Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   42771   clinical trials with a EudraCT protocol, of which   7044   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).


    Phase 1 trials conducted solely in adults and that are not part of an agreed PIP are not public in the EU CTR (refer to European Guidance 2008/C 168/02   Art. 3 par. 2 and   Commission Guideline 2012/C 302/03,   Art. 5) .

    Clinical Trials marked as "Trial now transitioned" were transitioned to the Clinical Trial Regulation 536/2014 and can be further followed in the Clinical Trial Information System  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A prospective, open label, multicenter, partially randomized, safety study of one cycle of Promethera HepaStem in Urea Cycle Disorders and Crigler-Najjar Syndrome patients

    Summary
    EudraCT number
    2011-004074-28
    Trial protocol
    GB   BE   IT  
    Global end of trial date
    04 Nov 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Mar 2017
    First version publication date
    11 Mar 2017
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    HEP001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01765283
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    PROMETHERA Biosciences S.A./N.V.
    Sponsor organisation address
    Watson & Crick Hill, Rue Granbonpré, 11, Mont-Saint-Guibert, Belgium, 1435
    Public contact
    John Tchelingerian, Promethera Biosciences, 32 10 39 43 00, contact@promethera.com
    Scientific contact
    Etienne Sokal, Promethera Biosciences, 32 10 39 43 00, contact@promethera.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001155-PIP01-11
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Nov 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Nov 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Nov 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The study was designed to assess the safety of one cycle of HepaStem infusions up to 6 months in pediatric patients suffering from CN or UCD in terms of clinical status, portal-vein hemodynamics, morphology of the liver, de novo detection of circulating anti-human leukocyte antigen (HLA) antibodies, and/or other immune related markers as well as serious adverse events (SAEs) and clinically significant adverse events (AEs) related to infusion.
    Protection of trial subjects
    The study was conducted in accordance with the International Conference on Harmonization (ICH) Guideline for Good Clinical Practice (GCP) E6(R1) - Step 4 version dated 10 June 1996, the ethical principles that have their origins in the Declaration of Helsinki and local regulations.” The protocol, all amendments and the informed consent forms (ICFs) / patient information sheets (PIS) were reviewed and approved by the competent authorities (CA) and relevant ethics committee (EC) in each participating country.
    Background therapy
    Patients included in the trial were provided with best medical care. It was recommended that their UCD or CN treatment was carried out/continued at the discretion of the investigator responsible for the treatment of the patient. All UCD patients included in the study had chronic limitation in natural protein intake. This reflects the severe disease phenotypes with low tolerance to natural proteins. All patients chronically received at least one ammonium scavenger medication, with half of them receiving both sodium benzoate and sodium phenylbutyrate. All patients, except the arginase deficiency patient, chronically received supplements of citrulline or arginine or both. All CN patients were treated with long daily overnight phototherapy (10-12h) and had variable but elevated total blood bilirubin values.
    Evidence for comparator
    -
    Actual start date of recruitment
    06 Mar 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    Italy: 1
    Worldwide total number of subjects
    20
    EEA total number of subjects
    16
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    3
    Children (2-11 years)
    11
    Adolescents (12-17 years)
    6
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    Patients were recruited primarily at hospitals with a specialized pediatric metabolic or hepatology center. Patients could be referred for screening, treatment, 3, 6 and 12 month follow-up visits to academic hospitals with a transplant unit (infusion centers).

    Pre-assignment
    Screening details
    A total of 21 patients were screened between March 2012 and September 2013. There was one screening failure: an UCD patient presented an exclusion criterion (the patient had a thrombosis in the portal vein) and was therefore not included in the study. Hence, 20 patients were enrolled in the study and received the IMP: 14 UCD and 6 CN patients.

