs
    • Time to death and survival 6 months after liver cell infusion
    Exploratory variable:
    • Total urea and orotic acid (except CPS1D) in 12-hour urine
    • Urea in serum
    E.5.2.1Timepoint(s) of evaluation of this end point
    Descriptive analysis:
    After treatment of the 5th patient an interim analysis has been conducted and did not reveal any safety concerns (conducted in July 2010).
    A second interim analysis was performed after the treatment of the 11th patient in Q4 2013.
    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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 No
    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
    The end of the trial is defined as the database lock. This time point is when the last clinical data will be reported. The last visit of the last patient is not the end of the study, as the analysis of biopsies from explanted organ after OLT (if applicable) derived at this visit may require an extended period of time (samples frozen in liquid nitrogen, shipped to analytical laboratory, and there possibly analyzed in batches).
    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 Yes
    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.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.5Children (2-11years) Yes
    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
    Neonates and infants within the first three months (including) of life and children aged 3 months less than 6 years including. Parents or legal guardians will give informed consent on their behalf.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    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)
    OLT is strongly recommended as the best therapeutic option after LCT and parents will be asked to list their child for OLT during participation in the study CCD02. OLT itself is however not part of the study CCD02 (acceptance of an organ for transplantation will mean PT/FV of the study). OLT and post-transplantation treatments will be carried out according to local standard. A FU 3 months or up to 24 months - depending if the child has undergone OLT or not - after FV will be conducted .
    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 Decision2008-03-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2007-11-26
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-11-23
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