    Period 1
    Period 1 title
    HepaStem infusion - Test period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Pediatric patients suffering from CN
    Arm description
    Pediatric CN patients presenting Criggler-Najjar type I or type II poorly controlled under phenobarbital treatment, or experiencing serious impairment in QoL.
    Arm type
    Experimental

    Investigational medicinal product name
    Hepastem
    Investigational medicinal product code
    HHALPC
    Other name
    Heterologous Human Adult Liver-derived Progenitor Cells
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intraportal use
    Dosage and administration details
    HepaStem (5x10E6 cells/mL) infused through percutaneous transhepatic catheter inserted in portal vein under radio-guidance. 3 doses investigated: o Low: 12.5x10E6 cells/kg o Intermediate: 50x10E6 cells/kg o High: 200x10E6 cells/kg (max. 4x10E9 total cells) in pooled UCD/CN patients set in 3 weight cohorts: >20kg; ≥10-20 kg; < 10kg Dose escalation performed both intra- and inter-cohort: Intra-cohort: lowest dose given first. Inter-cohort: 1 given dose to be safe in a higher weight cohort first. Dose allocation partially randomized: intermediate and high doses randomized from patient 4 onwards in cohorts 1 and 2. Before portal catheter placement, patients received antibiotics. During HepaStem infusion, bivalirudin was administered (for anticoagulation). Patients received tacrolimus (for immunosuppression) throughout the study. They also received treatments to prevent opportunistic infections according to recommendations of chemoprophylaxis after liver transplantation.

    Arm title
    Pediatric patients suffering from UCD
    Arm description
    UCD Pediatric patients diagnosis with of one of the UCD subtypes (CPSID, OTCD, ASSD, ASLD, ARGD or NAGSD)
    Arm type
    Experimental

    Investigational medicinal product name
    Hepastem
    Investigational medicinal product code
    HHALPC
    Other name
    Heterologous Human Adult Liver-derived Progenitor Cells
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intraportal use
    Dosage and administration details
    HepaStem (5x10E6 cells/mL) infused through percutaneous transhepatic catheter inserted in portal vein under radio-guidance. 3 doses investigated: o Low: 12.5x10E6 cells/kg o Intermediate: 50x10E6 cells/kg o High: 200x10E6 cells/kg (max. 4x10E9 total cells) in pooled UCD/CN patients set in 3 weight cohorts: >20kg; ≥10-20 kg; < 10kg Dose escalation performed both intra- and inter-cohort: Intra-cohort: lowest dose given first. Inter-cohort: 1 given dose to be safe in a higher weight cohort first. Dose allocation partially randomized: intermediate and high doses randomized from patient 4 onwards in cohorts 1 and 2. Before portal catheter placement, patients received antibiotics. During HepaStem infusion, bivalirudin was administered (for anticoagulation). Patients received tacrolimus (for immunosuppression) throughout the study. They also received treatments to prevent opportunistic infections according to recommendations of chemoprophylaxis after liver transplantation.

    Number of subjects in period 1
    Pediatric patients suffering from CN Pediatric patients suffering from UCD
    Started
    6
    14
    Completed
    5
    13
    Not completed
    1
    1
         patient received a liver transplant
    -
    1
         Consent withdrawn by subject
    1
    -

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Pediatric patients suffering from CN
    Reporting group description
    Pediatric CN patients presenting Criggler-Najjar type I or type II poorly controlled under phenobarbital treatment, or experiencing serious impairment in QoL.

    Reporting group title
    Pediatric patients suffering from UCD
    Reporting group description
    UCD Pediatric patients diagnosis with of one of the UCD subtypes (CPSID, OTCD, ASSD, ASLD, ARGD or NAGSD)

    Reporting group values
    Pediatric patients suffering from CN Pediatric patients suffering from UCD Total
    Number of subjects
    6 14 20
    Age categorical
    Diversity was observed in terms of age at baseline. Two female CPSID patients with early onset disease were 4.4 and 7 years old. The OTCD group included 2 male OTCD patients with early onset disease and 4 male OTCD patients with late onset disease, with a large range of age at baseline (5.9 weeks to 17.2 years of age). It included also 3 female adolescent patients (15.2 to 16.7 years of age) with late onset disease. Two ASLD patients with early onset disease were 1.3 and 10.4 years old. One ARGD patient with early onset disease was 7.2 years old. The CN population ranged from 3.5 to 8.8 years
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 3 3
        Children (2-11 years)
    6 5 11
        Adolescents (12-17 years)
    0 6 6
        Adults (18-64 years)
    0 0 0
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age continuous
    mean age of the full study (CN + UCD)
    Units: years
        arithmetic mean (standard deviation)
    7.98 ± 5.73 9.12 ± 6.46 -
    Gender categorical
    The sex ratio for UCD patients was 6 female and 8 male patients. The sex ratio for CN patients was 4 female and 2 male patients. This makes a total of 10 female and 10 male patients
    Units: Subjects
        Female
    4 6 10
        Male
    2 8 10

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Pediatric patients suffering from CN
    Reporting group description
    Pediatric CN patients presenting Criggler-Najjar type I or type II poorly controlled under phenobarbital treatment, or experiencing serious impairment in QoL.

    Reporting group title
    Pediatric patients suffering from UCD
    Reporting group description
    UCD Pediatric patients diagnosis with of one of the UCD subtypes (CPSID, OTCD, ASSD, ASLD, ARGD or NAGSD)

    Primary: HepaStem related adverse events of one cycle of HepaStem infusion

    Close Top of page
    End point title
    HepaStem related adverse events of one cycle of HepaStem infusion [1]
    End point description
    The primary endpoint was the safety assessment of the technical intervention (infusion of HepaStem in portal vein) common to both indications and all cohorts during the active phase of the study (0-6 months post-infusion). The secondary endpoints included safety assessment up to the 12-month FU. Safety endpoints defined for assessing safety of HepaStem infusion and HepaStem safety FU included a series of investigations: vital signs, physical examinations, clinical laboratory tests (liver and renal function, hematology, coagulation), anti-HLA and auto-immune antibodies, portal vein pressure, echography and Doppler exam of the liver, liver biopsy and also AEs related to HepaStem infusion and concomitant treatments (antibiotic, and chemoprophylactic treatment, anticoagulation and immunosuppressive treatment). Clinically significant abnormal values were reported as adverse events which are therefore included in the adverse event tables.
    End point type
    Primary
    End point timeframe
    From Day of portal catheter placement and HepaStem infusion until end of the study up to 12 month FU (primary and secondary safety objectives pooled)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: In view of the exploratory nature of the study and the limited number of patients, all safety analyses were performed on an Intent-To-Treat basis on the Total Safety Population including both CN and UCD indications and the 3 cohorts. Descriptive statistics are used to report adverse events up to 6 months (primary endpoint) and up to 12 months FU.
    End point values
    Pediatric patients suffering from CN Pediatric patients suffering from UCD
    Number of subjects analysed
    6
    14
    Units: nr of patients with related events
    6
    8
    Attachments
    safety evaluation HEP001
    No statistical analyses for this end point

    Secondary: ureagenesis based on 13C tracer method

    Close Top of page
    End point title
    ureagenesis based on 13C tracer method [2]
    End point description
    For paediatric patients suffering from UCD, the functional test based on a 13C tracer method was used to evaluate ureagenesis in vivo pre- and post-HepaStem infusion. During the test, blood was collected before labelled precursor ingestion and every 30 minutes for 2h after labelled precursor ingestion. In order to integrate plasma [13C] urea concentrations measured over 2h, plasma [13C] urea Area Under the Curve (AUC)-120 min was calculated (μmol*min/L). Some measurements were missing due to tests not performed at a given visit or missing blood samplings during a test.
    End point type
    Secondary
    End point timeframe
    From Day of portal catheter placement and HepaStem infusion until end of the study up to 12 month FU
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The ureagenesis analysis was only performed in the UCD arm of the study as it is disease specific for UCD and not for CN
    End point values
    Pediatric patients suffering from UCD
    Number of subjects analysed
    14 [3]
    Units: μmol*min/L
        number (not applicable)
    14
    Attachments
    HEP001 ureagenesis efficacy
    Notes
    [3] - Tests performed at baseline, 3-, 6-, 12-month visits respectively for 13, 12, 12 and 13 patients
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    From Day of portal catheter placement and HepaStem infusion until end of the study up to 12 month FU (primary and secondary safety objectives pooled)
    Adverse event reporting additional description
    In HEP001, the adverse events were tabulated as 'all adverse events' and 'serious adverse events'. In the EudraCt table 'serious adverse events', serious adverse events are reported. In the EudraCt table 'non-serious adverse events' all adverse events, non-serious and serious are included.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Pediatric patients suffering from UCD or CN
    Reporting group description
    Overall trial

    Serious adverse events
    Pediatric patients suffering from UCD or CN
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 20 (75.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Transfusion reaction
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Coagulation factor decreased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Portal vein flow decreased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Mycosis fungoides
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Portal vein thrombosis
    Additional description: 2 events occurred: 1: thrombosis of the left branch of the portal vein 2: partial thrombus in the main portal vein
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hyperammonaemia
         subjects affected / exposed
    6 / 20 (30.00%)
         occurrences causally related to treatment / all
    4 / 15
         deaths causally related to treatment / all
    0 / 0
    Metabolic disorder
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences causally related to treatment / all
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Pediatric patients suffering from UCD or CN
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 20 (100.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Hot flush
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Hypotension
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Pallor
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Mycosis fungoides
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Immune system disorders
    Food allergy
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Hypersensitivity
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Catheter site haemorrhage
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Catheter site pain
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    7
    Device dislocation
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Extravasation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    4
    Hyperthermia
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Infusion site pain
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    4
    Injection site haematoma
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Injection site pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Local swelling
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Malaise
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    6
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Aggression
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Agitation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Confusional state
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Depression
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Insomnia
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Mood altered
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Mood swings
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Balanitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Breast swelling
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Fall
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Head injury
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Ligament sprain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Procedural pain
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    5
    Transfusion reaction
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Amino acid level decreased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Amino acid level increased
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    7
    Ammonia increased
         subjects affected / exposed
    8 / 20 (40.00%)
         occurrences all number
    23
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Blood bicarbonate decreased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Blood bilirubin increased
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    5
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Blood fibrinogen decreased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Blood homocysteine increased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Blood potassium decreased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    C-reactive protein increased
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Coagulation factor decreased
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Coagulation time prolonged
         subjects affected / exposed
    8 / 20 (40.00%)
         occurrences all number
    12
    Culture urine positive
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Fibrin D dimer increased
         subjects affected / exposed
    8 / 20 (40.00%)
         occurrences all number
    8
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Haematocrit decreased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Haemoglobin decreased
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Hepatic enzyme increased
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    HLA marker study positive
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    6
    Immunosuppressant drug level decreased
         subjects affected / exposed
    8 / 20 (40.00%)
         occurrences all number
    11
    Immunosuppressant drug level increased
         subjects affected / exposed
    6 / 20 (30.00%)
         occurrences all number
    8
    International normalised ratio increased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Neutrophil count decreased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Portal vein flow decreased
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Red blood cell count decreased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Streptococcus test positive
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Ultrasound scan abnormal
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Transaminases increased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Cough
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    4
    Epistaxis
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Laryngeal oedema
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Nasal congestion
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Oropharyngeal pain
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Pleural effusion
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Rales
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Respiratory distress
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Respiratory failure
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Rhinorrhoea
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Tonsillar hypertrophy
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Hypergammaglobulinaemia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Lymphadenopathy
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Thrombocytosis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 20 (30.00%)
         occurrences all number
    6
    Hypertonia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Hypotonia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Somnolence
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Speech disorder developmental
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Tremor
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    5
    Abdominal pain upper
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Ascites
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Dental caries
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    8 / 20 (40.00%)
         occurrences all number
    12
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Haematochezia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    9 / 20 (45.00%)
         occurrences all number
    16
    Renal and urinary disorders
    Renal tubular acidosis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Hepatobiliary disorders
    Hepatic fibrosis
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    4
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Portal vein thrombosis
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Alopecia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Dermatitis atopic
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Eczema
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Granuloma skin
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Petechiae
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Pigmentation disorder
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Skin exfoliation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Skin hypopigmentation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Skin irritation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Urticaria
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Pain in extremity
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hyperammonaemia
         subjects affected / exposed
    6 / 20 (30.00%)
         occurrences all number
    16
    Decreased appetite
         subjects affected / exposed
    7 / 20 (35.00%)
         occurrences all number
    9
    Hyperglycaemia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Hypoglycaemia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Hypokalaemia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Hypomagnesaemia
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Iron deficiency
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Metabolic disorder
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    13
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    6 / 20 (30.00%)
         occurrences all number
    7
    Cystitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Ear infection
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Fungal infection
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Gastroenteritis
         subjects affected / exposed
    6 / 20 (30.00%)
         occurrences all number
    7
    Gingivitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Impetigo
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    9 / 20 (45.00%)
         occurrences all number
    20
    Oral herpes
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Otitis media
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Pharyngitis
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Rhinitis
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    7
    Tonsillitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    4
    Urinary tract infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Viral infection
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Vulvovaginitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Laryngitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Rhinovirus infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Feb 2012
    Belgium: • Amendment I: Protocol version 2.1 dated 13-Feb-2012, o The total l amount of cells that could be infused at once was defined. A second HepaStem bag could be infused directly after the first bag for the children who were to receive a high total cell count requiring several cell bags. o Description of the anticoagulation treatment after last infusion/completion of the cycle: once the last infusion was finished, anticoagulation was to be given at a lower concentration for 30 min and stopped. The removal of the catheter was recommended 30 min after bivalirudin stop because the half-life of bivalirudin is +/- 15 min. o Addition of the long term safety FU study (SAF001) upon request of the MHRA during the CTA evaluation. In accordance with ATMP guidance regular collection and review of safety data were to be proposed to the patient and will continue for 5 years after the infusion of HepaStem. o Addition of of oxygen saturation measurement prior to, during and after each infusion. o The guideline on liver biopsy harvest and sample preparation were annexed to the study protocol to reduce the potential risk inherent to liver biopsies, reducing the number of liver biopsies and the requested amount of tissue per biopsy. o 13C-sodium acetate route of administration was changed from IV to oral. o The guideline for the PBMC sub-study was also annexed.
    18 Jun 2012
    Belgium: • Amendment II: Two additional sites were added: o UZ Gent, PI Ruth de Bruyne, Pediatry o UZ Leuven, PI Luc Régal, Pediatry
    16 Jul 2012
    Belgium: • Amendment III: Additional study documents: o Patient notebook: CN diary_version 1.0_120621 o Patient notebook: UCD diary_ version 1.0_120621 o Patient study card version 1.0_120621
    13 Sep 2012
    Belgium: • Amendment IV: Protocol version 3.0 dated 01-Aug-2012, o The minimum flow rate of infusion was decreased in order to allow more flexibility in applying the optimal flow rate for cell infusion especially in small children, o The dose escalation process was clarified, o A random allocation dose from the third patient onwards was described for CN patients, o Appropriate target and way to reach the recommended level were clarified for the immunosuppressive treatment. o ACT values which should be observed at each infusion stage to ensure appropriate anticoagulation at the time of cell infusion were specified in order to increase safety, o The anticoagulation protocol was clarified, o Protocol for D-dimer measurements was clarified, o Use of a patient diary to collect diet/phototherapy, medication and any other relevant events occurring at the patient’s home, o Description of some investigational events (tacrolimus blood levels, urine tests, D-dimer, ammonia blood level and general laboratory tests) to be reported as AEs were added, o The fasting requirements for the 13C test were modified to avoid prolonged fasting in patients with a metabolic disorder, o The aim of the PBMC sub-study was clarified and its study design updated.
    09 Nov 2012
    UK: • Amendment I: Protocol version 3.0 dated 01-Aug-2012 + change of PI o Protocol amendment: see amendment IV from Belgium. o Change of PI: - Former PI: Dr. Anhil Dhawan – King’s College Hospital – London - New PI: Dr. Patrick McKiernan – Birmingham Children’s Hospital – Birmingham.
    14 Dec 2012
    France: • Amendment II: One additional site o CHU Toulouse, PI Pierre Broué, Pediatric hepatology, gastroenterology, and nutrition unit.
    24 Jan 2013
    France: • Amendment I: Protocol version 3.0 dated 01-Aug-2012 + two additional sites o Protocol amendment: see amendment IV from Belgium. o Two additional sites: - CHRU Tours, PI François Labarthe, Pediatric Medecine - CHU Paris-Robert Debré, PI Hélène Ogier, Pediatric neurology and metabolic diseases.
    25 May 2013
    Israel: • Amendment I: HEP001-IL Protocol version 1.0 dated 20-Mar-2013 o Israel-specific procedures were highlighted to emphasize the responsibility of each physician, and to clearly explain who is responsible for which specific study procedure. o The timeline set for Europe (recruitment ended March 2013) was prolonged for an additional 3 months specifically for Israel due to prolonged study set-up. This was to provide sufficient time to enroll 5 patients. o It was highlighted that the monitoring of the data collected from the Israeli subjects was to be performed by an Israeli CRO, Clinipace Worldwide, representing Promethera Biosciences (PB). o Informed consent procedure was clarified.
    05 Aug 2013
    Belgium: • Amendment V: Protocol version 3.1 dated 25-Jul-2013. o The study was opened to centers outside Europe (Israel), o The number of participating patients was increased and the recruitment period was extended, o The location of formulation of the drug product was updated (IMP could be formulated in Promethera Biosciences or in a mobile unit/hospital laboratory with a fully closed formulation system based on SEPAX device), o The collection of a 5 mL blood sample to collect DNA was added to be used as control for the chimerism analysis and for HLA typing, o The laboratory tests were clarified, o The possibility to prolong hospitalization after the 24h following catheter removal was added, o The placement of the catheter was allowed in the left branch of the portal vein to increase feasibility, o The recommendation to perform hepatic US and Doppler one hour after catheter removal was added to increase safety for the patient, o Some corrections to units were made.
    11 Sep 2013
    France: • Amendment III : Protocol version 3.1 dated 25-Jul-2013 o See amendment V from Belgium. Belgium: • Amendment V: Protocol version 3.1 dated 25-Jul-2013. o The study was opened to centers outside Europe (Israel), o The number of participating patients was increased and the recruitment period was extended, o The location of formulation of the drug product was updated (IMP could be formulated in Promethera Biosciences or in a mobile unit/hospital laboratory with a fully closed formulation system based on SEPAX device), o The collection of a 5 mL blood sample to collect DNA was added to be used as control for the chimerism analysis and for HLA typing, o The laboratory tests were clarified, o The possibility to prolong hospitalization after the 24h following catheter removal was added, o The placement of the catheter was allowed in the left branch of the portal vein to increase feasibility, o The recommendation to perform hepatic US and Doppler one hour after catheter removal was added to increase safety for the patient, o Some corrections to units were made.
    16 Sep 2013
    UK: • Amendment IV: Protocol version 3.1 dated 25-Jul-2013. o same as amendment V from Belgium. Belgium: • Amendment V: Protocol version 3.1 dated 25-Jul-2013. o The study was opened to centers outside Europe (Israel), o The number of participating patients was increased and the recruitment period was extended, o The location of formulation of the drug product was updated (IMP could be formulated in Promethera Biosciences or in a mobile unit/hospital laboratory with a fully closed formulation system based on SEPAX device), o The collection of a 5 mL blood sample to collect DNA was added to be used as control for the chimerism analysis and for HLA typing, o The laboratory tests were clarified, o The possibility to prolong hospitalization after the 24h following catheter removal was added, o The placement of the catheter was allowed in the left branch of the portal vein to increase feasibility, o The recommendation to perform hepatic US and Doppler one hour after catheter removal was added to increase safety for the patient, o Some corrections to units were made.
    18 Oct 2013
    UK: • Amendment II: Due to change of PI, the initial approach to surgically insert the catheter changed. BCH’s approach to insert the catheter percutaneously was then considered as a national approach. A national review by a Medical Physics expert and a Clinical Radiation Expert was required. PIS were updated accordingly.
    10 Dec 2013
    Italy: • Amendment I: Protocol version 3.1 dated 25-Jul-2013 o See amendment V from Belgium. Belgium: • Amendment V: Protocol version 3.1 dated 25-Jul-2013. o The study was opened to centers outside Europe (Israel), o The number of participating patients was increased and the recruitment period was extended, o The location of formulation of the drug product was updated (IMP could be formulated in Promethera Biosciences or in a mobile unit/hospital laboratory with a fully closed formulation system based on SEPAX device), o The collection of a 5 mL blood sample to collect DNA was added to be used as control for the chimerism analysis and for HLA typing, o The laboratory tests were clarified, o The possibility to prolong hospitalization after the 24h following catheter removal was added, o The placement of the catheter was allowed in the left branch of the portal vein to increase feasibility, o The recommendation to perform hepatic US and Doppler one hour after catheter removal was added to increase safety for the patient, o Some corrections to units were made.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, visit the EMA Service Desk , log in using your EMA account and open a ticket specifying "EU CTR" in your request.
    If you do not have an account, please visit the EMA Account management page page click on "Create an EMA account" and follow the instructions.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2022 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA